WO2004045369A2 - Nuclear receptor-based diagnostic, therapeutic, and screening methods - Google Patents

Nuclear receptor-based diagnostic, therapeutic, and screening methods Download PDF

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Publication number
WO2004045369A2
WO2004045369A2 PCT/US2003/036229 US0336229W WO2004045369A2 WO 2004045369 A2 WO2004045369 A2 WO 2004045369A2 US 0336229 W US0336229 W US 0336229W WO 2004045369 A2 WO2004045369 A2 WO 2004045369A2
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WO
WIPO (PCT)
Prior art keywords
disease
disorder
nuclear receptor
receptor polypeptide
patient
Prior art date
Application number
PCT/US2003/036229
Other languages
French (fr)
Other versions
WO2004045369A3 (en
Inventor
George A. Gaitanaris
John E. Bergmann
Alexander Gracerov
John Hohmann
Fusheng Li
Linda Madisen
Kellie L. Mcilwain
Maria N. Pavlova
Demetri Vassilatis
Hongkui Zeng
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Nura, Inc.
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Publication date
Application filed by Nura, Inc. filed Critical Nura, Inc.
Priority to AU2003295500A priority Critical patent/AU2003295500A1/en
Publication of WO2004045369A2 publication Critical patent/WO2004045369A2/en
Publication of WO2004045369A3 publication Critical patent/WO2004045369A3/en

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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6875Nucleoproteins
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/72Receptors; Cell surface antigens; Cell surface determinants for hormones
    • C07K14/723G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00Screening for compounds of potential therapeutic value
    • G01N2500/04Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00Screening for compounds of potential therapeutic value
    • G01N2500/10Screening for compounds of potential therapeutic value involving cells
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00Detection or diagnosis of diseases

Definitions

  • Mammalian nuclear receptors constitute a superfamily of diverse proteins with more than fifty human members (Table 1). Nuclear receptors act as intracellular receptors for a multitude of diverse, usually small lipophilic ligands. Known ligands for the nuclear receptor superfamily include cortisol, estradiol, thyroxine, testosterone, vitamin D3, retinoic acid, progesterone, aldosterone, palmitic acid, stearic acid, and eicosapentaenoic acid. Ligands to nuclear receptors have a number of biological effects and are known to influence human reproduction and sexuality, development, behavior, inflammation, growth, and homeostasis.
  • nuclear receptors are localized in either the cytoplasm or nucleus in an inactive state.
  • the nuclear receptor Upon interaction of the nuclear receptor with a ligand, the nuclear receptor adopts an active conformation and, in conjunction with coregulators, acts as a transcriptional regulator.
  • coregulators acts as a transcriptional regulator.
  • Nuclear receptors are composed of four independent but interacting functional modules, the modulator domain, DNA-binding domain, hinge region, and ligand-binding domain.
  • the modulator domain usually contains the transcriptional activation function, and is also known to interact with co-regulators to enhance the activity of the receptor complex.
  • the DNA-binding domain is typically the most conserved domain among nuclear receptors and is involved in DNA interaction.
  • the hinge region is a flexible region that is believed to serve as a hinge between the DNA-binding and ligand-binding domains.
  • the ligand-binding domain is a multifunctional domain that mediates ligand binding, nuclear receptor dimerization, nuclear localization, and interaction with repressor molecules or transcriptional regulators.
  • nuclear receptors Although many of the nuclear receptors have a known physiological ligand, there are nuclear receptors that have no known biological ligand; these nuclear receptors are referred to as orphan receptors (see, e.g., Table 2). There is a need to study members of this receptor family for nuclear receptor polypeptides, polynucleotides, antibodies, genetic models, and modulating compounds for use in the treatment and diagnosis of a wide variety of disorders and diseases.
  • the present invention provides nuclear receptor polypeptides and polynucleotides, recombinant materials, and transgenic mice, as well as methods for their production.
  • the polypeptides and polynucleotides are useful, for example, in methods of diagnosis and treatment of diseases and disorders.
  • the invention also provides methods for identifying compounds (e.g., agonists or antagonists) using the nuclear receptor polypeptides and polynucleotides of the invention, and for treating conditions associated with nuclear receptor dysfunction with the nuclear receptor polypeptides, polynucleotides, or identified compounds.
  • the invention also provides diagnostic assays for detecting diseases or disorders associated with inappropriate nuclear receptor activity or levels.
  • the invention features a method of preventing or treating a neurological disease or disorder, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 operably linked to a promoter.
  • the invention features a method of treating or preventing a neurological disease or disorder, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a neurological disease or disorder.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder.
  • the nuclear receptor polypeptide can be in a cell or may be in a cell-free assay system.
  • the invention features another method for determining whether a candidate compound is a compound that may be useful for the treatment of a neurological disease or disorder.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a neurological disease or disorder.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the nuclear receptor polypeptide in the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a neurological disease or disorder.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in any one of Tables 3-14, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a neurological disease or disorder.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction between the candidate compound and the polypeptide. Interaction between the compound and the polypeptide indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a neurological disease or disorder.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein a change in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a neurological disease or disorder.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in one of Tables 3-14, wherein presence of the mutation indicates that the patient has an increased risk for developing a neurological disease or disorder.
  • the invention features another method for determining whether a patient has an increased risk for developing a neurological disease or disorder.
  • This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in any one of Tables 3-14, wherein presence of the polymorphism indicates that the patient has an increased risk for developing a neurological disease or disorder.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the expression level or biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a neurological disease or disorder.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in any one of Tables 3-14, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a neurological disease or disorder.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a neurological disease or disorder.
  • the method includes the step of measuring the patient's expression level of a polypeptide listed in any one of Tables 3-14, wherein an alteration in the expression, relative to normal, indicates that the patient has an increased risk for developing a neurological disease or disorder.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Preferred neurological diseases or disorders that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include, without limitation, abetalipoproteinemia, abnormal social behaviors, absence (petit mal) epilepsy, absence seizures, abulia, acalculia, acidophilic adenoma, acoustic neuroma, acquired aphasia, acquired aphasia with epilepsy (Landau- Kleffner syndrome) specific reading disorder, acquired epileptic aphasia, acromegalic neuropathy, acromegaly, action myoclonus-renal insufficiency syndrome, acute autonomic neuropathy, acute cerebellar ataxia in children, acute depression, acute disseminated encephalomyelitis, acute idiopathic sensory neuronopathy, acute intermittent porphyria, acute mania, acute mixed episode, acute pandysautonomia, acute polymorphic disorder with symptoms of schizophrenia, acute polymorphic psychotic disorder without symptoms of
  • Turner's syndrome typhus fever, ulegyria, uncinate fits, Unverricht-Lundborg's disease, upper airway resistance syndrome, upward transtentorial herniation syndrome, uremic encephalopathy, uremic neuropathy, urophilia, vaccinia, varicella-zoster, vascular dementia, vascular malformations, vasculitic neuropathies, vasogenic edema, velocardiofacial syndrome, venous malformations, ventilatory arrest, vertigo, vincristine toxicity, viral infections, visuospatial impairment, Vogt-Koyanagi-Harada syndrome, Von Hippel-Lindau disease, Von Racklinghousen disease, voyeurism, Waldenstr ⁇ m's macroglobulinemia, Walker- Warburg syndrome, Wallenburg's syndrome, Walleyed syndrome, Weber's syndrome, Wenicke's encephalopathy, Werdnig-Hoffmann disease, Wernicke's
  • Neurological diseases and disorders that are treated or diagnosed by methods of the invention or for which candidate therapeutic compounds are identified preferably involve at least one of the following neurological tissues: hypothalamus, amygdala, pituitary, nervous system, brainstem, cerebellum, cortex, frontal cortex, hippocampus, striatum, and thalamus or other regions of the central or peripheral nervous system.
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14.
  • the invention features a method of preventing or treating a disease of the adrenal gland including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the adrenal gland including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the adrenal gland.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the adrenal gland.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the adrenal gland.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g.,
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 15, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system;
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 15, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the adrenal gland.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland.
  • This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 15, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the adrenal gland.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 15, wherein increased or decreased levels in the nuclear receptor biological, activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the adrenal gland.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 15, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the adrenal gland.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the adrenal gland that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include 11-hydroxylase deficiency, 17-hydroxylase deficiency, 3 ⁇ -dehydrogenase deficiency, acquired immune deficiency syndrome, ACTH-dependent adrenal hyperfunction (Cushing disease), ACTH-independent adrenal hyperfunction, acute adrenal insufficiency, adrenal abscess, adrenal adenoma, adrenal calcification, adrenal cysts, adrenal cytomegaly, adrenal dysfunction in glycerol kinase deficiency, adrenal hematoma, adrenal hemorrhage, adrenal histoplasmosis, adrenal hyperfunction, adrenal hyperplasia, adrenal medullary hyperplasia, adrenal myelolipoma, adrenal tuberculosis, adrenocortical adenoma, adrenocortical adenoma with primary hyperaldosteronism
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
  • the invention features a method of preventing or treating a disease of the colon including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16, operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the colon including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the colon.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the colon.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the colon.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the colon.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 16, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the colon.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the colon.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the colon.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 16, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the colon.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the colon. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed, in Table 16, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the colon.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the colon.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 16, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the colon.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the colon.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 16, wherem altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the colon.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the colon that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute self-limited infectious colitis, adenocarcinoma, adenoma, adenoma-carcinoma sequence, adenomatous polyposis coli, adenosquamous carcinomas, allergic (eosinophilic) proctitis and colitis, amebiasis, amyloidosis, angiodysplasia, anorectal malformations, blue rubber bleb nevus syndrome, brown bowel syndrome, Campylobacter fetus infection, carcinoid tumors, carcinoma of the anal canal, carcinoma of the colon and rectum, chlamidial proctitis, Crohn's disease, clear cell carcinomas, Clostridium difficile pseudomembranous enterocolitis, collagenous colitis, colonic adenoma, colonic diverticulosis, colonic inertia, colonic ischemia, con
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
  • the invention features a method of preventing or treating cardiovascular disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17 operably linked to a promoter.
  • the invention features a method of treating or preventing cardiovascular disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a cardiovascular disease or disorder.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a cardiovascular disease or disorder.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a cardiovascular disease or disorder.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 17, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 17, wherein presence of the mutation indicates that the patient may have an increased risk for developing a cardiovascular disease or disorder.
  • the invention features another method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 17, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a cardiovascular disease or disorder.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 17, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a cardiovascular disease or disorder.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 17, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a cardiovascular disease or disorder.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • coronary artery disease One preferred cardiovascular disease that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified is coronary artery disease.
  • Others include acute coronary syndrome, acute idiopathic pericarditis, acute rheumatic fever, American trypanosomiasis (Chagas' disease), angina pectoris, ankylosing spondylitis, anomalous pulmonary venous connection, anomalous pulmonary venous drainage, aortic atresia, aortic regurgitation, aortic stenosis, aortic valve insufficiency, aortopulmonary septal defect, asymmetric septal hypertrophy, asystole, atrial fibrillation, atrial flutter, atrial septal defect, atrioventricular septal defect, autoimmune myocarditis, bacterial endocarditis, calcific aortic stenosis, calcification of the cental valve, calcification of the valve ring, carcino
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
  • the invention features a method of preventing or treating a disease of the intestine including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the intestine including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the intestine.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the intestine.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the intestine.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine.
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the intestine.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 18, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the intestine.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Tables 18; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine.
  • the invention features another method for determining réelle whether a candidate compound may be useful for the treatment of a disease or disorder of the intestine.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine.
  • the nuclear receptor polypeptide is in a cell or a.cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 18, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the intestine.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine.
  • This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 18, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the intestine.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 18, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the intestine.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 18, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the intestine.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the intestine that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abdominal hernia, abetalipoproteinemia, abnormal rotation, acute hypotensive hypoperfusion, acute intestinal ischemia, acute small intestinal infarction, adenocarcinoma, adenoma, adhesions, amebiasis, anemia, arterial occlusion, atypical mycobacteriosis, bacterial diarrhea, bacterial overgrowild typeh syndromes, botulism, Campylobacter fetus infection, Campylobacter jejuni, carbohydrate absorption defects, carcinoid tumors, celiac disease (nontropical sprue, gluten-induced enteropathy), cholera, Crohn's disease, chronic intestinal ischemia, Clostridium difficile pseudomembranous enterocolitis, Clostridium perfringens, congenital umbilical hernia, Cronkite-Canada syndrome, cytomegalovirus
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
  • the invention features a method of preventing or treating a disease of the kidney including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the kidney including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the kidney.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the kidney.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the kidney.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the kidney.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 19, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the kidney.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the kidney.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1 , wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the kidney.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney.
  • This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the kidney.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 19, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the kidney.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 19, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the kidney.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the kidney that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acquired cystic disease, acute (postinfectious) glomerulonephritis, acute infectious interstitial nephritis, acute interstitial nephritis, acute pyelonephritis, acute renal failure, acute transplant failure, acute tubular necrosis, adult polycystic kidney disease, AL amyloid, analgesic nephropathy, anti-glomerular basement membrane disease (Goodpasture's Syndrome), asymptomatic hematuria, asymptomatic proteinuria, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bence Jones cast nephropathy, benign familial hematuria, benign nephrosclerosis and atheromatous embolization, bilateral cortical necrosis, chronic glomerulonephritis, chronic interstitial nephritis, chronic py
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
  • the invention features, a method of preventing or treating a disease of the liver including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the liver including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the liver.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the liver.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the liver.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the liver.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 20, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the liver.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the liver.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the liver.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 20, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the liver.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the liver.
  • This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 20, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the liver.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the liver.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 20, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the liver.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the liver.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 20, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the liver.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • liver diseases of the liver that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute alcoholic hepatitis (acute sclerosing hyaline necrosis of the liver), acute graft- versus-host disease, acute hepatitis, acute hepatocellular injury associated with infectious diseases other than viral hepatitis., acute liver failure, acute viral hepatitis, adenovirus hepatitis, Alagille syndrome, alcoholic cirrhosis, alcoholic hepatitis, alcoholic liver disease, alphal-antitrypsin deficiency, amebic abscess, angiolmyolipoma, angiosarcoma, ascending cholangitis, autoimmune chronic active hepatitis (lupoid hepatitis), bile duct adenoma, bile duct cystadenocarcinoma, bile duct cystadenoma, biliary atresia
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
  • the invention features a method of preventing or treating lung disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21 operably linked to a promoter.
  • the invention features a method of treating or preventing lung disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a lung disease or disorder.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a lung disease or disorder.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the lung.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the lung.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the lung.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the lung.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a lung disease or disorder.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 21, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a lung disease or disorder.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a lung disease or disorder.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a lung disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a lung disease or disorder.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a lung disease or disorder.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a lung disease or disorder.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 21, wherein presence of the mutation indicates that the patient may have an increased risk for developing a lung disease or disorder.
  • the invention features another method for determining whether a patient has an increased risk for developing a lung disease or disorder.
  • This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 21, wherem presence of the polymorphism indicates that the patient may have an increased risk for developing a lung disease or disorder.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a lung disease or disorder.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 21 , wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a lung disease or disorder.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a lung disease or disorder.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 21, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a lung disease or disorder.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Preferred lung diseases include abnormal diffusion, abnormal perfusion, abnormal ventilation, accelerated silicosis, actinomycosis, acute air space pneumonia (acute bacterial pneumonia), acute bronchiolitis, acute congestion, acute infections of the lung, acute interstitial pneumonia, acute necrotizing viral pneumonia, acute organic dust toxic syndrome, acute pneumonia, acute radiation pneumonitis, acute rheumatic fever, acute silicosis, acute tracheobronchitis, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adenovirus, adult respiratory distress syndrome (shock .
  • acute air space pneumonia acute bacterial pneumonia
  • acute bronchiolitis acute congestion
  • acute infections of the lung acute interstitial pneumonia, acute necrotizing viral pneumonia, acute organic dust toxic syndrome
  • acute pneumonia acute radiation pneumonitis, acute rheumatic fever, acute silicosis, acute tracheobronchitis, adenocarcinoma, adenoid cystic carcinoma,
  • lung agenesis, AIDS, air embolism, allergic bronchopulmonary mycosis, allergic granulomatosis and angiitis (Churg-Strauss), allograft rejection, aluminum pneumoconiosis, alveolar microlithiasis, alveolar proteinosis, amebic lung abscess, amniotic fluid embolism, amyloidosis of the lung, anomalies of pulmonary vasculature, anomalous pulmonary venous return, aspiration pneumonia, aplasia, asbestosis, asbestos-related diseases, aspergillosis, asthma, atelectasis, atriovenous fistulas, atypical mycobacterial infection, bacteremia, bacterial pneumonia, benign clear cell tumor, benign epithelial tumors, benign fibrous mesothelioma, berylliosis, blastomycosis, bromchial atresia, bronchial asthma, bronchial carcinoid
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
  • the invention features a method of preventing or treating muscular disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22 operably linked to a promoter.
  • the invention features a method of treating or preventing muscular disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a muscular disease or disorder.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a muscular disease or disorder.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a muscular disease or disorder.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a muscular disease or disorder.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 22, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a muscular disease or disorder.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a muscular disease or disorder.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a muscular disease or disorder.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 22, wherein presence of the mutation indicates that the patient may have an increased risk for developing a muscular disease or disorder.
  • the invention features another method for determining whether a patient has an increased risk for developing a muscular disease or disorder. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 22, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a muscular disease or disorder.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a muscular disease or disorder.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 22, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a muscular disease or disorder.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a muscular disease or disorder.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 22, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a muscular disease or disorder.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Preferred muscular diseases that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abnormalities of ion channel closure, acetylcholine receptor deficiency, acetylcholinesterase deficiency, acid maltase deficiencies (type 2 glycogenosis), acquired myopathies, acquired myotonia, adult myotonic dystrophy, alveolar rhabdomyosarcoma, aminoglycoside drags, amyloidosis, amyotrophic lateral sclerosis, antimyelin antibodies, bacteremic myositis, Batten's disease (neuronal ceroid lipofuscinoses), Becker's muscular dystrophy, benign neoplasms, Bomholm disease, botulism, branching enzyme deficiency (type 4 glycogenosis), carbohydrate storage diseases, carnitine deficiencies, carnitine palmitoyltransferase deficiency, central core disease, centronucle
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
  • the invention features a method of preventing or treating a disease of the ovary including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the ovary including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the ovary.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be usefubfor the treatment of disease or disorder of the ovary.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the ovary.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherem altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the ovary.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 23, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the ovary.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the ovary.
  • This .method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 23, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the ovary.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary.
  • This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 23, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the ovary.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 23, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the ovary.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 23, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the ovary.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the ovary that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include autoimmune oophoritis, brenner tumors, choriocarcinoma, clear cell adenocarcinoma, clear cell carcinoma, corpus luteal cysts, decidual reaction, dysgerminoma, embryonal carcinoma, endometrioid tumors, endometriosis, endometriotic cysts, epithelial inclusion cysts, fibrothecoma, follicular cysts, gonadoblastoma, granulosa-stroma cell tumors, granulosa-theca cell tumor, gynandroblastoma, hilum cell hype ⁇ lasia, luteal cysts, luteal hematomas, luteoma of pregnancy, massive ovarian edema, metastatic neoplasm, mixed germ cell tumors, monodermal tumors, mucinous tumors, neoplastic cysts
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
  • the invention features a method of preventing or treating blood disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24 operably linked to a promoter.
  • the invention features a method of treating or preventing blood disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
  • an animal e.g., a human
  • a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24 including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a blood disease or disorder.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor, polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a blood disease or disorder.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a blood disease or disorder.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a blood disease or disorder.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a blood disease or disorder.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a blood disease or disorder.
  • a transgenic non- human mammal e.g., a mouse
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a blood disease or disorder.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 24, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a blood disease or disorder.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a blood disease or disorder.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a blood disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a blood disease or disorder.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the , polypeptide not contacted with the compound, ndicates that the candidate compound may be useful for the treatment of a blood disease or disorder.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a blood disease or disorder.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 24, wherein presence of the mutation indicates that the patient may have an increased risk for developing a blood disease or disorder.
  • the invention features another method for determining whether a patient has an increased risk for developing a blood disease or disorder. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 24, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a blood disease or disorder.
  • the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a blood disease or disorder.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 24, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a blood disease or disorder.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a blood disease or disorder.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 24, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a blood disease or disorder.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Preferred blood diseases that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abnormal hemoglobins, abnormalities in granulocyte count, abnormalities in lymphocyte count, abnormalities in monocyte count, abnormalities of blood platelets, abnormalitites of platelet function, acanthocytosis, acquired neutropenia, acute granulocytic leukemia, acute idiopathic thrombocytopenic pu ⁇ ura, acute infections, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloblastic leukemia, acute myelocytic leukemia, acute myeloid leukemia, acute pyogenic bacterial infections, acute red cell aplasia, acute response to endotoxin, adult T-cell leukemial/lymphoma, afibrinogenemia, alpha thalassemia, altered affinity of hemoglobin for oxygen, amyloidosis, anemia, anemia due to acute blood loss, anemia due to chronic blood loss
  • coli early preleukemic myeloid leukemia, eosinophilia, eosinophilic granuloma, erythrocute enzyme deficiency, erythrocyte membrane defects, essential thrombocythemia, factor 7 deficiency, familial cyclic neutropenia, Felty's syndrome, fibrinolytic activity, folate antagonists, folic acid deficiency, Gaucher disease, Glanzmann's thrombasthenia, glucose-6-phosphate dehydrogenase deficiency, granulated T-cell lymphocyte leukemia, granulocytic sarcoma, granulocytosis, Hageman trait, hairy cell leukemia (leukemic reticuloendotheliosis), Hand-Sch ⁇ ller-Christian disease, heavy-chain disease, hemoglobin C disease, hemoglobin constant spring, hemoglobin S, hemoglobinopathies, hemolysis caused by infectious agents, hemolytic anemia,
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptpr polypeptide substantially identical to a polypeptide listed in Table 24.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
  • the invention features a method of preventing or treating a disease of the prostate including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the prostate including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the prostate.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the prostate.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a blood disease or disorder of the prostate.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate.
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g., a
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the prostate.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 25, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the prostate.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the prostate.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 25, wherem presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the prostate.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 25, wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the prostate.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 25, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the prostate.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 25, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the prostate.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the prostate that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute bacterial prostatitis, acute prostatitis, adenoid basal cell tumor (adenoid cystic-like tumor), allergic (eosinophilic) granulomatous prostatitis, atrophy, atypical adenomatous hype ⁇ lasia, atypical basal cell hype ⁇ lasia, basal cell adenoma, basal cell hype ⁇ lasia, BCG-induced granulomatous prostatitis, benign prostatic hype ⁇ lasia, benign prostatic hypertrophy, blue nevus, carcinosarcoma, chronic abacterial prostatitis, chronic bacterial prostatitis, cribriform hype ⁇ lasia, ductal (endometrioid) adenocarcinoma, granulomatous prostatitis, hematuria, iatrogenic granulomatous prostatitis, idiopathic (nonspecific) gran
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
  • the invention features a method of preventing or treating skin disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26 operably linked to a promoter.
  • the invention features a method of treating or preventing skin disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a skin disease or disorder.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a skin disease or disorder.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a skin disease or disorder
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a skin disease or disorder.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease skin disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a skin disease or disorder.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 26, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a skin disease or disorder.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a skin disease or disorder.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a skin disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a skin disease or disorder.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a skin disease or disorder.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a skin disease or disorder.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 26, wherein presence of the mutation indicates that the . patient may have an increased risk for developing a skin disease or disorder.
  • the invention features another method for determining whether a patient has an increased risk for developing a skin disease or disorder.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 26, wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a skin disease or disorder.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a skin disease or disorder.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 26, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a skin disease or disorder.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a skin disease or disorder.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 26, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a skin disease or disorder.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Preferred skin diseases that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acanthosis nigricans, acne vulgaris, acquired epidermolysis bullosa, acrochordons, acrodermatitis enteropathica, acropustulosis, actinic keratosis, acute cutaneous lupus erythematosus, age spots, allergic dermatitis, alopecia areata, angioedema, angiokeratoma, angioma, anthrax, apocrine tumors, arthropid-bite reactions, atopic dermatitis, atypical fibroxanthoma, Bart's syndrome, basal cell carcinoma (basal cell epithelioma), Bateman's pu ⁇ ura, benign familial pemphigus (Hailey-Hailey disease), benign keratoses, Berloque dermatitis, blue nevus, borderline leprosy, Borreli
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that-includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
  • a non-human mammal e.g., a mouse
  • a transgene that-includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
  • the invention features a method of preventing or treating a disease of the spleen including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the spleen including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the spleen.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the spleen.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the spleen.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
  • the invention features another method for determining • whether a candidate compound may be useful for the treatment of a disease or disorder of the spleen.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 27, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted With the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
  • the invention features yet another method for determining whether a candidate compound maybe useful for the treatment of a disease or disorder of the spleen.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the spleen.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 27, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the spleen.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 27, wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the spleen.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 27, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the spleen.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 27, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the spleen.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the spleen that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abnormal immunoblastic proliferations of unknown origin, acute infections, acute parasitemias, agnogenic myeloid metaplasia, amyloidosis, angioimmunoblastic lymphadenopathy, antibody-coated cells, asplenia, autoimmune diseases, autoimmune hemolytic anemias, B-cell chronic lymphocytic leukemia and prolymphocytic leukemia, babesiosis, bone marrow involvement by carcinoma, brucellosis, carcinoma, ceroid histiocytosis, chronic alcoholism, chronic granulomatous disease, chronic hemolytic anemias, chronic hemolytic disorders, chronic immunologic inflammatory disorders, chronic infections, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic parasitemias, chronic uremia, cirrhosis, cold agglutinin disease, congestive splenomegaly, cryo
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
  • the invention features a method of preventing or treating a disease of the stomach including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the stomach including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the stomach.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the stomach.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the stomach.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g., a mouse
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the stomach.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 28, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the stomach.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the stomach.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 28, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the stomach.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 28, wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the stomach.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 28, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the stomach.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 28, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the stomach.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the stomach that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute erosive gastropathy, acute gastric ulcers, adenocarcinomas, adenomas, adenomatous polyps, advanced gastric cancer, ampullary carcinoma, atrophic gastritis, bacterial gastritis, carcinoid tumors, carcinoma of the stomach, chemical gastritis, chronic (nonerosive) gastritis, chronic idiopathic gastritis, chronic nonatrophic gastritis, Cronkite-Canada syndrome, congenital cysts, congenital diaphragmatic hernias, congenital diverticula, congenital duplications, congenital pyloric stenosis, congestive gastropathy, cyclic vomiting syndrome, decreased mucosal resistance to acid, diffuse or infiltrating adenocarcinoma, early gastric cancer, emphysematous gastritis,
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
  • the invention features a method of preventing or treating a disease of the testes including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the testes including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the testes.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder, of the testes.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the testes.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the testes.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the testes.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 29, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the testes.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the testes.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the testes.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 29, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the testes.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the testes.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 29, wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the testes.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the testes.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 29, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the testes.
  • the invention features yet another method for detemiining whether a patient has an increased risk for developing a disease or disorder of the testes.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 29, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the testes.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the testes that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include aberrant ducts of Haller, abnormal productions of hormones, abnormalities of testicular descent, acute epididymoorhcitis, adenomatoid tumor, adenomatous hype ⁇ lasia of the rete testis, adenovirus, administration of estrogens, adrenal rests, alcoholic cirrhosis, amyloidosis, anorchism, appendix testes, bacterial infections, Bracella, cachexia, carcinoma in situ, carcinoma of the rete testis, chlamydia, choriocarcinoma, choristomas, chronic fibrosing epididymoorchitis, coxsackie virus B, cryptorchidism, cystic dysplasia of the rete testis, cytomegalovirus, dystopia, E.
  • Echinococcus granulosus Echitopic testes, embryonal carcinoma, epididymoorchitis, Fournier's scrotal gangrene, fungal infection, germ cell aplasia, germ cell neoplasms, gonadal dysgenesis, gonadal stromal neoplasms, granulomatous orchitis, granulosa cell tumors, Haemophilus influenzae, HIV, hypergonadism, hypogonadotropic hypogonadism, hypopituitarism, hypospermatogenesis, hyrocele, idiopathic granulomatous orchitis, incomplete maturation arrest, infarction, infertility, inflammatory diseases, inflammatory lesions, interstitial (Leydig) cell tumors, Klinefelter's syndrome, latrogenic lesions, Leydig cell tumors, malakoplakia, malignant lymphoma, malnutrition, maturation arrest of spermatogenesis
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
  • a non-human mammal e.g., a mouse
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
  • the invention features a method of preventing or treating a disease of the thymus including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the thymus including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thymus.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thymus.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor .
  • a transgenic non-human mammal e.g., a knock-out mouse
  • polypeptide in the transgenic non-human mammal wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thymus.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus.
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thymus.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 30, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thymus.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thymus.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 30, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the thymus.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 30, wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the thymus.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 30, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the thymus.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 30, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the thymus.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the thymus that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include accidental involution, acute accidental involution, acute lymphoblastic leukemia of T cell type, agenesis, age-related involution, anaplastic carcinoma, ataxia telangiectasia, atrophy, bacterial infections, bacterial mediastinitis, basaloid carcinoma, bone marrow transplantation, Braton's agammaglobulinemia, carcinosarcoma, chronic accidental involution, clear cell carcinoma, cortical thymoma, cytomegalovirus, DiGeorge syndrome, dysgenesis, dysplasia with pattern similar to severe atrophy, dysplasia with pseudoglandular appearance, dysplasia with stromal conticomedullary differentiation, ectopia, germ cell tumors, Grave's disease, histiocytosis X, HIV, Hodgkin's disease, hype ⁇ lasia, infectious mononucleosis, involution,
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
  • the invention features a method of preventing or treating a disease of the thyroid including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the thyroid including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thyroid.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thyroid.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a • polypeptide listed in Table 31 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of transgenic non-human mammal, wherein altered biological activity, relative to that of the nuclear receptor transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thyroid.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 31, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or • disorder of the thyroid.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 31, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the thyroid.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 31, wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the thyroid.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 31 , wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the thyroid.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 31, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the thyroid.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the thyroid that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include aberrant thyroid glands, accessory thyroid glands, adenoma with seemingly nuclei, agenesis, amphicrine variant of medullary carcinoma, anaplastic (undifferentiated) carcinoma, aplasia, atrophic thyroiditis, atypical adenoma, autoimmune thyroiditis, carcinoma, C-cell hype ⁇ lasia, clear cell tumors, clear cell variant of medullary carcinoma, colloid adenoma, columnar variant of papillary carcinoma, congenital hypothyroidism (cretinism), diffuse nontoxic goiter, diffuse sclerosing variant of papillary carcinoma, dyshormonogenic goiter, embryonal adenoma, encapsulated variant of papillary carcinoma, endemic cretinism, endemic goiter, enzyme deficiency, fetal adenoma, follicular adenoma, follicular carcinoma,
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
  • the invention features a method of preventing or treating a disease of the uterus including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the uterus including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the uterus.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the uterus.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non- human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or • disorder of the uterus.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uteras.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the uterus.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 32, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the uterus.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus .
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the uterus.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the uterus.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 32, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the uteras.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the uteras.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 32, wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the uterus.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the uterus.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 32, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the uterus.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the uterus.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 32, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the uterus.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the uterus that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute cervicitis, acute endometritis, adenocanthoma, adenocarcinoma, adenocarcinoma in situ, adenoid cystic carcinoma, adenomatoid tumor, adenomyoma, adenomyosis (endometriosis interna), adenosquamous carcinoma, amebiasis, arias-Stella phenomenon, atrophy of the endometrium, atypical hype ⁇ lasia, benign polypoid lesions, benign stromal nodule, carcinoid tumors, carcinoma in situ, cervical intraepithelial neoplasia, chlamydia, chronic cervicitis, chronic nonspecific endometritis, ciliated (tubal) metaplasia, clear cell adenocarcinoma, clear cell carcinoma, clear cell metap
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
  • the invention features a cell from a non-human mamirial having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
  • the invention features a method of preventing or treating a disease of the pancreas including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the pancreas including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the pancreas.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the pancreas.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the pancreas.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
  • a transgenic non-human mammal e.g., a mouse
  • a transgenic non-human mammal e.g., a mouse
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pa creas.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the pancreas.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the pancreas.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the pancreas.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1 , wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the pancreas.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • pancreas Diseases of the pancreas that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include ACTHoma, acute pancreatitis, adult onset diabetes, annulare pancreas, carcinoid syndrome, carcinoid tumors, carcinoma of the pancreas, chronic pancreatitis, congenital cysts, Cushing's syndrome, cystadenocarcinoma, cystic fibrosis (mucoviscidosis, fibrocystic disease), diabetes mellitus, ectopic pancreatic tissue, gastinoma, gastrin excess, glucagon excess, glucagonomas, GRFomas, hereditary pancreatitis, hyperinsulinism, impaired insulin release, infected pancreatic necrosis, insulin resistance, insulinomas, islet cell hype ⁇ lasia, islet cell neoplasms, juvenile onset diabetes, macroamylasemia, maldevelopment of the pancreas, maturity-onset diabetes of
  • the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • a non-human mammal e.g., a mouse
  • a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • the invention features a method of preventing or treating a disease of the bone and joints including introducing into a human an expression vector that includes a nucleic acid molecule .encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the bone and joints including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the bone and joints.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the bone and joints.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the bone and joints.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the.
  • nuclear receptor polypeptide in the transgenic non-human mammal wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1 , the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the bone and joints.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the bone and joints.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in . Table 1, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the bone and joints.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the bone and joints.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the bone and joints that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include achondroplasia, acute bacterial arthritis, acute pyogenic osteomyelitis, Albright's syndrome, alkaptonuria (ochronosis), aneurysmal bone cyst, ankylosing spondylitis, arthritic, arthropathies associated with hemoglobinopathies, arthropathy of acromegaly, arthropathy of hemochromatosis, bone cysts, calcium hydroxyapatite deposition disease, calcium pyrophosphate deposition disease, chondrocalcinosis, chondroma, chondrosarcoma, chostochondritis, chrondromblastoma, congenital dislocation of the hip, congenital disorders of joints, echondromatosis
  • the invention features a method of preventing or treating a disease of the breast including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the breast including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the breast.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the breast.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding, a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast.
  • a transgenic non- human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the breast.
  • This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the freatment of a disease or disorder of the breast.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the breast.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1 , the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the breast.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the breast.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the breast.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the breast.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the breast. This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the ' polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the breast.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the breast.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1 , wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the breast.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the breast.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the breast.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the breast that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute mastitis, breast abcess, carcinoma, chronic mastitis, congenital breast anomalies, cystic mastopathy, ductal carcinoma, ductal carcinoma in situ, ductal papilloma, fat necrosis, fibroadenoma, fibrocystic changes, fibrocystic disease, galactorrhea, granular cell tumor, gynecomastia, infiltrating ductal carcinoma, inflammatory breast carcinoma, inflammatory breast lesions, invasive lobular carcinoma, juvenile hypertrophy of the breast, lactating adenoma, lobular carcinoma in situ, neoplasms, Paget's disease of the nipple, phyllodes tumor (cystosarcome phyllodes), polymastia, polymazia, polythelia, silicone granuloma, supernumerary breast, and super
  • the invention features a method of preventing or treating a disease of the immune system including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter.
  • the invention features a method of treating or preventing a disease of the immune system including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the immune system.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the immune system.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the freatment of a disease or disorder of the immune system.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear.receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the immune system.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1 , the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter, activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the immune system.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the freatment of a disease or disorder of the immune system.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the immune system.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the immune system.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 1, wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a disease or disorder of the immune system.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the immune system.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1 , wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the immune system.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Diseases of the immune system that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abnormal neutrophil function, acquired immunodeficiency, acute rejection, Addison's disease, advanced cancer, aging, allergic rhinitis, angioedema, arthras-type hypersensitivity reaction, ataxia-telangiectasia, autoimmune disorders, autoimmune gastritis, autosomal recessive agammaglobulinemia, blood transfusion reactions, Bloom's syndrome, Braton's congenital agammaglobulinemia, bullous pemphigoid, Chediak-Higashi syndrome, chronic active hepatitis, chronic granulomatous disease of childhood, chronic rejection, chronic renal failure, common variable immunodeficiency, complement deficiency, congenital (primary) immunodeficiency, contact dermatitis, deficiencies of immune response, deficiency of the vascular response, dermatomyositis, diabetes mellitus, disorders of mi
  • Wiskott-Aldrich syndrom x-linked agammaglobulinemia, x-linked immunodeficiency with hyper IgM, x-linked lymphoproliferative syndrome, zap70 tyrosine kinase deficiency.
  • the invention features a method of preventing or treating a metabolic or nutritive disease or disorder, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter.
  • the invention features a method of treating or preventing a metabolic or nutritive disease or disorder, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
  • an animal e.g., a human
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • the nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • a transgenic non-human mammal e.g., a knock-out mouse
  • the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1 , the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • the invention features another method for determining whether a candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
  • the nuclear receptor polypeptide is in a cell or a cell free assay system.
  • the invention features a method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder.
  • the method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a metabolic or nutritive disease or disorder.
  • the invention features another method for detennining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder.
  • This method includes the step of determining whether the patient has a polymo ⁇ hism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the polymo ⁇ hism indicates that the patient may have an increased risk for developing a metabolic or nutritive disease or disorder.
  • the mutation or polymo ⁇ hism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
  • the invention features another method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder.
  • the method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a metabolic or nutritive disease or disorder.
  • the invention features yet another method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder.
  • the method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a metabolic or nutritive disease or disorder.
  • the expression levels are determined by measuring levels of polypeptide or mRNA.
  • Prefened metabolic or nutritive diseases and disorders that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include 5 , 10-methylenetefrahydrofolate reductase deficiency, achondrogenesis type IB, acid ⁇ -1,4 glucosidase deficiency, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Ba ⁇ aquer-Simons syndrome), acute intermittent po ⁇ hyria, acute panniculitis, adenine phosphoribosyltransferase deficiency, adenosine deaminase deficiency, adenylosuccinate lyase deficiency, adiposis dolorosa (Dercum disease), ALA dehydratase-deficient po ⁇ hyria, albinism, alkaptonuria, amulopectinosis, Andersen disease, argin
  • the invention features a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1.
  • the transgene may be operably linked, e.g., to an inducible, cell-type, or tissue-specific promoter.
  • the transgenic mouse has a mutation in a gene that is orthologous to the transgene.
  • the transgene encoding the human nuclear receptor polypeptide may entirely replace the coding sequence of the orthologous mouse gene or the transgene might complement a knock out of the orthologous mouse gene.
  • the transgenic mouse has a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1.
  • the invention features an isolated cell or population of cells derived from a transgenic mouse either expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1 or has a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1.
  • a mutation e.g., a deletion, frameshift, insertion or a point mutation
  • the invention also features a method for identifying a compound that may be useful for the treatment of a disease or disorder described herein.
  • the method includes the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a nuclear receptor polypeptide listed in Table 1 ; and determining whether the candidate compound decreases the biological activity of the nuclear receptor polypeptide, wherein a decrease in the biological activity of the nuclear receptor polypeptide identifies the candidate compound as a compound that may be useful for the treatment of a disease or disorder.
  • the transgenic mouse has a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1.
  • the mouse has a mutation in the gene that is orthologous to the transgene.
  • the invention features another method for identifying a compound that may be useful for the treatment of a disease or disorder described herein.
  • This method includes the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a nuclear receptor polypeptide in a gene listed in Table 1, and having a disease or disorder caused by the expression of the transgene; and determining whether the candidate compound treats the disease or disorder.
  • the invention features another method for identifying a compound that may be useful for the treatment of a disease or disorder described herein.
  • This method includes the steps of administering a candidate compound to a transgenic mouse fransgenic mouse containing a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1, and having a disease or disorder caused by gene disruption; and determining whether candidate compound treats the disease or disorder.
  • a mutation e.g., a deletion, frameshift, insertion or a point mutation
  • the invention features a method for identifying a compound that may be useful for the treatment of a disease or disorder described herein.
  • This method includes the steps of contacting a candidate compound with a cell from a transgenic mouse expressing a transgene encoding a nuclear receptor polypeptide in a gene listed in Table 1 ; and determining whether the candidate compound decreases the biological activity of the nuclear receptor polypeptide.
  • activity of the nuclear receptor polypeptide identifies the candidate compound as a compound that may be useful for the treatment of a disease or disorder.
  • the transgenic mouse from which the cell was derived has a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1.
  • the mouse has a mutation in the polypeptide that is orthologous to the nuclear receptor polypeptide encoded by the transgene.
  • the invention also features a kit that includes a plurality of polynucleotides, wherein each polynucleotide hybridizes under high stringency conditions to a nuclear receptor polynucleotide of Table 1. At least 50 different polynucleotides, each capable of hybridizing under high stringency conditions to a different human nuclear receptor polynucleotide listed on Table 1, are present in the kit.
  • the invention features another kit that includes a plurality of polynucleotides.
  • polynucleotides that hybridize under high stringency conditions, each to a different nuclear receptor polynucleotide listed on one of Tables 3-32 are present in the kit such that the kit includes polynucleotides that collectively hybridize to every nuclear receptor polynucleotide listed on one of Tables 3-32.
  • the invention features another kit, this kit including a plurality of mice, each mouse having a mutation in a nuclear receptor polynucleotide of Table 1, wherein at least 50 mice, each having a mutation in a different nuclear receptor polynucleotide listed on Table 1, are present in the kit.
  • This kit may optionally include a plurality of polynucleotides, wherein each polynucleotide hybridizes under high stringency conditions to a nuclear receptor polynucleotide of Table 1, wherein at least 50 different polynucleotides, each capable of hybridizing under high stringency conditions to a different mouse nuclear receptor polynucleotide listed on Table 1, are present in the kit.
  • the invention features another kit that includes a plurality of mice having a mutation in a nuclear receptor polynucleotide. In this kit, mice having a mutation in each nuclear receptor polynucleotide listed on one of Tables 3-32 are present in the kit.
  • polypeptide any chain of more than two amino acids, regardless of post-translational modification such as glycosylation or phosphorylation.
  • substantially identical is meant a polypeptide or nucleic acid exhibiting at least 50%, preferably 85%, more preferably 90%, and most preferably 95% identity to a reference amino acid or nucleic acid sequence.
  • the length of comparison sequences will generally be at least 16 amino acids, preferably at least
  • the length of comparison sequences will generally be at least 50 nucleotides, preferably at least 60 nucleotides, more preferably at least 75 nucleotides, and most preferably 110 nucleotides or the full- length polynucleotide.
  • Sequence identity is typically measured using a sequence analysis program (e.g., BLAST 2; Tatusova et al., FEMS Microbiol Lett. 174:247-250, 1999) with the default parameters specified therein.
  • BLAST 2 Altschul et al., FEMS Microbiol Lett. 174:247-250, 1999
  • high stringency conditions hybridization in 2X SSC at 40°C with a DNA probe length of at least 40 nucleotides.
  • high stringency conditions see F. Ausubel et al., Current Protocols in Molecular Biology, pp. 6.3.1- 6.3.6, John Wiley & Sons, New York, NY, 1994, hereby inco ⁇ orated by reference.
  • Substantially identical polynucleotides also include those that hybridize under high stringency conditions.
  • Substantially identical” polypeptides include those encoded by polynucleotides that hybridize under high stringency conditions.
  • substantially pure polypeptide is meant a polypeptide that has been separated from the components that naturally accompany it.
  • the polypeptide is substantially pure when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated.
  • the polypeptide is a nuclear receptor polypeptide that is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, pure.
  • a substantially pure nuclear receptor polypeptide may be obtained, for example, by extraction from a natural source (e.g., a pancreatic cell), by expression of a recombinant nucleic acid encoding a nuclear receptor polypeptide, or by chemically synthesizing the polypeptide. Purity can be measured by any appropriate method, e.g., by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.
  • a polypeptide is substantially free of naturally associated components when it is separated from those contaminants that accompany it in its natural state.
  • a polypeptide which is chemically synthesized or produced in a cellular system different from the cell from which it naturally originates will be substantially free from its naturally associated components.
  • substantially pure polypeptides include those which naturally occur in eukaryotic organisms but are synthesized in E. coli, yeast or other microbial system.
  • purified antibody is meant antibody that is at least 60%, by weight, free from proteins and naturally occurring organic molecules with which it is naturally associated. Preferably, the preparation is at least 75%, more preferably 90%, and most preferably at least 99%, by weight, antibody.
  • a purified antibody may be obtained, for example, by affinity chromatography using recombinantly-produced protein or conserved motif peptides and standard techniques.
  • telomere binding protein a small molecule, peptide, antibody, or polypeptide that recognizes and binds, for example, a human nuclear receptor polypeptide but does not substantially recognize and bind other molecules in a sample, e.g., a biological sample, that naturally includes the protein.
  • nucleotide is meant that a nucleotide or nucleotide region is characterized as occu ⁇ ing in several different sequence forms.
  • a “mutation” is a forai of a polymo ⁇ hism in which the expression level, stability, function, or biological activity of the encoded protein is substantially altered.
  • nuclear receptor related polypeptide is meant a polypeptide having substantial identity to any of the polypeptides listed in Table 1, including polymo ⁇ hic forms (e.g., sequences having one or more SNPs) and splice variants.
  • nuclear receptor biological activity is meant measurable effect or change in an organism or a cell resulting from the modulation of a nuclear receptor at the molecular, cellular, physiological or behavioral levels or alteration in the extent of activation or deactivation that can be elicited by an agonist or antagonist.
  • Dominant negative means an effect of a mutant form of a gene product that dominantly interferes with the function of the normal gene product.
  • Reporter system means any gene, compound or polypeptide whose product can be assayed, measured or monitored. Examples include, but are not limited to neomycin (Kang et al., Mol Cells 1997; 7:502-8), luciferase (Welsh et al., Curr Opin Biotechnol 1997; 8:617-22), lacZ (Spergel et al, Prog Neurobiol 2001; 63:673-86), aequorin (Deo et al., J Anal Chem 2001; 369:258-66) and green fluorescent protein (Tsien, Annu Rev Biochem 1998; 67:509-44).
  • Constant mutant is any gene, cell or organism for which the expression of the mutant phenotype can be controlled through alteration in the temperature, diet or other external conditions.
  • isolated or purified means altered from its natural state, i.e., if it occurs in nature, it has been changed or removed from its original environment, or both.
  • a polynucleotide or a polypeptide naturally present in a living organism is not “isolated,” but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is “isolated,” as the term is employed herein.
  • a polynucleotide or polypeptide that is introduced into an organism by transformation, genetic manipulation, or by any other recombinant method is "isolated” even if it is still present in the organism.
  • Polynucleotide generally refers to any polyribonucleotide (RNA) or polydeoxribonucleotide (DNA), which may be unmodified or modified RNA or DNA.
  • Polynucleotides include, without limitation, single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double- stranded or a mixture of single- and double-stranded regions.
  • Polynucleotide can also refer to triple helix nucleic acids.
  • Variant refers to a polynucleotide or polypeptide that differs from a reference polynucleotide or polypeptide, but retains the essential properties thereof.
  • a typical variant of a polynucleotide differs in nucleotide sequence from the reference polynucleotide. Changes in the nucleotide sequence of the variant may or may not alter the amino acid sequence of a polypeptide encoded by the reference polynucleotide. Nucleotide changes may result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence, as discussed below.
  • a typical variant of a polypeptide differs in amino acid sequence from the reference polypeptide.
  • a variant and reference polypeptide may differ in amino acid sequence by one or more substitutions, insertions, or deletions in any combination.
  • a substituted or inserted amino acid residue may or may not be one encoded by the genetic code. Typical conservative substitutions include Gly, Ala; Val, Ile, Leu; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe and Tyr.
  • a variant of a polynucleotide or polypeptide may be naturally occurring such as an allele, or it may be a variant that is not known to occur naturally.
  • Non-naturally occurring variants of polynucleotides and polypeptides may be made by mutagenesis techniques or by direct synthesis. Also included as variants are polypeptides having one or more post-translational modifications, for instance glycosylation, phosphorylation, methylation, ADP ribosylation and the like.
  • Embodiments include methylation of the N-terminal amino acid, phosphorylations of serines and threonines and modification of C-terminal glycines.
  • Allele refers to one of two or more alternative forms of a gene occu ⁇ ing at a given locus in the genome.
  • a "transgenic organism,” as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art.
  • the nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection, transfection or by infection with a recombinant virus.
  • the transgenic organisms contemplated in accordance with the present invention include mice, bacteria, cyanobacteria, fungi, plants and animals.
  • the isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or fransconjugation.
  • transgenic mice is a mouse, in which one or more of the cells of the organism contains nucleic acid introduced by way of human intervention, such as by fransgenic techniques well known in the art.
  • the nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, by methods known in the art, for example microinjection, infection, transfection, or transformation.
  • Transgene is any exogenously added nucleic acid.
  • Antisense or “Reverse complement” means a nucleic acid sequence complementary to the messenger RNA.
  • Single nucleotide polymo ⁇ hism or “SNP” refers to the occurrence of nucleotide variability at a single nucleotide position in the genome, within a population.
  • An SNP may occur within a gene or within intergenic regions of the genome.
  • SNPs can be assayed using Allele Specific Amplification (ASA).
  • ASA Allele Specific Amplification
  • a common primer is used in reverse complement to the polymo ⁇ hism being assayed. This common primer can be between 50 and 1500 bps from the polymo ⁇ hic base.
  • the other two (or more) primers are identical to each other except that the final 3' base wobbles to match one of the two (or more) alleles that make up the polymo ⁇ hism.
  • Two (or more) PCR reactions are then conducted on sample DNA, each using the common primer and one of the Allele Specific Primers.
  • RNA variant refers to cDNA molecules produced from RNA molecules initially transcribed from the same genomic DNA sequence but which have undergone alternative RNA splicing.
  • Alternative RNA splicing occurs when a primary RNA transcript undergoes splicing, generally for the removal of introns, which results in the production of more than one distinct mRNA molecules each of which may encode different amino acid sequences.
  • the term splice variant also refers to the polypeptides encoded by the above mRNA molecules.
  • Fusion protein refers to a polypeptide encoded by two, often unrelated, fused genes or fragments thereof.
  • test compound a chemical, be. it naturally-occurring or artificially-derived, that is assayed for its ability to modulate gene activity or protein stability or binding, expression levels, or activity, by employing any standard assay method.
  • Test compounds may include, for example, peptides, polypeptides, synthesized organic molecules, naturally occurring organic molecules, polynucleotide molecules, and components thereof.
  • promoter is meant a minimal sequence sufficient to direct transcription. Also included in the invention are those promoter elements which are sufficient to render promoter-dependent gene expression controllable for cell type-specific, tissue- specific, temporal-specific, or inducible by external signals or agents; such elements may be located in the 5' or 3' or intron sequence regions of the native gene.
  • operably linked is meant that a gene and one or more regulatory sequences are connected in such a way as to permit gene expression.
  • nuclear receptor polypeptides and polynucleotides may be relevant for the treatment or diagnosis of various disease or disorders.
  • polymo ⁇ hic, splice variant, mutagenzied, and recombinant forms of a nuclear receptor polypeptide may also be targets for treatment or diagnosis of diseases and disorders or for assaying for therapeutic compounds.
  • Recombinant nuclear receptor polypeptides may be produced using standard techniques known in the art. Such recombinant nuclear receptor polypeptides are, for example, useful in in vitro assays for identifying therapeutic compounds.
  • the present invention relates to expression systems that include a polynucleotide of the present invention, host cells that are genetically engineered with such expression systems, and production of polypeptides of the invention by recombinant techniques.
  • Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention.
  • host cells can be genetically engineered to inco ⁇ orate expression systems or portions thereof for any polynucleotide of the present invention.
  • Polynucleotides may be introduced into host cells by methods described in standard laboratory manuals.
  • Prefened methods of introducing polynucleotides into host cells include, for instance, calcium phosphate transfection, DEAE-dextran mediated transfection, transvection, microinjection, cationic lipid-mediated transfection, electroporation, transduction, ballistic introduction, infection or fusion with carriers such as liposomes, micelles, ghost cells, and protoplasts.
  • chromosomal, episomal, and virus-derived systems such as vector derived bacterial plasmids, bacteriophage, transposons, yeast episomes, insertion elements, yeast chromosomal elements, viruses (such as baculoviruses, papova viruses, such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses, and retroviruses), and vectors derived from combinations .thereof, such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids.
  • viruses such as baculoviruses, papova viruses, such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses, and retroviruses
  • vectors derived from combinations .thereof such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids.
  • Prefened expression vectors include, but are not limited to, pcDNA3 (Invitrogen) and pSVL (Pharmacia Biotech).
  • Other expression vectors include, but are not limited to, pSPORTTm vectors, pGEMTm vectors (Promega), pPROEXvectorsTm (LTI, Bethesda, MD), BIuescriptTm vectors (Stratagene), pQETm vectors (Qiagen), pSE420Tm (Invitrogen), and pYES2Tm (Invitrogen).
  • the expression systems may contain control regions that regulate as well as engender expression.
  • any system or vector that is able to maintain, propagate, or express a polynucleotide to produce a polypeptide in a host may be used.
  • the appropriate polynucleotide may be inserted into an expression system by any of a variety of well-known and routine techniques, including transformation, transfection, electroporation, nuclear injection, or fusion with carriers such as liposomes, micelles, ghost cells, and protoplasts.
  • Expression systems of the invention include bacterial, yeast, fungal, plant, insect, invertebrate, vertebrate, and mammalian cells systems.
  • eukaryotic cells are cells of higher eukaryotes.
  • Suitable eukaryotic cells include, but are not limited to, non-human mammalian tissue culture cells and human tissue culture cells.
  • Prefened host cells include, but are not limited to, insect cells, HeLa cells, Chinese hamster ovary cells (CHO cells), African green monkey kidney cells (COS cells), human 293 cells, murine embryonal stem (ES) cells and murine 3T3 fibroblasts.
  • yeast host may be employed as a host cell.
  • Preferred yeast cells include, but are not limited to, the genera, Saccharomyces, Pichia, and Kluveromyces.
  • Prefened yeast hosts are S. cerevisiae and P. pastoris.
  • Prefened yeast vectors can contain an origin of replication sequence from a 2T yeast plasmid, an autonomously replication sequence (ARS), a promoter region, sequences for polyadenylation, sequences for transcription termination, and a selectable marker gene.
  • ARS autonomously replication sequence
  • Shuttle vectors for replication in both yeast and E. coli are also included herein.
  • insect cells may be used as host cells.
  • the polypeptides of the invention are expressed using a baculovirus expression system (see, Luckow et al., BioTechnology, 1988, 6. and Baculovirus Expression Vectors: A Laboratory Manual, O'Rielly et al. (Eds.), W.H. Freeman and Company, New York, 1992, each of which is inco ⁇ orated herein by reference in its entirety).
  • Bac-to-BacTm complete baculovirus expression system can, for example, be used for production in insect cells.
  • Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein.
  • Such fusion vectors typically serve three pu ⁇ oses: 1) to increase expression of recombinant protein; 2) to increase the solubility of the recombinant protein; and 3) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification.
  • a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protem from the fusion moiety subsequent to purification of the fusion protein.
  • enzymes, and their cognate recognition sequences include Factor Xa, thrombin and enterokinase.
  • Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith, D.B. and Johnson, K.S. (1988) Gene 67:31 -40), pMAL (New England Biolabs, Beverly, MA) and pRIT5 (Pharmacia, Piscataway, NJ) which fuse glutathione S- transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.
  • GST glutathione S- transferase
  • a polypeptide of the present invention is to be expressed for use in screening assays, it maybe produced at the surface of the cell. In this event, the cells may be harvested prior to use in the screening assay. If the polypeptide is secreted into the medium, the medium can be recovered in order to recover and purify the polypeptide. If produced intracellularly, the cells must first be lysed before the polypeptide is recovered.
  • Polypeptides of the present invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxyapatite chromatography and lectin chromatography. Most preferably, high perfo ⁇ nance liquid chromatography is employed for purification. Well- known techniques for refolding proteins may be employed to regenerate active conformation when the polypeptide is denatured during intracellular synthesis, isolation, and/or purification.
  • TR4 Recombinant expression of TR4 or other nuclear receptor encoding polynucleotide listed in Table 1 is expressed in a suitable host cell using a suitable expression vector by standard genetic engineering teclmiques.
  • the TR4 is subcloned into the commercial expression vector, for example pcDNA3.1 (Invitrogen, San Diego, CA) and transfected into Chinese Hamster Ovary (CHO) cells using the transfection reagent FuGENE ⁇ (Boehringer-Mannheim) and the transfection protocol provided in the product insert.
  • Nuclear receptors stably expressing nuclear receptor are selected by growth in the presence of 100 ⁇ g/ml zeocin (Stratagene, LaJolla, CA).
  • nuclear receptors may be purified from the cells using standard chromatographic techniques.
  • antisera is raised against one or more synthetic peptide sequences that conespond to portions of the nuclear receptor amino acid sequence, and the antisera is used to affinity purify the nuclear receptor.
  • TR4 also may be expressed in-frame with a tag sequence (e.g., polyhistidine, hemagluttinin, FLAG) to facilitate purification.
  • tag sequence e.g., polyhistidine, hemagluttinin, FLAG
  • nuclear receptors in 293 cells For expression of nuclear receptor polypeptides in mammalian cells HEK293 (transformed human, primary embryonic kidney cells), a plasmid bearing the relevant nuclear receptor coding sequence is prepared (Table 1), using vector pcDNA3.1 (Invitrogen).
  • the forward primer for amplification of this nuclear receptor cDNA is determined by routine procedures and preferably contains a 5' extension of nucleotides to introduce the Hindlll cloning site and nucleotides matching the nuclear receptor sequence.
  • the reverse primer is also determined by routine procedures and preferably contains a 5' extension of nucleotides to introduce an Xbal restriction site for cloning and nucleotides conesponding to the reverse complement of the nuclear receptor sequence.
  • the PCR product is gel purified and cloned into the Hindlll-Xbal sites of the vector.
  • the expression vector containing the nuclear receptor gene is purified using Qiagen chromatography columns and transfected into 293 cells using DOTAPTm transfection media (Bochringer Mannheim, Indianapolis, IN). Transiently transfected cells are tested for expression after 24 hours of transfection, using western blots probed with anti-His and anti- nuclear receptor peptide antibodies. Permanently transfected cells are selected with Zeocin and propagated. Production of the recombinant protein is detected from both cells and media by western blots probed with anti-His, or anti- nuclear receptor peptide antibodies.
  • a polynucleotide molecule having a sequence selected from the group consisting of polynucleotide sequences listed in Table 1, can be cloned into vector p3-CI or similar expression vector.
  • This vector is a pUCl 8-derived plasmid that contains the HCMV (human cytomegalovirus) promoter-intron located upstream from the bGH (bovine growth hormone) polyadenylation sequence and a multiple cloning site.
  • the plasmid contains the DHRF (dihydrofolate reductase) gene which provides selection in the presence of the drug methofrexane (MTX) for selection of stable transformants.
  • the forward primer is determined by routine procedures and preferably contains a 5' extension which introduces an Xbal restriction site for cloning, followed by nucleotides which conespond to a sequence selected from the group consisting of sequences listed in Table 1.
  • the reverse primer is also determined by routine procedures and preferably contains 5' extension of nucleotides which introduces a restriction cloning site followed by nucleotides which conespond to the reverse complement of a sequence selected from the group consisting of sequences listed in Table 1.
  • the PCR reaction is perfonned as described in the manufactures instructions.
  • the PCR product is gel purified and ligated into the p3-Cl or similar expression vector.
  • This construct is transformed into E. coli cells for amplification and DNA purification.
  • the expression vector containing the nuclear receptor polynucleotide sequence is purified with Qiagen chromatography columns and transfected into COS 7 cells using LipofectamineTm reagent from BRL, following the manufacturer's protocols. Forty-eight and 72 hours after transfection, the media and the cells are tested for recombinant protein expression.
  • Nuclear receptor expressed from a COS cell culture can be purified by concentrating the cell- growth media to about 10 mg of protein/ml, and purifying the protein by chromatography.
  • a polynucleotide molecule having a sequence selected from the group consisting of sequences listed in Table 1 can be amplified by PCR.
  • the forward primer is determined by routine procedures and preferably contains a 5' extension which adds the Ndel cloning site, followed by nucleotides which conespond to a sequence selected from the group consisting of sequences listed in Table 1.
  • the reverse primer is also determined by routine procedures and preferably contains a 5' extension which introduces the Kpnl cloning site, followed by nucleotides which conespond to the reverse complement of a sequence selected from the group consisting of sequences listed in Table 1.
  • the PCR product is gel purified, digested with Ndel and Kpnl, and cloned into the conesponding sites of vector pACHTL-A (Pharmingen, San Diego, CA).
  • the pAcHTL-A expression vector contains the strong polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus (AcMNPV), and a 6xHis tag upstream from the multiple cloning site.
  • a protein kinase site for phosphorylation and a thrombin site for excision of the recombinant protein precede the multiple cloning site is also present.
  • baculovirus vectors could be used in place of pAcHTL-A, such as pAc373, pVL941 and pAcIML.
  • suitable vectors for the expression of nuclear receptor polypeptides can be used, provided that the vector construct includes appropriately located signals for transcription, translation, and trafficking, such as an in- frame AUG and a signal peptide, as required.
  • Such vectors are described in Luckow et al., Virology 170:31-39, among others.
  • the virus is grown and isolated using standard baculovirus expression methods, such as those described in Summers et al. (A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agricultural Experimental Station Bulletin No. 1555 (1987)).
  • pAcHLT-A containing a nuclear receptor gene is introduced into baculovirus using the "BaculoGoIdTm" transfection kit (Pharmingen, San Diego, CA) using methods established by the manufacturer.
  • Individual virus isolates are analyzed for protein production by radiolabeling infected cells with 35S-methionine at 24 hours post infection. Infected cells are harvested at 48 hours post infection, and the labeled proteins are visualized by SDS-PAGE. Viruses exhibiting high expression levels can be isolated and used for scaled up expression.
  • a polynucleotide molecule having a sequence selected from the group consisting of sequences listed in Table 1 can be amplified by PCR using the primers and methods described above for baculovirus expression.
  • the nuclear receptor cDNA is, cloned into vector pAcHLT-A (Pharmingen) for expression in Sf9 insect cells.
  • the insert is cloned into the Ndel and Kpnl sites, after elimination of an internal Ndel site (using the same primers described above for expression in baculovirus).
  • DNA is purified with Qiagen chromatography columns and expressed in Sf9 cells. Preliminary Western blot experiments from non- purified plaques are tested for the presence of the recombinant protein of the expected size which reacted with the nuclear receptor-specific antibody.
  • Nuclear Receptor Expression Profiles Related Diseases and Disorders Expression profiles for nuclear receptors of the present invention were determined with human or mice tissues using RT-PCR and/or tissue in situ hybridization methods. Our findings are summarized below.
  • RNA preparation RNA was extracted using the Totally RNA kit (Ambion) including LiCl precipitation and DNAse (Epicenter) treatment.
  • RNAse H Epicenter
  • RNAse A Ambion
  • Primers were designed using the Oligo 6.0 program (Mol. Bio. Insights). Their specificity was evaluated by BLAST searches of the human and mouse genomes. Gene specific amplicons were and confirmed by sequencing the bands obtained from RT-PCR. In situ Hybridization
  • Tissue dissection and sectioning 8-10 week old male 129Sl/SvIMJ mice (Jackson Laboratory) were sacrificed and their brains were dissected, snap frozen on dry ice, and stored at-70°C. Brains were sectioned at 10-14 ⁇ m onto microscope slides. Sections were collected in series so that each gene was sampled at 100 ⁇ m intervals through the hypothalamus and amygdala, and at 500 ⁇ m intervals through the remainder of the brain.
  • Riboprobe preparation T3 (sense) and T7 (antisense) promoters were attached to either side of the gene of interest and amplified by PCR, using primers with the conesponding gene and promoter sequences. Transcription reactions were performed using Ambion Maxiscript kits.
  • PCR generated templates (500ng) were added to 100 ⁇ Ci of dried down 33 P-UTP (Perkin Elmer) in lO ⁇ l reactions.
  • Hybridization Prehybridization and hybridization reactions were performed as previously described with modifications. Briefly, 33 P labeled riboprobes ( ⁇ 5xl0 cpm/slide) were applied to slides overnight at 55°C. Slides were then digested with RNAse and rinsed in SSC, with a final rinse in 0.1X SSC at 70°C for 30min. Slides were subsequently dipped in NTB-2 emulsion, and developed after 3 weeks. Analysis: Specific mRNA distributions were determined by examination of two complete brains for each gene, with light and darkfield microscopy.
  • nuclear receptor polypeptides and polynucleotides may be relevant for the treatment or diagnosis of various disease br disorders, particularly behavioral disorders.
  • polymo ⁇ hic, splice variant, mutagenzied, and recombinant forms of a nuclear receptor polypeptide may also be targets for treatment or diagnosis of diseases and disorders or for assaying for therapeutic compounds.
  • Nuclear receptors expressed in the hypothalamus are listed in Table 3. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the hypothalamus.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease involving the hypothalamus, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Amygdala Nuclear receptors expressed in the amygdala are listed in Table 4. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the amygdala. These polypeptides, or polymo ⁇ hs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Nuclear receptors expressed in the pituitary are listed in Table 5. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the pituitary.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Nuclear receptors expressed in the female brain are listed in Table 6, and nuclear receptors expressed in the male brain are listed in Table 7. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the female or male nervous system.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the nervous system, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the nervous system, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Cerebellum Nuclear receptors expressed in the cerebellum are listed in Table 9. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the cerebellum.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Cerebral cortex Nuclear receptors expressed in the regions of the cerebral cortex other than the frontal cortex are listed in Table 10. These receptors are thus potential targets for therapeutic compounds that may modulate nuclear receptor activity, expression, or stability in the cerebral cortex. These polypeptides, or polymo ⁇ hs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder involving the cerebral cortex, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Frontal cortex Nuclear receptors expressed in the frontal cortex are listed in Table 11. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the frontal cortex. These polypeptides, or polymo ⁇ hs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder involving the frontal cortex, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Hippocampus Nuclear receptors expressed in the hippocampus are listed in Table 12. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the hippocampus.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the hippocampus, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Thalamus Nuclear receptors expressed in the thalamus are listed in Table 14. . These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the thalamus.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the thalamus, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders of the nervous system include abetalipoproteinemia, abnormal social behaviors, absence (petit mal) epilepsy, absence seizures, abulia, acalculia, acidophilic adenoma, acoustic neuroma, acquired aphasia, acquired aphasia with epilepsy (Landau-Kleffher syndrome) specific reading disorder, acquired epileptic aphasia, acromegalic neuropathy, acromegaly, action myoclonus-renal insufficiency syndrome, acute autonomic neuropathy, acute cerebellar ataxia in children, acute depression, acute disseminated encephalomyelitis, acute idiopathic sensory neuronopathy, acute intermittent po ⁇ hyria, acute mania, acute mixed episode, acute pandysautonomia, acute polymo ⁇ hic disorder with symptoms of schizophrenia, acute polymo ⁇ hic psychotic disorder without symptoms of schizophrenia, acute purulent meningitis, addiction, Add
  • Raymond-Cestan-Chenais syndrome receptive language disorder, recovered memories, recunent bipolar episodes, recunent brief depression, recunent hypersomnia, recunent major depression, refsum disease, reiterative speech disturbances, relational problems, rem sleep behavior disorder, rem sleep behavioral disorder, repetitive self-mutilation, repressed memories, respiratory dysrhythmia, restless legs syndrome, Rett's syndrome, Reye syndrome, rhythmic movement disorders, rocky mountain spotted fever, rostral basal pontine syndrome, rubella, Rubinstein-Taybi syndrome, sadistic personality disorder, salla disease, Sandhoff disease, Sanfilippo syndrome, sarcoid neuropathy, sarcoidosis, scapuloperoneal syndromes, schistosomiasis (bilharziasis), schizencephaly, schizoaffective disorder, schizoid personality disorder, schizophrenia, schizophrenia and other psychotic disorders, schizophrenia-like psychosis, schizophren
  • the intensity of a particular drive or emotion is highly variable from one person to another. There is also variation in the extent to which different individuals experience particular drives and emotions. For instance, one person may experience hunger more frequently than another, or feel more anxious or stressed. - There also are differences in how one responds to drives and emotions. For example, anxiety in a stressful circumstance might motivate a person to gain control of the matter, while in another, the same feelings might cause a behavior directed at avoiding the situation altogether;
  • Basic drives and emotions are components of everyday life, and are important to one's physical and psychological well-being. Abnormalities in any of them may profoundly affect an individual's ability to think, feel and act. Behavioral problems are also very common. More individuals are afflicted every year by these conditions than by cancer and heart diseases combined.
  • Eating disorders such as anorexia nervosa and bulimia nervosa affect over a million Americans. These disorders are characterized by a constant preoccupation with food and a fear of fatness. Cunent treatments for anorexia nervosa include hospitalization, high caloric diet, and psychological counseling. In the case of bulimia nervosa, psychiatric treatment and antidepressant medications are being prescribed. The success rate in both cases is low.
  • insomnia is the continued inability to fall asleep or stay asleep. Almost everyone occasionally suffers from short-term insomnia. However, for people who suffer chronically from the insomnia, the disease can severely disrupt their ability to function. Narcolepsy, on the other hand, is the sudden, inesistible daytime episodes of sleepiness. People with narcolepsy have frequent "sleep attacks" at various times of the day, even if they have had a normal amount of night-time sleep.
  • Benzodiazepine products are benzodiazepine products (sleeping pills).
  • Benzodiazepines although somewhat effective' for short-term insomnia, are not indicated for mild or severe insomnia, as they have several side effects and can cause physical dependence.
  • Stimulants like amphetamines, can help reduce the symptoms, but do not alleviate them entirely.
  • Sexual Disorders Tens of millions of men have some form of erectile dysfunction (impotence) — mild, moderate, severe, acute, or chronic. An even larger number of women are estimated to suffer from sexual arousal (inability to attain or maintain sexual excitement) and orgasmic (lack of orgasm during sex) disorders. Several million American men and women have symptoms of compulsive sexual disorder (sex addiction). Sexual disorders can be caused by either physical or psychological factors.
  • VIAGRATM a malignant neoplasm originating from libido.
  • VIAGRATM a malignant neoplasm originating from libido.
  • VIAGRATM a malignant neoplasm originating from libido.
  • VIAGRATM a malignant neoplasm originating from libido.
  • Anxiety Disorders Personal anxieties and fears are part of everyday life. For millions of individuals, however, anxieties and fears are overwhelming and persistent, often drastically interfering with daily life. These people suffer from anxiety disorders, a widespread group of illnesses that can bethreatening and crippling. These conditions include panic disorder, phobias, obsessive-compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder.
  • Cunent pharmacologic treatments for anxiety include tranquilizers or anxiolytic drug (e.g., valium, and tranxene) and antidepressants. While these medications can be effective at relieving anxiety symptoms, they also cany undesirable side effects such as sedation, fatigue, weight gain, sexual difficulties, and withdrawal reactions.
  • Depression is the most commonly diagnosed emotional problem. Each year, millions of people will suffer from a depressive illness, such as major depression, or bipolar disorder. As many as one in five Americans will have at least one episode of depression during their lifetime. Many of them will be incapacitated for weeks or months.
  • Memory loss is the prevailing symptom of mild cognitive impairment. Dementia is a more severe condition. People with dementia suffer from short-term memory loss, inability to think through or complete complex tasks without step-by-step instructions, confusion, difficulty concentrating, and paranoid, inappropriate, or bizane behavior. Cunently, there are no medications available to treat or prevent memory impairments.
  • ADHD attention-deficit hyperactivity disorder
  • the disease has its onset in childhood and is characterized by lack of attention, impulsiveness, and hyperactivity. ADHD often continues into adolescence and adulthood. The disease has long-term adverse affects on success at school, work, and in social relationships. Stimulants are used to treat the symptoms of ADHD. Children with the disorder seldom outgrow it, and long-term therapy is not advised.
  • Adrenal gland Nuclear receptors expressed in the adrenal gland are listed in Table 15. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of a nuclear receptor in the adrenal gland.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the adrenal gland, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders of the adrenal gland include 11-hydroxylase deficiency, 17-hydroxylase deficiency, 3 ⁇ -dehydrogenase deficiency, acquired immune deficiency syndrome, ACTH-dependent adrenal hyperfunction (Gushing disease), ACTH-independent adrenal hyperfunction, acute adrenal insufficiency, adrenal abscess, adrenal adenoma, adrenal calcification, adrenal cysts, adrenal cytomegaly, adrenal dysfunction in glycerol kinase deficiency, adrenal hematoma, adrenal hemonhage, adrenal histoplasmosis, adrenal hyperfunction, adrenal hype ⁇ lasia, adrenal medullary hype ⁇ lasia, adrenal myelolipoma, adrenal tuberculosis, adrenocortical adenoma, adrenocortical adenoma with primary hyperaldosteronism (Conn's syndrome), adrenocortical carcinoma, adrenocortical carcinoma with Cushing's syndrome, ad
  • Nuclear receptors expressed in the colon are listed in Table 16. These receptors are thus potential targets for therapeutic compounds that may modulate the . activity, expression, or stability of these nuclear receptors in the colon. These polypeptides, or polymo ⁇ hs of these polypeptides, may form the basis of therapeutic regimen or a diagnostic test to determine, e.g., the presence of disease or disorder involving the colon, the risk of developing a particular disease or disorder, or an appropriate therapeutic course. Table 16. Nuclear Receptors Expressed in the Colon
  • Exemplary diseases and disorders involving the colon include acute self-limited infectious colitis, adenocarcinoma, adenoma, adenoma-carcinoma sequence, adenomatous polyposis coli, adenosquamous carcinomas, allergic (eosinophilic) proctitis and colitis, amebiasis, amyloidosis, angiodysplasia, anorectal malformations, blue rubber bleb nevus syndrome, brown bowel syndrome, Campylobacter fetus infection, carcinoid tumors, carcinoma of the anal canal, carcinoma of the colon and rectum, chlamidial proctitis, Crohn's disease, clear cell carcinomas, Clostridium difficile pseudomembranous enterocolitis, collagenous colitis, colonic adenoma, colonic diverticulosis, colonic inertia, colonic ischemia, congenital atresia, congenital megacolon (Hir
  • Nuclear receptors expressed in the heart are listed in Table 17. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of any of these nuclear receptors in the heart.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may also form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular cardiovascular disease or disorder, or an appropriate therapeutic course.
  • Cardiovascular diseases and disorders include, for example, acute coronary syndrome, acute idiopathic pericarditis, acute rheumatic fever, American trypanosomiasis (Chagas' disease), angina pectoris, ankylosing spondyhtis, anomalous pulmonary venous connection, anomalous pulmonary venous drainage, aortic atresia, aortic regurgitation, aortic stenosis, aortic valve insufficiency, aortopulmonary septal defect, asymmetric septal hypertrophy, asystole, atrial fibrillation, atrial flutter, atrial septal defect, atrioventricular septal defect, autoimmune myocarditis, bacterial endocarditis, calcific aortic stenosis, calcification of the cental valve, calcification of the valve ring, carcinoid heart disease, cardiac amyloidosis, cardiac anhythmia, cardiac failure, cardiac myxo
  • Nuclear receptors expressed in the intestine are listed in Table 18. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the intestine.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease or disorder involving the intestine, the risk of developing a particular disease or disorder involving the intestine, or an appropriate therapeutic course.
  • Diseases and disorders involving the intestine include abdominal hernia, abetalipoproteinemia, abnormal rotation, acute hypotensive hypoperfusion, acute intestinal ischemia, acute small intestinal infarction, adenocarcinoma, adenoma, adhesions, amebiasis, anemia, arterial occlusion, atypical mycobacteriosis, bacterial dianhea, bacterial overgrowild typeh syndromes, botulism, Campylobacter fetus infection, Campylobacter jejuni infection, carbohydrate abso ⁇ tion defects, carcinoid tumors, celiac disease (nontropical sprue, gluten-induced enteropathy), cholera,
  • Kidney Nuclear receptors expressed in the kidney are listed in Table 19. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the kidney.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular kidney disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders of the kidney include acquired cystic disease, acute (postinfectious) glomerulonephritis, acute infectious interstitial nephritis, acute interstitial nephritis, acute pyelonephritis, acute renal failure, acute transplant failure, acute tubular necrosis, adult polycystic kidney disease, AL amyloid, analgesic nephropathy, anti-glomerular basement membrane disease (Goodpasture's Syndrome), asymptomatic hematuria, asymptomatic proteinuria, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bence Jones cast nephropathy, benign familial hematuria, benign nephrosclerosis and atheromatous embolization, bilateral cortical necrosis, chronic glomeralonephritis, chronic interstitial nephritis, chronic pyelonephritis, chronic renal failure, chronic transplant failure, circulating
  • Nuclear receptors expressed in the liver are listed in Table 20. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the liver.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular liver disease or disorder, or an appropriate therapeutic course.
  • liver diseases and disorders include acute alcoholic hepatitis (acute sclerosing hyaline necrosis of the liver), acute graft-versus-host disease, acute hepatitis, acute hepatocellular injury associated with infectious diseases other than viral hepatitis., acute liver failure, acute viral hepatitis, adenovirus hepatitis, Alagille syndrome, alcoholic cinhosis, alcoholic hepatitis, alcoholic liver disease, alphal-antitrypsin deficiency, amebic abscess, angiolmyolipoma, angiosarcoma, ascending cholangitis, autoimmune chronic active hepatitis (lupoid hepatitis), bile duct adenoma, bile duct cystadenocarcinoma, bile duct cystadenoma, biliary atresia, biliary cinhosis, biliary papillomatosis,
  • Nuclear receptors expressed in the lung are listed in Table 21. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptorin the lung.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a lung disease or disorder, the risk of developing such a disease or disorder, or an appropriate therapeutic course.
  • Exemplary lung diseases and disorders include abnormal diffusion, abnormal perfusion, abnormal ventilation, accelerated silicosis, actinomycosis, acute air space pneumonia (acute bacterial pneumonia), acute bronchiolitis, acute congestion, acute infections of the lung, acute interstitial pneumonia, acute necrotizing viral pneumonia, acute organic dust toxic syndrome, acute pneumonia, acute radiation pneumonitis, acute rheumatic fever, acute silicosis, acute tracheobronchitis, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adenovirus, adult respiratory distress syndrome (shock lung), agenesis, AIDS, air embolism, allergic bronchopulmonary mycosis, allergic granulomatosis and angiitis (Churg-Strauss), allograft rejection, aluminum pneumoconiosis, alveolar microlithiasis, alveolar proteinosis, amebic lung abscess, am
  • Nuclear receptors expressed in the muscle are listed in Table 22. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the muscle.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a muscular disease or disorder, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders involving the muscles include abnormalities of ion channel closure, acetylcholine receptor deficiency, acetylcholinesterase deficiency, acid maltase deficiencies (type 2 glycogenosis), acquired myopathies, acquired myotonia, adult myotonic dystrophy, alveolar rhabdomyosarcoma, aminoglycoside drugs, amyloidosis, amyotrophic lateral sclerosis, antimyelin antibodies, bacteremic myositis, Batten's disease (neuronal ceroid lipofuscinoses), Becker's muscular dystrophy, benign neoplasms, Bomholm disease, botulism, branching enzyme deficiency (type 4 glycogenosis), carbohydrate storage diseases, carnitine deficiencies, carnitine palmitoyltransferase deficiency, central core disease, centronuclear (myotubular) myopathy, Chagas' disease, cho
  • Nuclear receptors expressed in the ovary are listed in Table 23. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the ovary. These polypeptides, or polymo ⁇ hs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular ovarian disease or disorder, or an appropriate therapeutic course. Table 23. Nuclear Receptors Expressed in the Ovary
  • Exemplary ovarian diseases and disorders include autoimmune oophoritis, brenner tumors, choriocarcinoma, clear cell adenocarcinoma, clear cell carcinoma, co ⁇ us luteal cysts, decidual reaction, dysgerminoma, embryonal carcinoma, endometrioid tumors, endometriosis, endometriotic cysts, epithelial inclusion cysts, fibrothecoma, follicular cysts, gonadoblastoma, granulosa-stroma cell tumors, granulosa-theca cell tumor, gynandroblastoma, hilum cell hype ⁇ lasia, luteal cysts, luteal hematomas, luteoma of pregnancy, massive ovarian edema, metastatic neoplasm, mixed germ cell tumors, monodermal tumors, mucinous tumors, neoplastic cysts, ovarian changes secondary to cytotoxic drugs and radiation, ovarian fibro
  • Peripheral Blood Lymphocytes Nuclear receptors expressed in the lymphocytes are listed in Table 24. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in lymphocytes. These polypeptides, or polymo ⁇ hs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder, the risk of developing a particular disease or disorder, or an appropriate therapeutic course. Table 24. Nuclear Receptors Expressed in Peripheral Blood Lymphocytes
  • Exemplary blood diseases and disorders include abnormal hemoglobins, abnormalities in granulocyte count, abnormalities in lymphocyte count, abnormalities in monocyte count, abnormalities of blood platelets, abnormalitites of platelet function, acanthocytosis, acquired neutropenia, acute granulocytic leukemia, acute idiopathic thrombocytopenic pu ⁇ ura, acute infections, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloblastic leukemia, acute myelocytic leukemia, acute myeloid leukemia, acute pyogenic bacterial infections, acute red cell aplasia, acute response to endotoxin, adult T-cell leukemial/lymphoma, afibrinogenemia, alpha thalassemia, altered affinity of hemoglobin for oxygen, amyloidosis, anemia, anemia due to acute blood loss, anemia due to chronic blood loss, anemia of chronic disease, anemia of chronic renal failure, anemias associated with
  • coli early preleukemic myeloid leukemia, eosinophilia, eosinophilic granuloma, erythrocute enzyme deficiency, erythrocyte membrane defects, essential thrombocythemia, factor 7 deficiency, familial cyclic neutropenia, Felty's syndrome, fibrinolytic activity, folate antagonists, folic acid deficiency, Gaucher disease, Glanzmann's thrombasthenia, glucose-6-phosphate dehydrogenase deficiency, granulated T-cell lymphocyte leukemia, granulocytic sarcoma, granulocytosis, Hageman trait, hairy cell leukemia (leukemic reticuloendotheliosis), Hand-Sch ⁇ ller-Christian disease, heavy-chain disease, hemoglobin C disease, hemoglobin constant spring, hemoglobin S, hemoglobinopathies, hemolysis caused by infectious agents, hemolytic anemia,
  • Nuclear receptors expressed in the prostate are listed in Table 25. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the prostate. These polypeptides, or polymo ⁇ hs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder involving the prostate, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders involving the prostate include acute bacterial prostatitis, acute prostatitis, adenoid basal cell tumor (adenoid cystic-like tumor), allergic (eosinophilic) granulomatous prostatitis, atrophy, atypical adenomatous hype ⁇ lasia, atypical basal cell hype ⁇ lasia, basal cell adenoma, basal cell hype ⁇ lasia, BCG-induced granulomatous prostatitis, benign prostatic hype ⁇ lasia, benign prostatic hypertrophy, blue nevus, carcinosarcoma, chronic abacterial prostatitis, chronic bacterial prostatitis, cribriform hype ⁇ lasia, ductal (endometrioid) adenocarcinoma, granulomatous prostatitis, hematuria, iatrogenic granulomatous prostatitis, idiopathic (nonspecific) granulous prostatitis, impotence, infectious granulomatous
  • Nuclear receptors expressed in the skin are listed in Table 26. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the skin.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of skin disease or disorder, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary skin diseases and disorders include acanthosis nigricans, acne vulgaris, acquired epidermolysis bullosa, acrochordons, acrodermatitis enteropathica, acropustulosis, actinic keratosis, acute cutaneous lupus erythematosus, age spots, allergic dermatitis, alopecia areata, angioedema, angiokeratoma, angioma, anthrax, apocrine tumors, arthropid-bite reactions, atopic dermatitis, atypical fibroxanthoma, Bart's syndrome, basal cell carcinoma (basal cell epithelioma), Bateman's pu ⁇ ura, benign familial pemphigus (Hailey-Hailey disease), benign keratoses, Berloque dermatitis, blue nevus, borderline leprosy, Bonelia infection (lyme disease), Bowen's disease (carcinoma in situ),
  • Nuclear receptors expressed in the spleen are listed in Table 27. These receptors are thus potential targets for- therapeutic compounds that may modulate their activity, expression, or stability in the spleen.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the spleen, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders of the spleen include abnormal immunoblastic proliferations of unknown origin, acute infections, acute parasitemias, agnogenic myeloid metaplasia, amyloidosis, angioimmunoblastic lymphadenopathy, antibody- coated cells, asplenia, autoimmune diseases, autoimmune hemolytic anemias, B-cell chronic lymphocytic leukemia and prolymphocytic leukemia, babesiosis, bone manow involvement by carcinoma, brucellosis, carcinoma, ceroid histiocytosis, chronic alcoholism, chronic granulomatous disease, chronic hemolytic anemias, chronic hemolytic disorders, chronic immunologic inflammatory disorders, chronic infections, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic parasitemias, chronic uremia, cinhosis, cold agglutinin disease, congestive splenomegaly, cryoglobulinemia, disseminated tuberculosis, dysproteinemia
  • These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability in the stomach.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis ' of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the stomach, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders of the stomach include acute erosive gastropathy, acute gastric ulcers, adenocarcinomas, adenomas, adenomatous polyps, advanced gastric cancer, ampullary carcinoma, atrophic gastritis, bacterial gastritis, carcinoid tumors, carcinoma of the stomach, chemical gastritis, chronic (nonerosive) gastritis, chronic idiopathic gastritis, chronic nonatrophic gastritis, Cronkite-Canada syndrome, congenital cysts, congenital diaphragmatic hernias, congenital diverticula, congenital duplications, congenital pyloric stenosis, congestive gastropathy, cyclic vomiting syndrome, decreased mucosal resistance to acid, diffuse or infiltrating adenocarcinoma, early gastric cancer, emphysematous gastritis, endocrine cell hype ⁇ lasia, environmental gastritis, eo
  • pylori infection hamartomatous polyps, heterotopias, heterotopic pancreatic tissue, heterotopic polyps, hype ⁇ lastic gastropathy, hype ⁇ lastic polyps, hypersecretion of acid, infectious gastritis, inflammatory lesions of the stomach, inflammatory polyps, intestinal metaplasia, invasive carcinoma, ischemia, leiomyoma, linitis plastica, luminally acting toxic chemicals, lymphocytic gastritis, lymphomas, malignant gastric stromal neoplasms, malignant lymphoma, malignant transformation of a benign gastric ulcer, Menentrier's disease (hypertrophic gastritis, ragal hypertrophy), mesenchymal neoplasms, metastatic tumors, mucosal polyps, myoepithelial adenomas, myoepithelial hamartomas, neoplasms, neuroendocrine hype ⁇ lasias, neuroendocrine tumors, nonerosive
  • Nuclear receptors expressed in the testes are listed in Table 29. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability of the nuclear receptor in the testes.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder involving the testes, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders involving the testes include abenant ducts of Haller, abnormal productions of hormones, abnormalities of testicular descent, acute epididymoorhcitis, adenomatoid tumor, adenomatous hype ⁇ lasia of the rete testis, adenovirus, administration of estrogens, adrenal rests, alcoholic cinhosis, amyloidosis, anorchism, appendix testes, bacterial infections, Bracella, cachexia, carcinoma in situ, carcinoma of the rete testis, chlamydia, choriocarcinoma, choristomas, chronic fibrosing epididymoorchitis, coxsackie virus B, cryptorchidism, cystic dysplasia of the rete testis, cytomegalovirus, dystopia, E.
  • Thymus Nuclear receptors expressed in the thymus are listed in Table 30. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the thymus.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the thymus, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders of the thymus include accidental involution, acute accidental involution, acute lymphoblastic leukemia of T cell type, agenesis, age- related involution, anaplastic carcinoma, ataxia telangiectasia, atrophy, bacterial infections, bacterial mediastinitis, basaloid carcinoma, bone manow transplantation, Braton's agammaglobulinemia, carcinosarcoma, chronic accidental involution, clear cell carcinoma, cortical thymoma, cytomegalovirus, DiGeorge syndrome, dysgenesis, dysplasia with pattern similar to severe atrophy, dysplasia with pseudoglandular appearance, dysplasia with stromal conticomedullary differentiation, ectopia, germ cell tumors, Grave's disease, histiocytosis X, HIV, Hodgkin's disease, hype ⁇ lasia, infectious mononucleosis, involution, lymphoblastic lymphoma of T-cell type, lymphoepitheli
  • Thyroid Nuclear receptors expressed in the thyroid are listed in Table 31. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the thyroid. These polypeptides, or polymo ⁇ hs of these polypeptides, may form the basis of a therape ⁇ tic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the thyroid, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders of the thyroid include abenant thyroid glands, accessory thyroid glands, adenoma with bizane nuclei, agenesis, amphicrine variant of medullary carcinoma, anaplastic (undifferentiated) carcinoma, aplasia, atrophic thyroiditis, atypical adenoma, autoimmune thyroiditis, carcinoma, C-cell hype ⁇ lasia, clear cell tumors, clear cell, variant of medullary carcinoma, colloid adenoma, columnar variant of papillary carcinoma, congenital hypothyroidism (cretinism), diffuse nontoxic goiter, diffuse sclerosing variant of papillary carcinoma, dyshormonogenic goiter, embryonal adenoma, encapsulated variant of papillary carcinoma, endemic cretinism, endemic goiter, enzyme deficiency, fetal adenoma, follicular adenoma, follicular carcinoma, follicular variant of medullary carcinoma,
  • Nuclear receptors expressed in the uteras are listed in Table 32. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the uteras.
  • These polypeptides, or polymo ⁇ hs of these polypeptides may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the uteras, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
  • Exemplary diseases and disorders of the uteras include acute cervicitis, acute endometritis, adenocanthoma, adenocarcinoma, adenocarcinoma in situ, adenoid cystic carcinoma, adenomatoid tumor, adenomyoma, adenomyosis (endometriosis intema), adenosquamous carcinoma, amebiasis, arias-Stella phenomenon, atrophy of the endometrium, atypical hype ⁇ lasia, benign polypoid lesions, benign stromal nodule, carcinoid tumors, carcinoma in situ, cervical intraepithelial neoplasia, chlamydia, chronic cervicitis, chronic nonspecific endometritis, ciliated (tubal) metaplasia, clear cell adenocarcinoma, clear cell carcinoma, clear cell metaplasia, complex hype ⁇ lasia with atypia, complex
  • Nuclear receptors listed in Table 1 may also be expressed in the pancreas, bone and joints, breasts, immune system, or systemically. These nuclear receptors may thus be involved in metabolic diseases or disorders and diseases or disorders of the pancreas, bone and joints, breast, or immune system. Any nuclear receptors involved in these diseases are targets for diagnostic tests, drag design, and therapy.
  • Exemplary diseases and disorders of the pancreas include ACTHoma, acute pancreatitis, adult onset diabetes, annulare pancreas, carcinoid syndrome, carcinoid tumors, carcinoma of the pancreas, chronic pancreatitis, congenital cysts, Cushing's syndrome, cystadenocarcinoma, cystic fibrosis (mucoviscidosis, fibrocystic disease), diabetes mellitus, ectopic pancreatic tissue, gastinoma, gastrin excess, glucagon excess, glucagonomas, GRFomas, hereditary pancreatitis, hyperinsulinism, impaired insulin release, infected pancreatic necrosis, insulin resistance, insulinomas, islet cell hype ⁇ lasia, islet cell neoplasms, juvenile onset diabetes, macroamylasemia, maldevelopment of the pancreas, maturity-onset diabetes of the young, metastatic neoplasms, mucinous cystadenoma,
  • Exemplary diseases and disorders of the bone and joints include achondroplasia, acute bacterial arthritis, acute pyogenic osteomyelitis, Albright's syndrome, alkaptonuria (ochronosis), aneurysmal bone cyst, ankylosing spondyhtis, arthritic, arthropathies associated with hemoglobinopathies, arthropathy of acromegaly, arthropathy of hemochromatosis, bone cysts, calcium hydroxyapatite deposition disease, calcium pyrophosphate deposition disease, chondrocalcinosis, chondroma, chondrosarcoma, chostochondritis, chrondromblastoma, congenital dislocation of the hip, congenital disorders of joints, echondromatosis (dyschondroplasia, Ollier's disease), erosive osteoarthritis, Ewing's sarcoma, Felty's syndrome, fibromyalgia, fibrous cortical defect
  • Exemplary diseases and disorders of the immune system include abnormal neutrophil function, acquired immunodeficiency, acute rejection, Addison's disease, ' advanced cancer, aging, allergic rhinitis, angioedema, arthras-type hypersensitivity reaction, ataxia-telangiectasia, autoimmune disorders, autoimmune gastritis, autosomal recessive agammaglobulinemia, blood transfusion reactions, Bloom's syndrome, Braton's congenital agammaglobulinemia, bullous pemphigoid, Chediak-Higashi syndrome, chronic active hepatitis, chronic granulomatous disease of childhood, chronic rejection, chronic renal failure, common variable immunodeficiency, complement deficiency, congenital (primary) immunodeficiency, contact dermatitis, deficiencies of immune response, deficiency of the vascular response, dermatomyositis, diabetes mellitus, disorders of microbial killing, disorders of phagocytosis, Goodpasture
  • Exemplary diseases and disorders of the breasts include acute mastitis, breast abcess, carcinoma, chronic mastitis, congenital breast anomalies, cystic mastopathy, ductal carcinoma, ductal carcinoma in situ, ductal papiUoma, fat necrosis, fibroadenoma, fibrocystic changes, fibrocystic disease, galactonhea, granular cell tumor, gynecomastia, infiltrating ductal carcinoma, inflammatory breast carcinoma, inflammatory breast lesions, invasive lobular carcinoma, juvenile hypertrophy of the breast, lactating adenoma, lobular carcinoma in situ, neoplasms, Paget's disease of the nipple, phyllodes tumor (cystosarcome phyllodes), polymastia, polymazia, polythelia, silicone granuloma, supernumerary breast, and supernumerary nipples.
  • Exemplary metabolic or nutritive diseases or disorders include 5,10- methylenetetrahydrofolate reductase deficiency, achondrogenesis type IB, acid ⁇ -1,4 glucosidase deficiency, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Banaquer-Simons syndrome), acute intermittent po ⁇ hyria, acute panniculitis, adenine phosphoribosyltransferase deficiency, adenosine deaminase deficiency, adenylosuccinate lyase deficiency, adiposis dolorosa (Dercum disease), ALA dehydratase-deficient po ⁇ hyria, albinism, alkaptonuria, amulopectinosis, Andersen disease, argininemia, argininosuccinic aciduria, astelosteogenesis type 2, Bart
  • a large number of nuclear receptors are found in the nervous system. Over 89% of known nuclear receptors are active in the nervous system. Of particular importance is that up to 79% of the known nuclear receptors in the nervous system are active in the HAP (Hypothalamus, Amygdala and Pituitary). We hypothesize that the majority of these receptors serve as modulators of behavior, memory, cognition, pain and instinctive functions.
  • Nuclear receptors are ideal targets for drug development. They are located in the cytoplasm of cells, where they can be accessed by pharmaceutical compounds. There are significant numbers and varieties of nuclear receptors to provide for a high degree of specificity, a key requirement, in the discovery of medicines with few or limited side effects. Given these properties, nuclear receptors, as a group, have emerged among the most wished targets for drug development. The preference for nuclear receptors as specific drug targets derives, not only from their central role in biological processes, but also from the discriminating ability that these molecules have in recognizing and responding to their signals. Many nuclear receptors exist in several similar, but subtly distinct subtypes, which are found in different cells in the body. Such variety of sequence and location provides a high degree of selectivity, allowing the discovery of drags which specifically affect one subtype of receptor, but not another. This selectivity substantially reduces the risk of unwanted side effects.
  • Nuclear receptor polypeptides of the present invention have one or more biological functions that may be of relevance in one or more behavioral disorders, in particular the disorders of the invention hereinbefore mentioned.
  • the nuclear receptor polypeptides maybe expressed in other organs and tissues of the body, they may be of relevance to diseases and disorders that involve those organs and tissues. It is therefore useful to identify compounds that modulate nuclear receptor biological activity, expression level, or stability.
  • the present invention provides methods of screening candidate compounds to identify those that modulate nuclear receptor biological activity, expression level, or stability. Such methods identify potential modulators, e.g., agonists or antagonists that may be employed for therapeutic and prophylactic pu ⁇ oses for treating various disorders, e.g., behavioral disorders.
  • Compounds may be identified from a variety of sources, for example, cells, cell-free preparations, chemical libraries, collections of chemical compounds, and natural product mixtures. Modulators so identified may be natural or modified ligands, or small molecules. Such small molecules preferably have a molecular weight below 2,000 daltons, more preferably between 300 and 1,000 daltons, and most preferably between 400 and 700 daltons. It is prefened that these small molecules be organic molecules.
  • the screening method may simply measure the interaction of a candidate compound to the polypeptide, or to cells or membranes bearing the polypeptide, or a fusion protein thereof, by means of a label directly or indirectly associated with the candidate compound, or, alternatively, the polypeptide.
  • the screening method may involve measuring or detecting (qualitatively or quantitatively) the competitive interaction of a candidate compound to the polypeptide against a labeled competitor (e.g., agonist or antagonist). Further, these screening methods may test whether the candidate compound results in a signal generated by activation or inhibition of nuclear receptor polypeptide, using detection systems appropriate to the cells bearing the polypeptide. Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist by the presence of the candidate compound is observed.
  • a labeled competitor e.g., agonist or antagonist
  • the screening methods may include the steps of mixing a candidate compound with a solution containing a nuclear receptor polypeptide of the present invention, to form a mixture, measuring nuclear receptor biological activity in the mixture, and comparing the nuclear receptor activity of the mixture to a control mixture that contains no candidate compound.
  • Polypeptides of the present invention may be employed in conventional low capacity screening methods and also in high-tliroughput screening (HTS) formats.
  • HTS formats include not only the well-established use of 96- and, more recently, 384- well and 1536-well micotiter plates, but also emerging methods such as the nanowell method described by Schullek et al, Anal Biochem., 246, 20-29, (1997).
  • Fusion proteins and tagged recombinant proteins can also be used for high-throughput screening (HTS) assays to identify modulators of the nuclear receptor polypeptides of the present invention (see, e.g., Bennett et al., J Mol Recognition, 8:52-58 (1995); and Johanson et al., J Biol Chem, 270:9459-9471 (1995)).
  • HTS high-throughput screening
  • a nuclear receptor of the invention and its gene or cDNA can be used in screening assays for identification of compounds that modulate its activity and which may therefore be potential drugs.
  • Useful proteins include wild-type and polymo ⁇ hic nuclear receptors or fragments thereof (e.g., ligand binding domain, dimerization domain or DNA binding domain), in a recombinant form or endogenously expressed.
  • Drug screens to identify compounds acting on a normally occurring or an exogenously expressed nuclear receptor may employ any functional feature of the protein. In one example, transcriptional activation or repression is monitored as a measure of nuclear receptor biological activity. .
  • Drag screening assays can also be based upon the ability of a nuclear receptor to interact with other proteins or to dimerize.
  • interacting proteins can be identified by a variety of methods known in the art, including, for example, radioimmunoprecipitation, co-immunoprecipitation, co-purification, and yeast two- hybrid screening. Such interactions can be further assayed by means including but not limited to fluorescence polarization or scintillation proximity methods.
  • Drug screens can also be based upon putative functions of a nuclear receptor polypeptide deduced from structure determination (e.g., by x-ray crystallography) of the protein and comparison of its 3-D structure to that of proteins with known functions.
  • Drag screens can be based upon a function or feature apparent upon creation of a transgenic or knock-out mouse, or upon overexpression of the protein or protein fragment in mammalian cells in vitro.
  • expression of a mammalian (e.g., human) nuclear receptor in yeast or C. elegans allows for screening of candidate compounds in wild-type and polymo ⁇ hic backgrounds, as well as screens for polymo ⁇ bisms that enhance or suppress a nuclear receptor-dependent phenotype.
  • Modifier screens can also be performed in a nuclear receptor transgenic or knock-out mouse.
  • drug screening assays can be based upon nuclear receptor functions deduced upon antisense nucleic acid inl ibition or RNA interference (RNAi) with the nuclear receptor's gene function.
  • RNAi RNA interference
  • Intracellular localization of a nuclear receptor, or effects which occur upon a change in intracellular localization of the protein, can also be used as an assay for drug screening.
  • Immunocytochemical methods can be used to determine the exact location of a nuclear receptor protein.
  • Human and rodent nuclear receptors or peptides derived from nuclear receptors can be used as antigens to raise antibodies, including monoclonal antibodies. Such antibodies will be useful for a wide variety of pu ⁇ oses, including but not limited to functional studies and the development of drag screening assays and diagnostics. Monitoring the influence of agents (e.g., drags, compounds) on the expression or biological activity of a nuclear receptor can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase gene expression, protein levels, or biological activity of a nuclear receptor can be monitored in clinical trials of subjects exhibiting altered gene expression, protein levels, or biological activity of that nuclear receptor.
  • agents e.g., drags, compounds
  • the effectiveness of an agent determined by a screening assay to modulate the gene expression, protein levels, or biological activity of a nuclear receptor can be monitored in clinical trials of subjects exhibiting decreased altered gene expression, protein levels, or biological activity.
  • the expression or activity of a nuclear receptor and, preferably, other genes that have been implicated in one or more diseases or disorders can be used to ascertain the effectiveness of a particular drug.
  • genes that are modulated in cells by treatment with an agent e.g., compound, drag, or small molecule
  • an agent e.g., compound, drag, or small molecule
  • a nuclear receptor polypeptide e.g., identified in a screening assay as described herein
  • cells can be isolated and RNA prepared and analyzed for the levels of expression of a nuclear receptor and other genes implicated in the disorder.
  • the levels of gene expression can be quantified by northern blot analysis or RT-PCR, followed by real time PCR, or, alternatively, by measuring the amount of protein produced, by one of a number of methods known in the art, or by measuring the levels of biological activity of a nuclear receptor or other genes.
  • the expression of a nuclear receptor polypeptide can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent. For in vivo studies MRI, pet scans etc may be better assays.
  • the present invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drag candidate identified by the screening assays described herein) including the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a nuclear receptor polypeptide, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of a nuclear receptor polypeptide, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of a nuclear receptor polypeptide, mRNA, or genomic DNA in the pre-administration sample with the polypeptide, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly.
  • an agent
  • a nuclear receptor polynucleotide can be used as a tool to express the nuclear receptor polypeptide in an appropriate cell in vitro or in vivo (gene therapy), or can be cloned into expression vectors that can be used to produce large enough amounts of a nuclear receptor polypeptide for use in in vitro assays for drag screening.
  • Expression systems that may be employed include baculovirus, he ⁇ es viras, adenovirus, adeno- associated viras, bacterial systems, and eukaryotic systems such as CHO cells. Naked DNA and DNA-liposome complexes can also be used.
  • Assays of nuclear receptor activity include binding to intracellular interacting proteins. Furthermore, assays may be based upon the molecular dynamics of macromolecules, metabolites, and ions by means of fluorescent-protein biosensors. Alternatively, the effect of candidate modulators on expression or activity- may be measured at the level of nuclear receptor production using the same general approach in combination with standard immunological detection techniques, such as western blotting or immunoprecipitation with a nuclear receptor polypeptide-specific antibody. Again, useful modulators are identified as those that produce a change in nuclear receptor polypeptide production. Modulators may also affect nuclear receptor activity without any effect on expression level.
  • Candidate modulators may be purified (or substantially purified) molecules or maybe one component of a mixture of compounds (e.g., an extract or supernatant obtained from cells).
  • a mixed compound assay nuclear receptor expression is tested against progressively smaller subsets of the candidate compound pool (e.g., produced by standard purification techniques, e.g., HPLC or FPLC) until a single compound or minimal compound mixture is demonstrated to modulate nuclear receptor expression.
  • standard purification techniques e.g., HPLC or FPLC
  • diverse mixtures (i.e., libraries) of test compounds maybe assayed in such a way that the pattern of response indicates which compounds in the various mixtures are responsible for the effect (deconvolution).
  • Agonists, antagonists, or mimetics found to be effective at modulating the level of cellular nuclear receptor expression or activity may be confirmed as useful in animal models (for example, mice, pigs, dogs, or chickens).
  • the compound may increase survival or mitigate distress in animal models of one or more diseases or disorders.
  • a gene encoding a nuclear receptor polypeptide may have a polymo ⁇ hism that may be, for example, a causative or risk factor of the diseases and disorders discussed below. Screening methods that identify polymo ⁇ hisms may be of diagnostic and therapeutic benefit. For example, early detection of a particular polymo ⁇ hism may enable preventative treatment or prediction of a patient's response (e.g., increased or decreased efficacy or undesirable side effects of treatment).
  • Methods of identifying polymo ⁇ hisms include PCR, RT-PCR, northern blot (e.g., using clones encompassing discrete regions of cDNA), Southern blot, polymo ⁇ hic specific probes, sequencing analysis, hybridization assays, restriction endonuclease analysis, and exon-specific amplification.
  • One method for altering the biological activity of a nuclear receptor polypeptide is to increase or decrease the stabilization of the protein or to prevent its degradation.
  • compounds that increase the stability of a wild-type nuclear receptor polypeptide or decrease its catabolism may also be useful for the treatment of any condition resulting from loss of nuclear receptor biological activity.
  • Such polymo ⁇ hisms and compounds can be identified using the methods described herein. In an analogous manner, decreasing stability may be used to, ' decrease the activity of a nuclear receptor.
  • cells expressing a nuclear receptor polypeptide having a polymo ⁇ hism are transiently metabohcally labeled during translation and the half-life of the nuclear receptor polypeptide is determined using standard techniques.
  • Polymo ⁇ hisms that increase the half-life of a nuclear receptor polypeptide are ones that increase nuclear receptor protein stability. These polymo ⁇ hisms can then be assessed for biological activity. They can also be used to identify proteins that affect the stability of nuclear receptor mRNA or protein. One can then assay for compounds that act on these factors or on the ability of these factors to bind a nuclear receptor.
  • cells expressing a wild-type nuclear receptor polypeptide are transiently metabohcally labeled during translation, contacted with a candidate compound, and the half-life of the nuclear receptor polypeptide is determined using standard techniques.
  • Compounds that modulate the half-life of a nuclear receptor polypeptide are useful compounds in the present invention.
  • treatment with a modulator of a nuclear receptor of the invention may be combined with any other therapy.
  • a nuclear receptor polypeptide (purified or unpurified) can be used in an assay to determine its ability to bind another protein (including, but not limited to, proteins found to specifically interact with a nuclear receptor). The effect of a compound on that binding is then determined.
  • Methods of identifying compounds having the foregoing properties can be identified by standard methods known in the art. Exemplary methods for identifying compounds are described herein.
  • the effect of candidate compounds on nuclear receptor biological activity or cell survival may be measured at the level of translation by using the general approach described above with standard protein detection techniques, such as western blotting, sandwich or competitive immunoassays (both enzyme and radioactive tracer based) or immunoprecipitation with a nuclear receptor-specific antibody.
  • Compounds that modulate the level of a nuclear receptor may be purified, or substantially purified, or may be one component of a mixture of compounds such as an extract or supernatant obtained from cells (Ausubel et al, supra).
  • nuclear receptor expression is measured in cells administered progressively smaller subsets of the compound pool (e.g., produced by standard purification teclmiques such as HPLC or FPLC) until a single compound or minimal number of effective compounds is demonstrated to affect nuclear receptor expression.
  • diverse mixtures i.e., libraries
  • Compounds may also be screened for their ability to modulate nuclear receptor biological activity.
  • the degree of nuclear receptor biological activity in the presence of a candidate compound is compared to the degree of activity in its absence, under equivalent conditions.
  • the screen may begin with a pool of candidate compounds, from which one or more useful modulator compounds are isolated in a step-wise fashion.
  • Nuclear receptor biological activity may be measured by any standard assay, for example, those described herein.
  • Another method for detecting compounds that modulate nuclear receptor biological activity is to screen for compounds that interact physically with a nuclear receptor polypeptide.
  • These compounds may be detected, for example, by adapting interaction trap expression systems known in the art. These systems detect protein interactions using a transcriptional activation assay and are generally described by Gyuris et al. (Cell 75:791-803, 1993) and Field et al., (Nature 340:245-246, 1989), and are commercially available.
  • a nuclear receptor polypeptide, or a fragment thereof can be labeled with a detectable label (e.g., direct 125 I labeling of tyrosines or 125 I Bolton-Hunter reagent; Bolton et al. Biochem. J.
  • a detectable label e.g., direct 125 I labeling of tyrosines or 125 I Bolton-Hunter reagent; Bolton et al. Biochem. J.
  • Candidate compounds previously anayed in the wells of a multi-well plate are incubated with the labeled nuclear receptor polypeptide. Following washing, the wells with bound, labeled nuclear receptor polypeptide are identified. Data obtained using different concentrations of nuclear receptor polypeptides are used to calculate values for the number, affinity, and association of the nuclear receptor polypeptide with the candidate compounds. If desirable, the candidate compounds can be labeled instead of the nuclear receptor polypeptide.
  • the nuclear receptor polypeptide may be immobilized, e.g., in wells of a multi-well plate or on a solid support, and soluble compounds are then contacted with the nuclear receptor polypeptide. Upon removal of unbound compound, the identity of bound candidate compounds is ascertained. Compounds that bind are considered to be candidate modulators of nuclear receptor biological activity. Alternatively, interaction of unlabeled nuclear receptor may be detected using direct or indirect antibody labeling.
  • Another such method comprises the steps of (a) contacting a composition comprising a nuclear receptor polypeptide with a compound suspected of binding a nuclear receptor; and (b) measuring binding between the compound and nuclear receptor polypeptide.
  • the binding may be measured directly, e.g., by using a labeled compound, or may be measured indirectly by several techniques, including measuring transcriptional modulation by the nuclear receptor polypeptide induced by the compound.
  • compounds identified as binding a nuclear receptor polypeptide can be further tested in other assays including, but not limited to, in vivo models, in order to confirm or quantify binding to a nuclear receptor polypeptide.
  • test compounds of the present invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the One-bead one-compound' library method; and synthetic library methods using affinity chromatography selection.
  • biological libraries are limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, K.S. (1997) Anticancer Drug Des. 12:145).
  • binding molecules including natural ligands and synthetic compounds, can be identified or developed using isolated or recombinant nuclear receptor products, nuclear receptor variants, or preferably, cells expressing such products. Binding partners are useful for purifying nuclear receptor products and detection or quantification of nuclear receptor products in fluid and tissue samples using known immunological procedures. Binding molecules are also manifestly useful in modulating (i.e., blocking, inhibiting or stimulating) biological activities of a nuclear receptor polypeptide, especially those activities involved in transcriptional activation.
  • the DNA and amino acid sequence information provided by the present invention also makes possible identification of binding partner compounds with which a nuclear receptor polypeptide or polynucleotide will interact.
  • Methods to identify binding partner compounds include solution assays, in vitro assays wherein nuclear receptor polypeptides are immobilized, and cell-based assays. Identification of binding partner compounds of nuclear receptor polypeptides provides candidates for therapeutic or prophylactic intervention in pathologies associated with nuclear receptor normal and abenant biological activity.
  • the invention includes several assay systems for identifying nuclear receptor polypeptide binding partners.
  • methods of the invention comprise the steps of (a) contacting a nuclear receptor polypeptide with one or more candidate binding partner compounds and (b) identifying the compounds that bind to the nuclear receptor polypeptide. Identification of the compounds that bind the nuclear receptor polypeptide can be achieved by isolating the nuclear receptor polypeptide/binding partner complex, and separating the binding partner compound from the nuclear receptor polypeptide.
  • an additional step of characterizing the physical, biological, and/or biochemical properties of the binding partner compound is also comprehended in another embodiment of the invention, wherein compounds identified as binding nuclear receptor can be further tested in other assays including, but not limited to, in vivo models, in order to confirm or quantify binding to nuclear receptor.
  • the nuclear receptor polypeptide/binding partner complex is isolated using an antibody immunospecific for either the nuclear receptor polypeptide or the candidate binding partner compound.
  • either the nuclear receptor polypeptide or the candidate binding partner compound comprises a label or tag that facilitates its isolation
  • methods of the invention to identify binding partner compounds include a step of isolating the nuclear receptor polypeptide/binding partner complex through interaction with the label or tag.
  • An exemplary tag of this type is a poly-histidine sequence, generally around six histidine residues, that permits isolation of a compound so labeled using nickel chelation.
  • Other labels and tags, such as the FLAG tag, well known and routinely used in the art, are embraced by the invention.
  • the invention provides a method comprising the steps of (a) contacting an immobilized nuclear receptor polypeptide with a candidate binding partner compound and (b) detecting binding of the candidate compound to the nuclear receptor polypeptide.
  • the candidate binding partner compound is immobilized and binding of nuclear receptor is detected. Immobilization is accomplished using any of the methods well known in the art, including covalent bonding to a support, a bead, or a chromatographic resin, as well as non-covalent, high affinity interactions such as antibody binding, or use of streptavidin/biotin binding wherein the immobilized compound includes a biotin moiety.
  • Detection of binding can be accomplished (i) using a radioactive label on the compound that is not immobilized, (ii) using of a fluorescent label on the non-immobilized compound, (iii) using an antibody immunospecific, for the non-immobilized compound, (iv) using a label on the non-immobilized compound that excites a fluorescent support to which the immobilized compound is attached, as well as other techniques well known and routinely practiced in the art.
  • the invention also provides cell-based assays to identify binding partner compounds of a nuclear receptor polypeptide.
  • the invention provides a method comprising the steps of contacting a nuclear receptor polypeptide expressed in a cell with a candidate binding partner compound and detecting binding of the candidate binding partner compound to the nuclear receptor polypeptide.
  • the detection comprises detecting a reporter response or other physiological event in the cell caused by the binding of the molecule.
  • Another aspect of the present invention is directed to methods of identifying compounds that bind to either a nuclear receptor polypeptide or nucleic acid molecules encoding a nuclear receptor polypeptide, comprising contacting nuclear receptor polypeptide, or a nucleic acid molecule encoding the same, with a compound, and determining whether the compound binds the nuclear receptor polypeptide or a nucleic acid molecule encoding the same.
  • Binding can be determined by binding assays which are well known to the skilled artisan, including, but not limited to, gel-shift assays, Western blots, radiolabeled competition assay, phage-based expression cloning, co- fractionation by chromatography, co-precipitation, cross linking, interaction trap/two- hybrid analysis, southwestern analysis, ELISA, and the like, which are described in, for example, Cunent Protocols in Molecular Biology, 1999, John Wiley & Sons, NY, which is inco ⁇ orated herein by reference in its entirety.
  • the compounds to be screened include (which may include compounds which are suspected to bind nuclear receptor polypeptides, or a nucleic acid molecule encoding the same), but are not limited to, . extracellular, intracellular, biologic or chemical origin.
  • the methods of the invention also embrace ligands, especially neuropeptides, that are attached to a label, such as a radiolabel (e.g., 1251, 35S, 32P, 33P, 3H), a fluorescence label, a chemiluminescent label, an enzymatic label and an immunogenic label.
  • Modulators falling within the scope of the invention include, but are not limited to, non-peptide molecules such as non-peptide mimetics, non-peptide allosteric effectors, and peptides.
  • the nuclear receptor polypeptide or polynucleotide employed in such a test may either be free in solution, attached to a solid support, bome on a cell surface or located intracellularly or associated with a portion of a cell.
  • One skilled in the art can, for example, measure the formation of complexes between the nuclear receptor polypeptide and the compound being tested.
  • one skilled in the art can examine the diminution in complex formation between a nuclear receptor polypeptide and its substrate caused by the compound being tested.
  • high throughput screening for compounds having suitable binding affinity to a nuclear receptor polypeptide is employed. Briefly, large numbers of different test compounds are synthesized on a solid substrate. The peptide test compounds are contacted with a nuclear receptor polypeptide and washed. Bound nuclear receptor is then detected by methods well known in the art. Purified polypeptides of the invention can also be coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies can be used to capture the protein and immobilize it on the solid support.
  • an expressed nuclear receptor polypeptide can be used for HTS binding assays in conjunction with its defined ligand, in this case the conesponding neuropeptide that activates it.
  • the identified peptide is labeled with a suitable radioisotope, including, but not limited to, 1251, 3H, 35S or 32P, by methods that are well known to those skilled in the art.
  • the peptides may be labeled by well-known methods with a suitable fluorescent derivative (Baindur et al., Drug Dev. Res., 1994, 33, 373-398; Rogers, Drug Discovery Today, 1997, 2, 156-160).
  • Radioactive ligand specifically bound to the recombinant nuclear receptor can be detected in HTS assays in one of several standard ways, including filtration of the receptor-ligand complex to separate bound ligand from unbound ligand (Williams, Med. Res. Rev., 1991, 11, 147-184; Sweetnam. et al., J Natural Products, 1993, 56, 441-455).
  • Alternative methods include a scintillation proximity assay (SPA) or a FlashPlate format in which such separation is unnecessary (Nakayama, Cur. Opinion Drag Disc. Dev., 1998, 1, 85-91; Boss et al., J Biomolecular Screening, 1998, 3, 285-292).
  • Binding of fluorescent ligands can be detected in various ways, including fluorescence energy transfer (FRET), direct specfrophotofluorometric analysis of bound ligand, or fluorescence polarization (Rogers, Drag Discovery Today, 1997, 2, 156-160; Hill, Cur. Opinion Drag Disc. Dev., 1998, 1, 92-97).
  • FRET fluorescence energy transfer
  • direct specfrophotofluorometric analysis of bound ligand or fluorescence polarization
  • assays may be used to identify specific ligands of a nuclear receptor, including assays that identify ligands of the target protein through measuring direct binding of test ligands to the target protein, as well as assays that identify ligands of target proteins through affinity ultrafiltration with ion spray mass spectroscopy/HPLC methods or other physical and analytical methods.
  • binding interactions are evaluated indirectly using the yeast two hybrid system described in Fields et al., Nature, 340:245-246 (1989), and Fields et al, Trends in Genetics, 10:286- 292 (1994), both of which are inco ⁇ orated herein by reference in its entirety.
  • the two-hybrid system is a genetic assay for detecting interactions between two proteins or polypeptides. It can be used to identify proteins that bind to a known protein of interest, or to delineate domains or residues critical for an interaction. Variations on this methodology have been developed to clone genes that encode DNA binding proteins, to identify peptides that bind to a protein, and to screen for drags.
  • the two- hybrid system exploits the ability of a pair of interacting proteins to bring a transcription activation domain into close proximity with a DNA binding domain that binds to an upstream activation sequence (UAS) of a reporter gene, and is generally performed in yeast.
  • UAS upstream activation sequence
  • the assay requires the construction of two hybrid genes encoding (1) a DNA- binding domain that is fused to a first protein and (2) an activation domain fused to a second protein.
  • the DNA-binding domain targets the first hybrid protein to the UAS of the reporter gene; however, because most proteins lack an activation domain, this DNA- binding hybrid protein does not activate transcription of the reporter gene.
  • the second hybrid protein which contains the activation domain, cannot by itself activate expression of the reporter gene because it does not bind the UAS. However, when both hybrid proteins are present, the noncovalent interaction of the first and second proteins tethers the activation domain to the UAS, activating transcription of the reporter gene.
  • this assay can be used to detect agents that interfere with the binding interaction.
  • Expression of the reporter gene is monitored as different test agents are added to the system. The presence of an inhibitory agent results in lack of a reporter signal.
  • the yeast two-hybrid assay can also be used to identify proteins that bind to the gene product.
  • a fusion polynucleotide encoding both a nuclear receptor (or fragment) and a UAS binding domain i.e., a first protein
  • a large number of hybrid genes each encoding a different second protein fused to an activation domain are produced and screened in the assay.
  • the second protein is encoded by one or more members of a total cDNA or genomic DNA fusion library, with each second protein-coding region being fused to the activation domain.
  • This system is applicable to a wide variety of proteins, and it is not even necessary to know the identity or function of the second binding protein.
  • the system is highly sensitive and can detect interactions not revealed by other methods; even transient interactions may trigger transcription to produce a stable mRNA that can be repeatedly translated to yield the reporter protein.
  • test ligands may be used to search for agents that bind to the target protein.
  • One such screening method to identify direct binding of test ligands to a target protein relies on the principle that proteins generally exist as a mixture of folded and unfolded states, and continually alternate between the two states.
  • the target protein molecule bound by the ligand remains in its folded state.
  • the folded target protein is present to a greater extent in the presence of a test ligand which binds the target protein, than in the absence of a ligand.
  • Binding of the ligand to the target protein can be determined by any method that distinguishes between the folded and unfolded states of the target protein.
  • the function of the target protein need not be known in order for this assay to be performed. Virtually any agent can be assessed by this method as a test ligand, including, but not limited to, metals, polypeptides, proteins, lipids, polysaccharides, polynucleotides and small organic molecules.
  • Determining whether a test compound binds to a nuclear receptor polypeptide can also be accomplished by measuring the intrinsic fluorescence of the nuclear receptor polypeptide and determining whether the intrinsic fluorescence is modulated in the presence of the test compound.
  • the intrinsic fluorescence of nuclear receptor polypeptide is measured as a function of the tryptophan residue(s) of the nuclear receptor.
  • fluorescence of the nuclear receptor polypeptide is measured and compared to the fluorescence intensity of the nuclear receptor polypeptide in the presence of the test compound, wherein a decrease in fluorescence intensity indicates binding of the test compound to a nuclear receptor.
  • Prefened methodology is set forth in "Principles of Fluorescence Spectroscopy" by Joseph R.
  • inventions comprise using competitive screening assays in which neutralizing antibodies capable of binding a polypeptide of the invention specifically compete with a test compound for binding to the polypeptide.
  • the antibodies can be used to detect the presence of any peptide that shares one or more antigenic determinants with a nuclear receptor polypeptide.
  • Radiolabeled competitive binding studies are described in A. H. Lin et al. Antimicrobial Agents and Chemotherapy, 1997, vol. 41, no. 10. pp. 2127-2131, the disclosure of which is inco ⁇ orated herein by reference in its entirety.
  • Another aspect of the present invention relates to methods of identifying a compound that binds to or modulates a nuclear receptor polypeptide.
  • the methods comprise contacting a composition comprising a nuclear receptor and Peptide A with a test compound, or a plurality of test compounds, and determining whether the test compound competes with Peptide A for binding to the nuclear receptor polypeptide.
  • the affinity or displacement of Peptide A is measured, wherein a low affinity indicates that the test compound interacts with the nuclear receptor polypeptide.
  • the composition that comprises a nuclear receptor polypeptide and Peptide A can be cells.
  • Compounds identified as binding to a nuclear receptor polypeptide are also expected to modulate nuclear receptor activity. Binding of a test compound to a nuclear receptor polypeptide can be determined by any of the binding assays described above.
  • the invention also provides methods for identifying a modulator of binding between a nuclear receptor polypeptide and a nuclear receptor binding partner, comprising the steps of (a) contacting a nuclear receptor binding partner and a composition comprising a nuclear receptor polypeptide in the presence and in the absence of a putative modulator compound; (b) detecting binding between the binding partner and the nuclear receptor polypeptide; and (c) identifying a putative modulator compound or a modulator compound in view of decreased or increased binding between the binding partner and the nuclear receptor polypeptide in the presence of the putative modulator, as compared to binding in the absence of the putative modulator.
  • nuclear receptor binding partners that stimulate nuclear receptor activity are useful as agonists in disease states or conditions characterized by insufficient nuclear receptor function (e.g., as a result of insufficient activity of a nuclear receptor ligand).
  • Nuclear receptor binding partners that block ligand-mediated nuclear receptor signaling are useful as nuclear receptor antagonists to treat disease states or conditions characterized by excessive nuclear receptor signaling.
  • nuclear receptor modulators in general, as well as nuclear receptor polynucleotides and polypeptides are useful in diagnostic assays for such diseases or conditions.
  • the invention provides methods for treating a disease or abnormal condition by administering to a patient in need of such treatment a substance that modulates the activity or expression of a polypeptide having sequences selected from the group consisting of sequences listed in Table 1.
  • Agents that modulate may be identified by incubating a putative modulator with a cell containing a nuclear receptor polypeptide or polynucleotide and determining the effect of the putative modulator on nuclear receptor activity or expression.
  • the selectivity of a compound that modulates the activity of a nuclear receptor can be evaluated by comparing its effects on nuclear receptor to its effect on other nuclear receptor compounds.
  • Methods of the invention to identify modulators include variations on any of the methods described above to identify binding partner compounds, the variations including teclmiques wherein a binding partner compound has been identified and the binding assay is canied out in the presence and absence of a candidate modulator.
  • a modulator is identified in those instances where binding between the nuclear receptor polypeptide and the binding partner compound changes in the presence of the candidate modulator compared to binding in the absence of the candidate modulator compound.
  • a modulator that increases binding between the nuclear receptor polypeptide and the binding partner compound is described as an enhancer or activator, and a modulator that decreases binding between the nuclear receptor polypeptide and the binding partner compound is described as an inhibitor.
  • HTS assays to identify compounds that interact with or inhibit biological activity (i.e., affect enzymatic activity, binding activity, etc.) of a nuclear receptor polypeptide.
  • HTS assays permit screening of large numbers of compounds in an efficient manner.
  • Cell-based HTS systems are contemplated to investigate nuclear receptor receptor-ligand interaction.
  • HTS assays are designed to identify "hits” or "lead compounds” having the desired property, from which modifications can be designed to improve the desired property. Chemical modification of the "hit” or "lead compound” is often based on an identifiable structure/activity relationship between the "hit” and the nuclear receptor polypeptide.
  • Another aspect of the present invention is directed to methods of identifying compounds which modulate (i.e., increase or decrease) activity of nuclear receptor comprising contacting a nuclear receptor polypeptide with a compound, and determining whether the compound modifies activity of the nuclear receptor.
  • the activity in the presence of the test compared is measured to the activity in the absence of the test compound. Where the activity of the sample containing the test compound is higher than the activity in the sample lacking the test compound, the compound will have increased activity. Similarly, where the activity of the sample containing the test compound is lower than the activity in the sample lacking the test compound, the compound will have inhibited activity.
  • the present invention is particularly useful for screening compounds by using nuclear receptor in any of a variety of drug screening techniques.
  • the compounds to be screened include (which may include compounds which are suspected to modulate nuclear receptor activity), but are not limited to, extracellular, intracellular, biologic or chemical origin.
  • the nuclear receptor polypeptide employed in such a test may be in any form, preferably, free in solution, attached to a solid support, on a cell surface or located intracellularly.
  • One skilled in the art can, for example, measure the formation of complexes between nuclear receptor and the compound being tested. Alternatively, one skilled in the art can examine the diminution in complex formation between nuclear receptor and its substrate caused by the compound being tested.
  • the activity of nuclear receptor polypeptides of the invention can be determined by, for example, examining the ability to bind or be activated by chemically synthesized peptide ligands. Alternatively, the activity of nuclear receptor polypeptides can be assayed by examining their ability to bind hormones, neuropeptides, neurotransmitters, nucleotides and lipids. Alternatively, the activity of the nuclear receptor polypeptides can be determined by examining the activation or repression of gene expression. Thus, modulators of nuclear receptor polypeptide activity may alter nuclear receptor function, such as a binding property of a receptor or an activity such as nuclear receptor-mediated transcriptional activation or repression.
  • the assay may take the form of a reporter assay for transcriptional activation or repression, a yeast growth assay, an Aequorin assay, a Luciferase assay, a FLIPR assay for intracellular Ca2+ concentration, a mitogenesis assay, a MAP Kinase activity assay, an assay for extracellular acidification rates, as well as other binding or function-based assays of nuclear receptor activity that are generally known in the art.
  • the modulators of the invention exhibit a variety of chemical structures, which can be generally grouped into non-peptide mimetics of natural nuclear receptor ligands, peptide and non-peptide allosteric effectors of nuclear receptor, and peptides that may function as activators or inhibitors (competitive, uncompetitive and non-competitive) (e.g., antibody products) of nuclear receptors.
  • the invention does not restrict the sources for suitable modulators, which may be obtained from natural sources such as plant, animal or mineral extracts, or non-natural sources such as small molecule libraries, including the products of combinatorial chemical approaches to library construction, and peptide libraries.
  • enzyme Assays can be used to examine enzymatic activity including, but not limited to, photometric, radiometric, BPLC, electrochemical, and the like, which are described in, for example, Enzyme Assays: A Practical Approach, eds. R. Eisenthal and M. J. Danson, 1992, Oxford University Press, which is inco ⁇ orated herein by reference in its entirety.
  • Recombinant receptors are prefened for binding assay HTS because they allow for better specificity (higher relative purity), provide the ability to generate large amounts of receptor material, and can be used in a broad variety of formats (see Hodgson, BioTechnology, 1992, 10, 973-980; each of which is inco ⁇ orated herein by reference in its entirety).
  • heterologous systems are available for functional expression of recombinant receptors that are well known to those skilled in the art.
  • Such systems include bacteria (Strosberg, et al., Trends in Pharmacological Sciences, 1992, 13, 95- 98), yeast (Pausch, Trends in Biotechnology, 1997, 15, 487-494), several kinds of insect cells (Vanden Broeck, Int. Rev. Cytology, 1996, 164, 189-268), amphibian cells
  • methods of screening for compounds that modulate nuclear receptor activity comprise contacting test compounds with nuclear receptor and assaying for the presence of a complex between the compound and nuclear receptor.
  • the ligand is typically labeled. After suitable incubation, free ligand is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of the particular compound to bind to nuclear receptor.
  • the invention contemplates a multitude of assays to screen and identify inhibitors of ligand binding to nuclear receptors.
  • the nuclear receptor is immobilized and interaction with a binding partner is assessed in the presence and absence of a candidate modulator such as an inhibitor compound.
  • interaction between the nuclear receptor and its binding partner is assessed in a solution assay, both in the presence and absence of a candidate inhibitor compound.
  • an inhibitor is identified as a compound that decreases binding between the nuclear receptor and its binding partner.
  • binding partners can be designed and include soluble forms of binding partners, as well as such binding partners as chimeric, or fusion, proteins.
  • Compounds may be identified which exhibit similar properties to the ligand for the nuclear receptor of the invention, but which are smaller and exhibit a longer half time than the endogenous ligand in a human or animal body.
  • a molecule according to the invention is used as a "lead” compound.
  • the design of mimetics to known pharmaceutically active compounds is a well-known approach in the development of pharmaceuticals based on such "lead” compounds. Mimetic design, synthesis and testing are generally used to avoid randomly screening a large number of molecules for a target property.
  • the present invention also encompasses a method of agonizing (stimulating) or antagonizing a nuclear receptor natural binding partner associated activity in a mammal comprising administering to said mammal an agonist or antagonist to one of the above disclosed polypeptides in an amount sufficient to effect said agonism or antagonism.
  • One embodiment of the present invention is a method of treating diseases in a mammal with an agonist or antagonist of the protein of the present invention comprises administering the agonist or antagonist to a mammal in an amount sufficient to agonize or antagonize nuclear receptor-associated functions.
  • modulators agonists and antagonists
  • the modulators that can be identified by these assays are natural ligand compounds of the receptor; synthetic analogs and derivatives of natural ligands; antibodies, antibody fragments, and/or antibody-like compounds derived from natural antibodies or from antibody-like combinatorial libraries; and/or synthetic compounds identified by high-throughput screening of libraries; and the like. All modulators that bind nuclear receptors are useful for identifying nuclear receptors in tissue samples (e.g., for diagnostic pu ⁇ oses, pathological pu ⁇ oses, and the like). Agonist and antagonist modulators are useful for up-regulating and down-regulating nuclear receptor activity, respectively, to treat disease states characterized by abnormal levels of nuclear receptor activity.
  • the assays may be performed using single putative modulators, and/or may be performed using a known agonist in combination with candidate antagonists (or visa versa).
  • the photoprotein luciferase provides another useful tool for assaying for modulators of nuclear receptor activity.
  • Cells e.g., CHO cells or COS 7 cells
  • a nuclear receptor expression construct e.g., nuclear receptor in pzeoSV2
  • a reporter construct which includes a gene for the luciferase protein downstream from a nuclear receptor transcription factor binding site, such as a hormone or other nuclear receptor response element.
  • Agonist binding to nuclear receptor causes the nuclear receptor to bind to the nuclear receptor response element and active expression of the luciferase gene.
  • Luciferase activity may be quantitatively measured using, e.g., luciferase assay reagents that are commercially available from Promega (Madison, WI).
  • CHO cells are plated in 24-well culture dishes at a density of 100,000 cells/well one day prior to transfection and cultured at 37°C in MEM (Gibco/13RL) supplemented with 10% fetal bovine serum, 2 mM glutamine, 10 U/ml penicillin and 10 ug/ml streptomycin.
  • Cells are transiently co-transfected with both a nuclear receptor expression construct and a reporter construct containing the luciferase gene.
  • Transfections are perfo ⁇ ned using the FuGENE 6 transfection reagent (Boehringer- Mannheim) according to the supplier's instructions. Cells transfected with the reporter construct alone are used as a control. Twenty-four hours after transfection, cells are washed once with PBS pre-warmed to 37°C. Seram-free MEM is then added to the cells either alone (control) or with one or more candidate modulators and the cells are incubated at 37°C for five hours. Thereafter, cells are washed once with ice-cold PBS and lysed by the addition of lysis buffer from the luciferase assay kit supplied by Promega.
  • lysate is mixed with substrate solution (Promega) in an opaque- white, 96-well plate, and the luminescence is read immediately on a scintillation and luminescence counter (Wallace Instruments, Gaithersburg, MD). Differences in luminescence in the presence versus the absence of a candidate modulator compound are indicative of modulatory activity.
  • Receptors that are either constitutively active or activated by agonists typically give a 3 to 20-fold stimulation of luminescence compared to cells transfected with the reporter gene alone. Modulators that act as inverse agonists will reverse this effect.
  • a mitogenesis assay the ability of candidate modulators to induce or inhibit nuclear receptor mediated cell division is determined (See, e.g., Lajiness et al., Journal of Pharmacology and Experimental Therapeutics 267(3): 1573-1581 (1993)).
  • CHO cells stably expressing nuclear receptor are seeded into 96-well plates at a density of 5000 cells/well and grown in MEM with 10% fetal calf serum for 48 hours, at which time the cells are rinsed twice with seram-free MEM. After rinsing, fresh MEM, or MEM containing a known mitogen, is added along with MEM containing varying concentrations of one or more candidate modulators or test compounds diluted in serum-free medium.
  • A B x [CI (D + Q + G
  • A the percent of serum stimulation
  • B the maximal effect minus baseline
  • C the EC50
  • D the concentration of the compound
  • G the maximal effect.
  • Parameters B, C and G are determined by Simplex optimization.
  • Agonists that bind to the receptor are expected to increase [3H]-thymidine inco ⁇ oration into cells.
  • Antagonists that bind to the receptor will inhibit the stimulation seen with a known agonist.
  • Isolated nuclear receptors can be used to isolate novel or known ligands (Saito et al., Nature, 400: 265-269, 1999).
  • the cDNAs that encode the isolated nuclear receptor selected from the group consisting of sequences listed in Table 1 can be cloned into mammalian expression vectors and used to stably or transiently fransfect mammalian cells including CHO, Cos or HEK293 cells.
  • Receptor expression can be determined by Northern blot analysis of transfected cells and identification of an appropriately sized mRNA band (predicted size from the cDNA) or PCR.
  • Tissues shown by mRNA analysis to express each of the nuclear receptor proteins could be processed for ligand extraction using any of several protocols ((Reinsheidk R.K. et al., Science 270: 243-247, 1996; Sakurai, T., et al., Cell 92; 573-585, 1998; Hinuma, S., et al., Nature 393: 272-276, 1998). Chromotographic fractions of organ extracts could be tested for ability to activate nuclear receptor proteins by measuring reporter gene activation. This assay could also be performed using baculovirases containing nuclear receptor proteins infected into SF9 insect cells.
  • the ligand which activates nuclear receptor proteins can be purified to homogeneity through successive rounds of purification using nuclear receptor protein activation as a measurement of activity.
  • the composition of the ligand can be detennined by mass spectrometry and other methods. Ligands isolated in this manner will be bioactive materials which will affect physiological processes.
  • Protein interaction assays may also be utilized to identify nuclear receptor modulator compounds.
  • a nuclear receptor polypeptide of the invention (or a polypeptide fragment thereof or an epitope-tagged form or fragment thereof) is harvested from a suitable source (e.g., from a prokaryotic expression system, eukaryotic cells, a cell-free system, or by immunoprecipitation from nuclear receptor polypeptide-expressing cells).
  • the nuclear receptor polypeptide is then bound to a suitable support (e.g., nitrocellulose or an antibody or a metal agarose column in the case of, for example, a his-tagged form of a nuclear receptor polypeptide).
  • Binding to the support is preferably done under conditions that allow polypeptides associated with a nuclear receptor polypeptide to remain associated with it. Such conditions may include use of buffers that minimize interference with protein-protein interactions.
  • the binding step can be done in the presence and absence of compounds being tested for their ability to interfere with interactions between a nuclear receptor polypeptide of the invention and other molecules. If desired, other proteins (e.g., a cell lysate) are added, and allowed time to associate with the polypeptide. The immobilized nuclear receptor polypeptide is then washed to remove proteins or other cell constituents that may be non-specifically associated with the polypeptide or the support.
  • the immobilized nuclear receptor polypeptide is then dissociated from its support, and so that proteins bound to it are released (for example, by heating), or alternatively, associated proteins are released from the nuclear receptor polypeptide without releasing the nuclear receptor polypeptide from the support.
  • the released proteins and other cell constituents can be analyzed, for example, by SDS-PAGE gel electrophoresis, western blotting and detection with specific antibodies, phosphoamino acid analysis, protease digestion, protein sequencing, or isoelectric focusing.
  • Normal and polymo ⁇ hic (or mutagenized) forms of a nuclear receptor polypeptide of the invention can be employed in these assays to gain additional information about the part of a nuclear receptor polypeptide to which a given factor binds.
  • the proceeding assay can be performed using a purified or semipurified protein or other molecule that is known to interact with a nuclear receptor polypeptide of the invention. This assay may include the following steps.
  • Another assay includes a Fluorescent Resonance Energy Transfer (FRET) assay.
  • FRET Fluorescent Resonance Energy Transfer
  • This assay can be performed as follows. 1. Provide a nuclear receptor polypeptide of the invention or a suitable polypeptide fragment thereof and couple a suitable FRET donor (e.g., nitro- benzoxadiazole (NBD)) to it;
  • a suitable FRET donor e.g., nitro- benzoxadiazole (NBD)
  • a FRET acceptor e.g., rhodamine
  • Quenching and FRET assays are related. Either one can be applied in a given case, depending on which pair of fluorophores is used in the assay.
  • the interaction trap/two-hybrid library screening method can be used. This assay was first described in Fields et al., Nature, 1989, 340, 245, which is inco ⁇ orated herein by reference in its entirety. A protocol is published in Cunent Protocols in Molecular Biology 1999, John Wiley & Sons, NY, and Ausubel, F. M. et 132 al. 1992, Short protocols in molecular biology, Fourth edition, Greene and Wiley-interscience, NY, each of which is inco ⁇ orated herein by reference in its entirety. Kits are available from Clontech, Palo Alto, CA (Matchmaker Two-Hybrid System).
  • a fusion of the nucleotide sequences encoding the nuclear receptor lacking the activation domain and the yeast transcription factor GAL4 DNA-binding domain is constructed in an appropriate plasmid (i.e., pGBKT7) using standard subcloning techniques.
  • a GAL4 active domain (AD) fusion library is constructed in a second plasmid (i.e., p GADT7) from cDNA of potential nuclear receptor-binding proteins (for protocols on forming cDNA libraries, see Sambrook et al. 1989, Molecular cloning: a laboratory manual, second edition, Cold Spring Harbor Press, Cold Spring Harbor, NY), which is inco ⁇ orated herein by reference in its entirety.
  • the DNA- BD/nuclear receptor fusion construct is verified by sequencing, and tested for autonomous reporter gene activation and cell toxicity, both of which would prevent a successful two-hybrid analysis. Similar controls are performed with the AD/library fusion construct to ensure expression in host cells and lack of transcriptional activity.
  • Yeast cells are transformed with both the nuclear receptor and library fusion plasmids according to standard procedures (Ausubel et al., 1992, Short protocols in molecular biology, fourth edition, Greene and Wiley-interscience, NY, which is inco ⁇ orated • herein by reference in its entirety).
  • yeast plasmid reporter genes i.e., lacZ, HIS3, ADE2, LEU2
  • Yeast cells are plated on nutrient-deficient media to screen for expression of reporter genes. Colonies are dually assayed for ⁇ -galactosidase activity upon growth in Xgal (5-bromo-4-chloro-3-indolyl-p-D-galactoside) supplemented media (filter assay for P-galactosidase activity is described in Breeden et al., Cold Spring Harb. Symp. Quant. Biol., 1985, 50, 643, which is inco ⁇ orated herein in its entirety).
  • Positive AD library plasmids are rescued from transformants and reintroduced into the original yeast strain as well as other strains containing unrelated DNA-BD fusion proteins to confirm specific nuclear receptor /library protein interactions. Insert DNA is sequenced to verify the presence of an open reading frame fused to GAL4 AD and to determine the identity of the nuclear receptor-binding protein.
  • Nucleic acid encoding a nuclear receptor polypeptide of the invention may be used in an assay based on the interaction of factors necessary for nuclear receptor gene transcription.
  • the association between the DNA and the binding factor may be assessed by means of any system that discriminates between protein-bound and non-protein- bound DNA (e.g., a gel retardation assay).
  • the effect of a compound on the interaction of a factor to DNA is assessed by means of such an assay.
  • in vitro binding assays in which the regulatory regions of a nuclear receptor gene are linked to reporter systems can also be performed.
  • a cell-based or cell-free system can be used to screen for compounds based on their effect on the half-life of nuclear receptor mRNA or polypeptide.
  • the assay may employ labeled mRNA or polypeptide.
  • nuclear receptor mRNA may be detected by means of specifically hybridizing probes or a quantitative PCR assay.
  • Protein can be quantified, for example, by fluorescent or radioactively labeled antibody- based methods. The following represent exemplary assays:
  • Polymo ⁇ hic nuclear receptor polypeptides may have dominant negative activity (i.e., activity that interferes with the function of a wild-type nuclear receptor).
  • An assay for a compound that can interfere with such a polymo ⁇ h may be based on any method of quantifying the normal activity of a nuclear receptor in the presence of the polymo ⁇ h.
  • a normal nuclear receptor facilitates signal transduction and gene activation, and a dominant negative polymo ⁇ h would interfere with this effect.
  • Measurement of the ability of a compound to counteract the effect of a dominant negative polymo ⁇ h may be based on signal transduction, or on any other normal activity of a wild-type nuclear receptor that was inhibited in the polymo ⁇ h.
  • Assays Measuring Phosphorylation The effect of a compound on phosphorylation of a nuclear receptor polypeptide of the invention can be assayed by methods that quantify phosphates on proteins or that assess the phosphorylation state of a specific residue of a nuclear receptor. Such methods include but are not limited to P and P labeling and immunoprecipitation, detection with antiphosphoamino acid antibodies (e.g., antiphosphoserine antibodies), phosphoamino acid analysis on 2-dimensional TLC plates, techniques involving mass spectroscopy of fragmented or digested nuclear receptors (e.g. MOLDI-TOF), and protease digestion finge ⁇ rinting of proteins followed by detection of 32 P- or 33 P- labeled fragments.
  • antiphosphoamino acid antibodies e.g., antiphosphoserine antibodies
  • phosphoamino acid analysis on 2-dimensional TLC plates 2-dimensional TLC plates
  • techniques involving mass spectroscopy of fragmented or digested nuclear receptors e.g
  • the effect of a compound on the post-translational modification of a nuclear receptor polypeptide of the invention may be based on any method capable of quantifying that particular modification.
  • effects of compounds on glycosylation may be assayed by treating a nuclear receptor polypeptide with glycosylase and quantifying the amount and nature of carbohydrate released.
  • Test compounds identified as having activity in any of the above-described assays may be subsequently screened in any available animal model system, including, but not limited to, mice, pigs, and dogs. Test compounds are administered to these animals according to standard methods. Test compounds may also be tested in mice bearing mutations in a gene encoding a nuclear receptor polypeptide. Additionally, compounds may be screened for their ability to modulate an interaction between a nuclear receptor polypeptide of the invention and a ligand that binds the protein.
  • An animal such as a mouse, that has had one or both alleles of a nuclear receptor polypeptide of the invention inactivated (e.g., by homologous recombination or by insertional mutagenesis) is a prefened animal model for screening for compounds that alleviate abenant behavior or symptoms from a disease or disorder associated with loss of a nuclear receptor activity.
  • the availability of inbred strains of genetically identical mice is of immense value in behavioral studies. Uniformity of mice in an inbred strain permits the assessment of subtle differences in the expression of behavioral traits. As a result, mice can be altered genetically, or bred in different combinations, to study specific behavioral characteristics.
  • ES cells mouse embryonic stem cells. These cells can be genetically modified in vitro and then implanted into a foster mother, where they develop into embryos and are brought to term. The resulting offspring are derived from the altered ES cells and cany the introduced genetic modification in their genome.
  • mice The most common laboratory procedure perfo ⁇ ried in ES cells is the elimination, or knock-out (KO), of a specific gene.
  • KO knock-out
  • a mutation inactivating a target gene is introduced into ES cells. These cells are then used to produce mice containing the faulty gene. Since mice, like humans, contain two copies of every gene, one from each parent, the first generation of mice reared from the modified ES cells contains one copy of the mutant gene and one healthy variety.
  • a single round of interbreeding leads to mice with two copies of the mutant gene and the full manifestation of the introduced mutation (KO mice) or mice bom by foster mothers are bred with wild type mice to produce heterozygotes, and these heterozygotes are interbred to produce KO mice.
  • a polynucleotide sequence may be desirable to insert into the mouse genome.
  • This technique commonly refened to as “knocking in,” can be accomplished using many of the methods described for the production of knock-out mice.
  • the knocked-in polynucleotide may be expressed under the control of the endogenous mouse regulatory sequence, or may have exogenous regulatory sequences.
  • the methods used to generate a library of ES cells with random gene disraptions and the screening and isolation of ES clones containing a nuclear receptor disraption may be canied out essentially as described in U.S. Patent No. 6,228,639.
  • we infected ES cells with a retroviral vector we infected ES cells with a retroviral vector.
  • the vector is designed to inactivate genes in which it gets inserted.
  • the ES cell insertional library is organized in a 3-D matrix of tubes.
  • One copy of the library is stored as viable cells and the other copy is used to isolate DNA.
  • DNA from the library pools is screened by PCR for the insertions in the genes of interest. The same insertion found by PCR in pools conesponding to the other dimensions of the library matrix determines the 3-D address of the ES clone containing the disrupted gene.
  • mice having mutations in a gene encoding a nuclear receptor polypeptide of the present invention are made using homologous recombination. Suitable methods and reagents are described, for example, in U.S. Patent Nos. 5,464,764, 5,487,992, 5,612,205, 5,627,059, 5,789,215, and 6,204,061.
  • Knock-out and knock-in mice are produced according to methods well known in the art (see, e.g., Manipulating the Mouse Embryo. A Laboratory Manual, 2nd ed. B. Hogan, R. Beddington, F. Constantini, E. Lacy, Cold Spring Harbor Laboratory press, 1984).
  • ES cells containing a disrupted nuclear receptor gene are injected into mice blastocysts. These blastocysts are then transfened into uteri of pseudopregnant female mice. Pups bom are scored for fur color, and chimeric mice (black and agouti color) with high contribution of agouti fur (50% or more) are tested for germ line transmission by breeding with C57B6/J mice.
  • mice Presence of agouti progeny indicates germ line transmission, and the same chimera mice are then bred to generate knock-out mice on an inbred background.
  • the chimeric mice may be bred directly to 129 mice and ge ⁇ n line transmission may be determined by PCR, Southern blotting, or other methods known in the art.
  • the resulting heterozygous mice would then be bred to generate knock-out mice on an inbred background.
  • mice are mated with other mice.
  • the progeny from these matings are genotyped by PCR, Southern blotting, or other methods known in the art for the presence of the knocked out copy of nuclear receptor gene.
  • Knock out mice homozygous for disraption of the nuclear receptor gene are generated by intercrossing heterozygous mice and genotyping progeny from these crosses.
  • Behavioral tests may be used to determine the behavioral phenotype of animals (e.g., mice in which one or more nuclear receptor gene of the present invention has been deleted or otherwise modified, and mice overexpressing one or more nuclear receptor polypeptides of the present invention).
  • Suitable tests include, but are not limited to, those that measure behaviors related to anxiety, hyperactivity, hypoactivity, appetite, eating habits, attention, drag abuse, drag addiction, learning and memory, mood, depression, schizophrenia, pain, sleep, arousal, sexuality, and social dominance.
  • the functional observational battery is a series of tests applied to an animal to determine gross sensory and motor deficits.
  • short-duration, non- hannful tactile, olfactory, and visual stimuli are applied to the animal to determine its ability to detect and respond normally to the stimuli.
  • the FOB also provides an opportunity for an investigator to closely observe each animal for skeletal and spontaneous neurological deficits (Crawley and Paylor, Hormones and Behavior 31 : 197-211 (1997)).
  • General observational tests include, for example, swim tests, the auditory click test, measurement of body temperature or body weight, the Irwin Observational Test Battery, the olfactory acuity test, and the visual cliff test.
  • Infrared photobeams provide information of when an animal is moving in its home cage. Animals in their home cages are placed in the photobeam boxes, and data are generated that provide insight into the animal's circadian rhythms activity, as well as general traits of activity (e.g., hypoactivity or hyperactivity) during the testing period.
  • Locomotor activity is detected by photobeam breaks as the animal crosses each beam. Measurements used to assess locomotor activity include, for example, total distance traveled, total number of rearing events (animal raises up on hindlimbs), and distance traveled in the center compared to total distance traveled (center: total distance ratio). Typically, mice are placed in the center of the field. Mice will normally explore the edges/walls first and then, over time, spend more time in the center as they become familiar with the environment. Open field activity determination provides data on the general activity level of mice (i.e. hypo- or hyper-active), as well as an indication of the animal's anxiety-related behaviors in an open-space.
  • EEG electroencephalograph
  • EMG electromyography
  • EEG electroencephalograph
  • EMG electromyography
  • EEG electroencephalograph
  • EMG electromyography
  • Stereotaxic placement of electrodes onto the cortex for EEG recording and bilateral placement of electrodes into the trapezius muscle in the neck (EMG) allow the different stages of wake and sleep to be analyzed.
  • Animals that display disrapted or altered sleep pattern may serve as models for screening for drugs that treat sleep disorders such as dysomnias and parasomnias.
  • Tests for determining whether a mouse has altered coordination or movement include the Balance Beam test, Bilateral Tactile Stimulation test, Circling Behavior test, Disengage test, Grip Strength test, Holeboard test, Paw Reaching test, Parallel Bar Walking test, Ring Catalepsy test, Rotorod test, Sterotypy Behavior test, or Vertical Pole test. Coordination and movement can also be assessed by assessment of exercise capacity, footprint pattern, forelimb asymmetry, posture, and gait.
  • motor coordination and skill learning is assessed using the rotarod assay, which measures the ability of an animal to maintain balance on an accelerating rotating rod.
  • the mice must walk continuously to avoid falling off (see Crawley and Paylor, Hormones and Behavior 31 : 197-211 (1997)). Animals are generally given multiple trials spaced at least 20 minutes apart to allow for recovery from any fatigue testing may cause. In general, the time the animal spends walking on top of the rotating rod increases over the trials, thus demonstrating motor coordination and the ability to leam a rudimentary skill. This test relates to coordination and balance deficiencies.
  • Feeding and ingestive behaviors can be examined, for example, by monitoring 24 hour food consumption, 24 hour water consumption, body weight during development, circadian feeding patterns, conditioned taste aversion, conditioned taste preference, fasting studies (e.g., weight loss during fasting, weight gain after fasting, feeding response after fasting), liquid intake, macronutrient choice, novel food preference, rebound food consumption response after restricted daily access to food, response to specialized diets (e.g., cafeteria diet, high or low protein diet, high or low fat diet, and high or low carbohydrate diet), susceptibility to acute administration of pharmacological agents in feeding paradigms, and susceptibility to chronic administration of pharmacological agents in feeding paradigms.
  • fasting studies e.g., weight loss during fasting, weight gain after fasting, feeding response after fasting
  • liquid intake macronutrient choice
  • novel food preference e.g., rebound food consumption response after restricted daily access to food
  • response to specialized diets e.g., cafeteria diet, high or low protein diet
  • Food consumption over consecutive days may be determined, e.g., during the monitoring of home cage activity.
  • the amount of consumed food and the body weight of the mouse are determined at various timepoints. If desired, the frequency and duration of eating may also be determined. This assay provides insight into the appetite and eating habits that might relate to eating conditions or disorders.
  • Sexual responsiveness can be tested, e.g., in a clear chamber with video recording.
  • Male mice are tested to determine if they respond normally to a female mouse.
  • Measurements used to assess normal male responsiveness include, but not limited to, mount latency, mount frequency, pelvic thrusts, intromissions, and ejaculation.
  • Female mice are also tested to determine their sexual receptivity to a male. Measurements used to assess normal female receptivity involve assessing the degree and frequency of lordosis behavior.
  • Sexual behaviors can also be measured by examining sexual motivation, ethologically relevant behaviors (e.g., anogenital investigation) as part of normal social interactions, susceptibility to acute administration of pharmacological agents in sexual responsiveness assays, and susceptibility to chronic administration of pharmacological agents in sexual responsiveness assays. These assays can be used to determine sexual activity in general and to detect any abnormal sexual behavior that might relate to sexual conditions or disorders.
  • Nociceptive behaviors can be assessed using a test that measures, for example, allodynia as a model for chronic pain, inflammatory pain, pain threshold, sensitivity to drag-induced analgesia, thermal pain, mechanical pain, chemical pain, hyperalgesia, or shock sensitivity.
  • allodynia as a model for chronic pain, inflammatory pain, pain threshold, sensitivity to drag-induced analgesia, thermal pain, mechanical pain, chemical pain, hyperalgesia, or shock sensitivity.
  • Particular tests include the allodynia/place avoidance, calibrated von Frey hairs for mechanical pain, cold plate test, cold water tail immersion test, conditioned suppression, formalin paw assay, Hargreaves test, hot plate test, hot water tail immersion test, paw pressure test, paw withdrawal, plantar test, tail flick test, tail pressure test, and the writhing test, susceptibility to acute administration of pharmacological agents in nociception tests, and susceptibility to chronic administration of pharmacological agents in nociception tests.
  • a mouse's nociception is assessed by placing the mouse on a 55°C hot plate. The latency to a hind limb response (shake or lick) is measured.
  • This assay provides data on the animal's general analgesic response to a thermal stimulus, and is used to detect a nociceptive condition or disorder.
  • the formalin paw assay measures the response to a noxious chemical injected into the hindpaw. Licking and biting of the hindpaw is quantified as the amount of time engaged in these activities. Two phases of responses are demonstrated with the first phase representing an acute pain response and the second phase representing a hyperalgesic response. Alterations in this normal biphasic display may serve as a model of various forms of pain and chronic pain disorders (Abbott et al., Pain 60: 91-102 (1995)).
  • Tests that measure or detect anxiety-related behaviors include acoustic startle habituation, acoustic startle reactivity, active avoidance, the canopy test, conditioned emotional response, conditioned suppression of drinking, conditioned ultrasonic vocalization, dark light emergence task, defensive burying, dPAG-induced flight, elevated plus maze, elevated zero maze, exploration tests in a novel environment, fear- potentiated startle, food exploration test, four plate test, Gellar-Seifter conflict test, light- dark box, light-enhanced startle, marble burying test, minor chamber, novelty supressed feeding, pain-induced ultrasonic vocalizations, petition test, passive avoidance, probe burying test, punished locomotion test, separation-induced ultrasonic vocalizations, shock sensitization of startle response, social competition, social interaction, staircase test, susceptibility to acute administration of pharmacological agents in anxiety-related assays, and susceptibility to chronic administration of pharmacological agents in anxiety-related assays.
  • the light-dark exploration test measures the conflict between the natural tendencies of mice to explore novel environments but to avoid the aversive properties of brightly lit (anxiety-provoking) open areas.
  • the brightly lit compartment encompasses about two-thirds of the surface area, while the dark compartment encompasses the remaining one-third of the area.
  • An opening is designed to allow the mouse access to both compartments.
  • the mouse is placed at the one end of the brightly lit compartment.
  • the latency to enter the dark compartment, total time spent in the dark compartment, and the number of transitions between the two compartments is measured to give a sense of an anxiety-related response that might be related to an anxiety condition or disorder.
  • Tests for identifying stress-related behaviors include electric footshock stress tests, handling stress test, maternal separation stress test, restraint induced stress test, sleep deprivation stress test, social isolation stress test, swim stress test, stress-induced hyperthermia, and susceptibility to acute or chronic administration of pharmacological agents in stress-related tasks. These assays provide the ability to study stress and to provide insight into behaviors that may be related to stress conditions or disorders.
  • Tests for identifying fear-related behaviors in rodents include conditioned fear, fear potentiated startle, fear-response behavior, mouse defense test battery, ultrasonic vocalization test, and susceptibility to acute or chronic adminisfration of pharmacological agents in fear-related tests. These assays provide the ability to study emotional based behaviors that may be related to fear-based conditions or disorders. Depression-related tests include acute restraint, chronic restraint, circadian activity, conditioned defensive burying, differential reinforcement to low rate of responding, learned helplessness, Porsolt forced swim test, tail suspension test, sucrose preference test, and susceptibility to acute or chronic administration of pharmacological agents in depression-related tests.
  • tail suspension test Another is the tail suspension test, which includes suspending a mouse by its tail and measuring the duration of time it continues to straggle to escape from an inescapable situation. The time spent struggling is considered a measure of learned helplessness behavior or behavioral despair. The latency to the onset of the end of the straggling can be increased by clinically effective antidepressants.
  • This assay therefore can be used to identify mice that may serve as models for depressive disorders.
  • Mood related behavioral assays include latent inhibition, marble burying, prepulse inhibition of the acoustic startle response, and susceptibility to acute and chronic administration in mood-related tests.
  • Prepulse inhibition of the acoustic startle response occurs when a loud (120 dB) startle stimulus is preceded by a softer tone that does not elicit a startle response (the prepulse). It is believed that this is a measure of a filtering mechanism in the nervous system that allows an individual to focus on important incoming information and to ignore unimportant information. Schizophrenic patients have been documented to have impaired prepulse inhibition; therefore this test can be used employing mice to identify those having a response that may be indicative of schizophrenia or another psychotic disorder.
  • Suitable tests for assessing a mouse's learning and memory capacity include, for example, those that measure active avoidance, autoshaping, bames maze, conditioned taste aversion, conditional spatial alternation, context and auditory cued conditioned fear, contextual discrimination, delayed matching to position, delayed matching/non- matching to position, eyeblink conditioning, fear potentiated startle, figure 8 maze, holeboard test, motor learning using an accelerated rotarod, place aversion test, novel object recognition, olfactory discrimination, passive-avoidance, position/response learning, schedule-induced operant behaviors, radial arm maze, social recognition, social transmission of food preference, step down avoidance, taste learning, temporal processing using the Peak procedure, trace conditioning, T maze avoidance, transverse patterning, visual discrimination, water maze, place memory test, vigilance test, and Y maze, and Y maze avoidance.
  • the Morris water maze test is an assay that measures spatial learning and memory.
  • An animal is trained in a pool of opaque water to locate a platform hidden under the water's surface using spatial cues external cues in the room. Measurements of spatial learning require analysis of spatial selectivity on a probe trial, in which the platform has been removed and the pattern in which the animal searches is examined. An animal that has learned the position of the platfonn using spatial cues will spend more time in the quadrant where the platform was located, and will also cross the precise location of the platform more often versus other possible sites.
  • This complex learning task provides a way to determine learning and memory deficits and enhancements, and offers insight into the neural mechanisms of learning and memory (Crawley et al., Psychopharmacology 132: 107-124 (1997)).
  • Context and auditory cue fear conditioning i.e., conditioned fear
  • The.training day consists of placing the mouse in the chamber and allowing it to explore the environment.
  • a white noise is turned on (i.e., the conditioning stimulus, CS).
  • a footshock is paired with the white noise turning off.
  • This training trial is then repeated again.
  • the mouse is returned to its home cage. The mouse is tested 24 hours later by separately assaying the amount of freezing exhibited in the context in which it was shocked (Context Test) and the amount of freezing exhibited to the white noise (CS Test).
  • Aggression and other social behaviors can be monitored by observation or quantification of behaviors such as grooming, home cage behaviors (e.g., nesting, huddling, playing, and barbering) isolation-induced fighting, maternal behavior, parental behavior, social interaction, social investigation.
  • behaviors include the Partition test, the social defeat test, the Resident versus Intruder test, and the Social Place Preference test. Any of the foregoing can be used to determine a mouse's susceptibility to acute or chronic administration of pharmacological agents.
  • the resident-intruder paradigm is an assay that demonstrates species-specific aggressive behavior. This test is conducted by individually housing an animal (the resident) and introducing a new animal of the same gender (the intrader) into the cage.
  • the new animal is viewed by the resident animal as an intruder and displays aggressive behaviors toward the intruder (Crasio, Behavior Genetics 26: 459-533 (1996)).
  • the normal display of aggression towards an intrader may serve as a model for examining increased or decreased aggression to a normal environmental situation.
  • One test for social dominance can be carried out to assay social interactions and social behaviors.
  • a mouse is placed into the end of a plexiglass cylinder and another mouse (called a social cohort) is placed at the other end of the tube.
  • the animal that backs out of the tube first is considered the loser and the mouse that remains in the tube is considered the winner.
  • an animal that backs out of the tube during the first round generally backs out of the tube in subsequent rounds.
  • a ranking can then be given to each animal, thus identifying the dominance or submissive status of an animal within a social context, as well as detecting abnormal social behaviors that can be related to antisocial personality conditions or disorders.
  • Behaviors relating to reward and addiction are assessed using tests that measure, for example, reward and place preference, self-administration of drags of abuse (acute and chronic), sensitization and tolerance to drags of abuse, sensitization to the motor activating properties of drags, tolerance to repeated analgesic drag adminisfration, or withdrawal symptoms after repeated self-administration of drags of abuse.
  • self-administration of drags of abuse acute and chronic
  • sensitization and tolerance to drags of abuse sensitization to the motor activating properties of drags
  • tolerance to repeated analgesic drag adminisfration tolerance to repeated analgesic drag adminisfration
  • withdrawal symptoms after repeated self-administration of drags of abuse.
  • the impact on self-administration of drags of abuse in stress tests can also be used to assess addiction.
  • mice Tolerance and sensitivity to. ethanol and cocaine can be tested, for example, by examining core body temperature of the mice after an infra-peritoneal (i.p.) injection of cocaine or ethanol.
  • Initial sensitivity to cocaine and alcohol can be measured in mice after a single (acute) dose. In rodents, repeated exposure to alcohol or cocaine via repeated injections across days has been shown to produce tolerance.
  • mice are administered an i.p. dose, and core body temperature is measured post injection with a digital thermometer with a rectal probe. On Day 2, mice are administered the same dose using the same route, and temperature again recorded post injection.
  • mice will be administered an i.p.
  • mice will be administered the same dose using the same route and temperature will be recorded post injection. Tolerance to the drug is indicated by an increase in body temperature on the second day of drag administration compared to the first day of drug administration.
  • the rewarding effects of various substances of abuse can be studied using the conditioned place preference paradigm and self-administration tests.
  • the place preference paradigm is a non-invasive method that is amenable to classical Pavlovian conditioning.
  • the rewarding drag serves as an unconditioned stimulus (US) that is paired with an environment that serves as the conditioned stimulus (CS).
  • US unconditioned stimulus
  • CS conditioned stimulus
  • This Pavlovian conditioned response to a drag of abuse has been postulated to be involved in drug-seeking behavior and relapse following exposure to cues that were previously associated with drag use.
  • a drag such as bicuculine can be utilized to study an animal's susceptibility to seizures or seizure-like events. Mice that enter into classical seizure symptoms earliest are considered to be more susceptible to seizures. Likewise, mice that present seizure symptoms later than normal, are considered to be more resistant to seizures. This assay may allow the identification of alterations central to the formation of seizure disorders and related conditions.
  • the animals having mutant nuclear receptor genes are useful for further testing of efficacy and safety of drags or agents first identified using one of the other screening methods described herein.
  • Cells taken from the animal and placed in culture can also be exposed to test compounds.
  • the effect of overexpression, underexpression, misexpression, or mutation of a nuclear receptor of the present invention can be assayed, for example, using any of a wide variety, of measurements or tests; Barbee et al., Am. J. Physiol. 263:R728-733,
  • General physiological tests and measurements include, for example, measurement of body temperature, body length and proportions, body mass index, general health appearance, vocalization during handling, and lacrimation and salivation, visual tests (e.g., visual cliff, reaching response, visual menace), auditory tests (e.g., click test, acoustic startle, acoustic threshold), olfactory tests (e.g., sniffing and habituation to a novel odor, finding buried food), reflex tests (e.g., righting reflex, eye blink, whisker twitch), measurement of metabolic hormones (e.g., leptin, IGF-1, insulin, metabolites), whole body densitometry by dual energy x-ray abso ⁇ tiomefry DEXA or high resolution radiography (Faxitron), and necropsy examination of organ systems. Identification of a skin disease or disorder may be made by histopathology, examination of fur and skin condition, examination of pigmentation of fur and skin, and determination of wound healing by an ear punch
  • Cardiac diseases and disorders can be identified, for example, by means of histopathology or electrocardiography, or by determination of blood pressure, blood velocity, blood flow, or pulse rate.
  • Identifying mice having a disorder of the respiratory system can be performed by histopathology, or by determination of lung capacity, respiration rate, VO 2 , pCO 2 , arterial pO 2 , and tidal volume.
  • mice for disorders of the immune and hematopoietic systems including blood, bone manow, thymus, spleen and lymph nodes, can be performed, for example, by histopathology, delayed hypersensitivity test, measurement of seram immunoglobins, blood pH, or coagulation time, volumetric analysis using Evans blue dye technique, or analysis of bone manow smears, hematocrit, hemoglobin, erythrocytes, reticulocytes, leukocytes, platelets, prothrombin, electrolytes, or lymphocytes.
  • Knock-out or transgenic mice of the present invention may have a disease or disorder of the digestive tract (e.g., the esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, and rectum). Testing for these diseases and disorders of the digestive tract, may include fecal analysis, measurement of digestive enzymes, or histopathology. Identification of mice having a disease or disorder of the liver may be by means of histopathology or analysis of total proteins, albumin, bilirabin, creatinine, transaminase, cholesterol, aldolase, ammonia, sorbitol dehydrogenase, or seram bile acids
  • Testing for disorders of the pancreas in mice may be performed, for example, by histopathology, a glucose tolerance test, an insulin challenge test, or analysis of glucose, insulin, glucogon, or exocrine enzymes.
  • Testing for diseases or disorders of the urinary system may include histolopathological examination, or analysis of sodium osmolality, potassium, urea nitrates, creatinine, chloride, bicarbonate, glucose, cystatin c, or urine electrolytes or blood pressure.
  • Testing mice for diseases or disorders of the female reproductive tract may include determination of fertility (e.g., by vaginal plugging), cyclicity (e.g., by vaginal smears), parturition (e.g., by litter size), maternal behavior (e.g., by pup survival and nesting, histopathology, or analysis of levels of estrogens, follicle-stimulating hormone, or luteinizing hormone.
  • determination of fertility e.g., by vaginal plugging
  • cyclicity e.g., by vaginal smears
  • parturition e.g., by litter size
  • maternal behavior e.g., by pup survival and nesting, histopathology, or analysis of levels of estrogens, follicle-stimulating hormone, or luteinizing hormone.
  • testing mice for diseases or disorders of the male reproductive tract including the testis, epididymus, prostate, seminal glands, accessory glands, and penis may include histopathological examination, determination of fertility, sperm counts and motility, erectile capacity (e.g., by plethysmography), and/or analysis of levels of androgens, follicle-stimulating hormone, PSA or luteinizing hormone.
  • Mice having diseases or disorders of the musculature may be identified by histopathology, electromyography, testing of muscle strength and contractibility, or analysis of levels of creatinine, lactate, myoglobin, or isoenzymes.
  • Testing mice for diseases or disorders of the skeletal system may include, for example, bone strength determination, histopathological examination, mineral analysis, dual energy x-ray abso ⁇ tiometry (DEXA), or analysis of osteocalcin, calcitrol, urine pyridinium, or N-telopeptide. Testing mice for diseases or disorders of the endocrine system, including the pituitary, thyroid gland, adrenal gland, and mammary glands, may also be performed.
  • Testing may include, for example, histopathological examination, determination of lactation capacity, testing of hormone release, and/or analysis of corticosterone, adrenocorticotrophic hormone, corticotrophin releasing hormone, thyroid hormone, thyrotropin releasing hormone, thyroid stimulating hormone, chorionic gonadotripin, growth hormone, growth hormone-releasing hormone, somatostatin, prolactin, alpha- melanocyte stimulating hormone, follicle-stimulating hormone, luteinizing hormone, or gonadofropin hormone-releasing hormone.
  • testing for mice for diseases or disorders of the nervous system may include determination of stroke susceptibility (e.g., by focal ischemia or cerebral occlusion), histopathological examination, determination of neurotransmitter release (e.g., by microdialysis or cell culture) or synaptic transmission (e.g., by electrophysiology in brain slices), brain wave analysis by electroencephalography (EEG), whole brain imaging by magnetic resonance imaging, transmitter content determination by HPLC, protein localization and cell type analysis (e.g., by immunohistochemistry), neuron apoptosis determination (e.g., by TUNEL assay), total cell count, or examination of fiber tract localization and integrity, dendritic and axonal mo ⁇ hology, and structural integrity by mo ⁇ hometric analysis.
  • stroke susceptibility e.g., by focal ischemia or cerebral occlusion
  • histopathological examination e.g., determination of neurotransmitter release (e.g., by microdialysis or cell culture) or synaptic
  • Compounds of the invention including but not limited to, nuclear receptor polypeptides, nuclear receptor polynucleotideis, and any therapeutic agent that modulates biological activity or expression of a nuclear receptor polypeptide identified using any of the methods disclosed herein, maybe administered with a pharmaceutically-acceptable diluent, carrier, or excipient, in unit dosage form.
  • a pharmaceutically-acceptable diluent, carrier, or excipient in unit dosage form.
  • Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer such compositions to patients. Any appropriate route of administration may be employed, for example, parenteral, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracistemal, intraperitoneal, intranasal, aerosol, or oral administration.
  • Therapeutic formulations maybe in the form of liquid solutions or suspension; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • parenteral delivery systems for agonists of the invention include ethylenevinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, or example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils,. polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged abso ⁇ tion of the injectable compositions can be brought about by including in the composition an agent which delays abso ⁇ tion, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by inco ⁇ orating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the prefened methods of preparation are vacuum drying and freeze- drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be inco ⁇ orated with excipients and used in the form of tablets, troches, or capsules.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention 5 enemas for rectal delivery.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in
  • ug/kg to 15 mg/kg (e.g., 0.1 to 20 mg/kg) of antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion.
  • a typical daily dosage might range from about 1 ug/kg to 100 mg/kg or more, depending on the factors mentioned above.
  • the treatment is sustained until a desired suppression of disease symptoms occurs.
  • other dosage regimens may be useful.
  • the progress of this therapy can be monitored by standard techniques and assays.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic.index and it can be expressed as the ratio
  • LD50/ED50 Compounds which exhibit large therapeutic indices are prefened. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any . compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
  • treatment of a subject with a therapeutically effective amount of a protein, polypeptide, or antibody can include a single treatment or, preferably, can include a series of treatments.
  • An agent may, for example, be a small molecule.
  • small molecules include, but are not limited to, peptides, peptidomimetics, amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e.,.
  • heteroorganic and organometallic compounds having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds. It is understood that appropriate doses of small molecule agents depends upon a number of factors within the ken of the ordinarily skilled physician, veterinarian, or researcher.
  • the dose(s) of the small molecule will vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable, and the effect which the practitioner desires the small molecule to have upon the nucleic acid or polypeptide of the invention.
  • appropriate doses of a small molecule depend upon the potency of the small molecule with respect to the expression or activity to be modulated. Such appropriate doses may be determined using the assays described herein.
  • an animal e.g., a human
  • a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
  • the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.
  • Expression, biological activity, and mutational analysis of a nuclear receptor gene of the invention can each serve as a diagnostic tool for a disease or disorder involving the nuclear receptor; thus determination of the genetic subtyping of a nuclear receptor gene sequence can be used to subtype individuals or families to determine their predisposition for developing a particular disease or disorder.
  • An exemplary method for detecting the presence or absence of a nuclear receptor protein or nucleic acid in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting nuclear receptor protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes nuclear receptor protein such that the presence of nuclear receptor protein or nucleic acid is detected in the biological sample.
  • a prefened agent for detecting nuclear receptor mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to nuclear receptor mRNA or genomic DNA.
  • the nucleic acid probe can be, for example, a full-length nuclear receptor nucleic acid, such as the nucleic acid of Table 1, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to nuclear receptor mRNA or genomic DNA.
  • a full-length nuclear receptor nucleic acid such as the nucleic acid of Table 1
  • an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to nuclear receptor mRNA or genomic DNA.
  • Other suitable probes for use in the diagnostic assays of the invention are described herein.
  • Another method for detecting the presence or absence of a nuclear receptor protein in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with an antibody that is capable of detecting nuclear receptor protein. Where said antibody capable of binding to the nuclear receptor protein preferably has a detectable label.
  • Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')2) can be used.
  • labeled with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled.
  • indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin.
  • biological sample is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.
  • the detection method of the invention can be used to detect nuclear receptor mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo.
  • in vitro techniques for detection of nuclear receptor mRNA include Northern hybridizations and in situ hybridizations.
  • in vitro techniques for detection of nuclear receptor protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence.
  • In vitro techniques for detection of nuclear receptor genomic DNA include Southern hybridizations.
  • in vivo techniques for detection of nuclear receptor protein include introducing into a subject a labeled anti-nuclear receptor antibody.
  • the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.
  • the biological sample contains protein molecules from the test subject.
  • the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject.
  • a prefened biological sample is a seram sample isolated by conventional means from a subject.
  • the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting nuclear receptor protein, mRNA, or genomic DNA, such that the presence of nuclear receptor protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of nuclear receptor protein, mRNA or genomic DNA in the control sample with the presence of nuclear receptor protein, mRNA or genomic DNA in the test sample.
  • kits for detecting the presence of nuclear receptor in a biological sample can comprise a labeled compound or agent capable of detecting nuclear receptor protein or mRNA in a biological sample; means for determining the amount of nuclear receptor in the sample; and means for comparing the amount of nuclear receptor in the sample with a standard.
  • the compound or agent can be packaged in a suitable container.
  • the kit can further comprise instructions for using the kit to detect nuclear receptor protein or nucleic acid.
  • the diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with abenant nuclear receptor expression or activity.
  • the assays described herein such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with a misregulation in nuclear receptor protein activity or nucleic acid expression, such as a weight, cardiovascular, neurological or endocrine disorder.
  • the prognostic assays can be utilized to identify a subject having or at risk for developing a disorder associated with a misregulation in nuclear receptor protein activity or nucleic acid expression, such as a weight, cardiovascular, neural or endocrine disorder.
  • the present invention provides a method for identifying a disease or disorder associated with abenant nuclear receptor expression or activity in which a test sample is obtained from a subject and nuclear receptor protein or nucleic acid (e.g., mRNA or genomic DNA) is detected, wherein the presence of nuclear receptor protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with abenant nuclear receptor expression or activity.
  • a test sample refers to a biological sample obtained from a subject of interest.
  • a test sample can be a biological fluid (e.g., seram), cell sample, or tissue.
  • the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, ' protein, peptide, nucleic acid, small molecule, or other drag candidate) to treat a disease or disorder associated with abenant nuclear receptor expression or activity.
  • an agent e.g., an agonist, antagonist, peptidomimetic, ' protein, peptide, nucleic acid, small molecule, or other drag candidate
  • such methods can be used to determine whether a subject can be effectively treated with an agent for a weight, cardiovascular, neural or endocrine disorder.
  • the present invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with abenant nuclear receptor expression or activity in which a test sample is obtained and nuclear receptor protein or nucleic acid expression or activity is detected.
  • the methods of the invention can also be used to detect genetic alterations in a nuclear receptor gene, thereby determining if a subject with the altered gene is at risk for a disorder characterized by misregulation in nuclear receptor protein activity or nucleic acid expression, such as a weight, cardiovascular, neural or endocrine disorder.
  • the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic alteration characterized by at least one of an alteration affecting the integrity of a gene encoding a nuclear receptor -protein, or the mis- expression of the nuclear receptor gene.
  • such genetic alterations can be detected by ascertaining the existence of at least one of 1) a deletion of one or more nucleotides from a nuclear receptor gene; 2) an addition of one or more nucleotides to a nuclear receptor gene; 3) a substitution of one or more nucleotides of a nuclear receptor gene, 4) a chromosomal reanangement of a nuclear receptor gene; 5) an alteration in the level of a messenger RNA transcript of a nuclear receptor gene, 6) abenant modification of a nuclear receptor gene, such as of the methylation pattern of the genomic DNA, 7) the presence of a non- wild type splicing pattern of a messenger RNA transcript of a nuclear receptor gene, 8) a non- wild type level of a nuclear receptor-protein, 9) allelic loss of a nuclear receptor gene, and 10) inappropriate post-translational modification of an nuclear receptor- protein.
  • assays known in the art which can be used for detecting alterations in
  • detection of the alteration involves the use of a probe/primer in a polymerase chain reaction (PCR) such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al. (1988) Science 241:1077-1080; and Nakazawa et al. (1994) Proc. Natl. Acad Sci. USA 91:360- 364), the latter of which can be particularly useful for detecting point mutations in the nuclear receptor - gene (see Abravaya et al. (1995) Nucleic Acids Res.23:675-682).
  • PCR polymerase chain reaction
  • LCR ligation chain reaction
  • This method can include the steps of collecting a sample of cells from a subject, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers which specifically hybridize to a nuclear receptor gene under conditions such that hybridization and amplification of the nuclear receptor gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.
  • nucleic acid e.g., genomic, mRNA or both
  • Alternative amplification methods include: self sustained sequence replication (Guatelli, J.C et al., (1990) Proc. Natl. Acad Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh, D. Y. et al., (1989) Proc. Nail. Acad Sci. USA 86:1173- 1177), Q-Beta Replicase (Lizardi, P.M. et al. (1988) Bio-Technology 6:1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.
  • mutations in a nuclear receptor gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns.
  • sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA.
  • sequence specific ribozymes can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.
  • genetic mutations in nuclear receptor can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density anays containing hundreds or thousands of oligonucleotides probes (Cronin, M.T. et al. (1996) Human Mutation 7: 244-255; Kozal, M.J. et al. (1996) Nature Medicine 2: 753- 759).
  • genetic mutations in nuclear receptor can be identified in two dimensional anays containing light-generated DNA probes as described in Cronin, M.T. et al. (1996) Human Mutation 7: 244-255.
  • a first hybridization anay of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear anays of sequential overlapping probes. This step allows the identification of point mutations. This step is followed by a second hybridization anay that allows the characterization of specific mutations by using smaller, specialized probe anays complementary to all variants or mutations detected.
  • Each mutation anay is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.
  • any of a variety of sequencing reactions known in the art can be used to directly sequence the nuclear receptor gene and detect mutations by comparing the sequence of the sample nuclear receptor with the conesponding wild- type (control) sequence.
  • sequencing reactions include those based on techniques developed by Maxam and Gilbert (1977) Proc. Natl. Acad. Sci. USA 74:560 or Sanger (1977) Proc. Nati. Acad. Sci. USA 74:5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays ((1995) Biotechniques 19:448), including sequencing by mass spectrometry (Cohen et al. (1996) Adv. Chromatogr.
  • RNA RNA or RNA/DNA heteroduplexes methods in which protection from cleavage agents is used to detect mismatched bases in RNA RNA or RNA/DNA heteroduplexes.
  • Myers et al. (1985) Science 230:1242 methods in which protection from cleavage agents is used to detect mismatched bases in RNA RNA or RNA/DNA heteroduplexes.
  • the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type nuclear receptor sequence with potentially mutant RNA or DNA obtained from a tissue sample.
  • RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with SI nuclease to enzymatically digesting the mismatched regions.
  • either DNA/DNA or RNA DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. For examples see, Cotton et al.
  • control DNA or RNA can be labeled for detection.
  • the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in nuclear receptor cDNAs obtained from samples of cells.
  • DNA mismatch repair enzymes
  • the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches (Hsu et al. (1994) Carcinogenesis 15:1657-1662).
  • a probe based on a nuclear receptor sequence e.g., a wild-type nuclear receptor sequence
  • a cDNA or other DNA product from a test cell(s).
  • the duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like.
  • alterations in electrophoretic mobility will be used to identify mutations in nuclear receptor genes.
  • single strand conformation polymo ⁇ hism maybe used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids (Orita et al. (1989) Proc Nati. Acad. Sci USA: 86:2766, see also Cotton (1993) Mutat. Res. 285:125-144; and Hayashi (1992) Genet. Anal. Tech. AppL. 9:73-79).
  • Single-stranded DNA fragments of sample and control LGR6 nucleic acids will be denatured and allowed to renature.
  • the secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change.
  • the DNA fragments may be labeled or detected with labeled probes.
  • the sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence.
  • RNA rather than DNA
  • the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet 7:5).
  • the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al. (1985) Nature 313:495).
  • DGGE denaturing gradient gel electrophoresis
  • DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR.
  • a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of confrol and sample DNA (Rosenbaum and Reissner (1987) Biophys Chem 265:12753).
  • oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions which permit hybridization only if a perfect match is found (Saiki et al. (1986) Nature 324:163); Saiki et al. (1989) Proc. Natl. Acad Sci USA 86:6230).
  • Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.
  • Oligonucleotides used as primers for specific amplification may cany the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization) (Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme 3' end of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (Prossner (1993) Tibtech 11 :238).
  • amplification may also be performed using Taq ligase for amplification (Barany (1991) Proc. Natl. Acad Sci USA 88:189). In such cases, ligation will occur only if there is a perfect match at the 3' end of the 5' sequence making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.
  • the methods described herein may be performed, for example, by utilizing prepackaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a nuclear receptor gene.
  • Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual is examined to determine the ability of the individual to respond to a particular agent).
  • agents e.g., drugs
  • Agents, or modulators, that have a stimulatory or inliibitory effect on the biological activity or gene expression of a nuclear receptor polypeptide of the invention can be administered to individuals to treat disorders associated with abenant nuclear receptor activity.
  • the pharmacogenomics i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drag
  • Differences in efficacy of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drag.
  • the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype.
  • Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of a nuclear receptor polypeptide of the invention, expression of a nuclear receptor nucleic acid, or polymo ⁇ hic content of nuclear receptor genes in an individual can be determined to select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.
  • Pharmacogenomics deals with clinically significant hereditary variations in the response to drags because of altered drug disposition and abnormal action in affected persons (Eichelbaum, Clin. Exp. Pharmacol. Physiol., 23:983-985, 1996; Linder, Clin. Chem., 43:254-266, 1997). In general, two types of pharmacogenetic conditions can be differentiated.
  • Altered drug action may occur in a patient having a polymo ⁇ hism (e.g., an single nucleotide polymo ⁇ hism or SNP) in promoter, intronic, or exonic sequences of a nuclear receptor polypeptide of the invention.
  • determining the presence and prevalence of polymo ⁇ hisms may allow for prediction of a patient's response to a particular therapeutic agent.
  • polymo ⁇ hisms in the promoter region may be critical in determining the risk that a patient will develop a particular disease or disorder.
  • Gene therapy is another potential therapeutic approach in which normal copies of a gene or nucleic acid encoding sense RNA for a nuclear receptor of the invention are introduced into cells to successfully produce nuclear receptor polypeptide.
  • the gene must be delivered to those cells in a form in which it can be taken up and encode for sufficient protein to provide effective function.
  • nuclear receptor antisense RNA or other inhibitory RNA or a gene that expresses such RNA may be introduced into cells that express, perhaps excessively, a wild-type or polymo ⁇ hic nuclear receptor polypeptide.
  • the gene or RNA must be delivered to those cells in a form in which it can be taken up and provide for sufficient RNA to provide effective function.
  • Retroviral vectors, adenoviral vectors, adenoviras-associated viral vectors, or other viral vectors with the appropriate tropism for a particular cell involved in disease may be used as a gene transfer delivery system for delivering such polynucleotides.
  • Numerous vectors useful for this pu ⁇ ose are generally known (Miller, Human Gene Therapy 15-14,, 1990; Friedman, Science 244:1275-1281, 1989; Eglitis and Anderson, BioTechniques 6:608-614, 1988; Tolstoshev and Anderson, Cun. Opin. Biotech. 1:55- 61, 1990; Sha ⁇ , Lancet 337: 1277-1278, 1991; Cometta et al., Nucl. Acid Res. and Mol.
  • Retroviral vectors are particularly well developed and have been used in clinical settings (Rosenberg et al., N. Engl. J. Med. 323: 370, 1990; Anderson et al., U.S. PatentNo. 5,399,346). Non-viral approaches may also be employed for the introduction of therapeutic DNA into diseased cells.
  • nuclear receptor may be introduced into a cell by lipofection (Feigner et al., Proc. Natl. Acad. Sci. USA 84: 7413, 1987; Ono et al., Neurosci. Lett. 117: 259, 1990; Brigham et al., Am. J. Med. Sci. 298:278, 1989; Staubinger et al., Meth. Enzymol. 101:512, 1983), asialorosonucoid-polylysine conjugation (Wu et al., J. Biol. Chem. 263:14621, 1988; Wu et al., J. Biol. Chem. 264:16985, 1989); or, less preferably, micro-injection under surgical conditions (Wolff et al., Science 247:1465, 1990).
  • Gene transfer can also be achieved using non- viral means requiring introduction of the nucleic acid in vitro.
  • This method would, for example, include calcium phosphate, DEAE dextran, electroporation, and protoplast fusion.
  • Liposomes may also be potentially beneficial for delivery of DNA into a cell.
  • vectors may be introduced into stem cells taken from the patient and clonally propagated for autologous transplant back into that same patient. Delivery by transfection and by liposome injections may be achieved using methods that are well known in the art.
  • nuclear receptor cDNA expression can be directed from any suitable promoter (e.g., the human cytomegalovirus (CMV), simian viras 40 (SV40), or metallothionein promoters), and regulated by any appropriate mammalian regulatory element.
  • CMV human cytomegalovirus
  • SV40 simian viras 40
  • metallothionein promoters e.g., metallothionein promoters
  • enhancers known to preferentially direct gene expression in a particular cell may be used to direct nuclear receptor expression.
  • the enhancers used could include, without limitation, those that are characterized as tissue- or cell-specific in their expression.
  • regulation may be mediated by the cognate regulatory sequences or, if desired, by regulatory sequences derived from a heterologous source, including any of the promoters or regulatory elements described above.
  • Antisense or interfering RNA based strategies may be employed to explore nuclear receptor gene function and as a basis for therapeutic drag design. The principle is based on the hypothesis that sequence-specific suppression of gene expression can be achieved by intracellular hybridization between mRNA and a complementary antisense species. The formation of a hybrid RNA duplex may then interfere with the processing/transport/translation and/or stability of the target nuclear receptor mRNA.
  • Antisense strategies may use a variety of approaches including the use of antisense oligonucleotides and injection of antisense RNA. Antisense effects can be induced by control (sense) sequences; however, the extent of phenotypic changes are highly variable.
  • Phenotypic effects induced by antisense effects are based on changes in criteria such as protein levels, protein activity measurement, and target mRNA levels.
  • sense or antisense oligomers, or larger fragments can be designed from various locations along the coding or control regions of sequences encoding a nuclear receptor of the invention.
  • the complementary oligonucleotide is designed from the most unique 5' sequence and used either to inhibit transcription by preventing promoter binding to the upstream nontranslated sequence or translation of a nuclear receptor encoding transcript by preventing the ribosome from binding.
  • an effective antisense oligonucleotide includes any 15-25 nucleotides spanning the region that translates into the signal or 5' coding sequence of the polypeptide or 21-23 nucleotide spanning region for small interfering RNAs.
  • gene therapy may also be accomplished by direct administration of antisense mRNA to a cell that is expected to be involved in a disease or disorder.
  • the antisense mRNA may be produced and isolated by any standard technique, but it is most readily produced by in vitro transcription using an antisense cDNA under the control of a high efficiency promoter (e.g., the T7 promoter).
  • Administration of antisense mRNA to cells can be carried out by any of the methods for direct nucleic acid administration described above.
  • Ribozymes enzymatic RNA molecules, may also be used to catalyze the specific cleavage of RNA.
  • the mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. Examples, which may be used, include engineered hammerhead motif ribozyme molecules that can specifically and efficiently catalyze endonucleolytic cleavage of sequences encoding a nuclear receptor of the invention.
  • Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites which include the following sequences: GUA, GUU, and GUC.
  • RNA sequences of, e.g., between 15 and 25 ribonucleotides conesponding to the region of the target gene containing the cleavage site may be evaluated for secondary structural features that render the oligonucleotide inoperable.
  • the suitability of candidate targets may also be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays.
  • Antisense molecules and ribozymes of the invention may be prepared by any method known in the art for the synthesis of nucleic acid molecules. These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis.
  • RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding a nuclear receptor polypeptide of the invention. Such DNA sequences may be inco ⁇ orated into a wide variety of vectors with suitable RNA polymerase promoters such as T7 or SP6.
  • these cDNA constructs that synthesize antisense RNA constitutively or inducibly can be introduced into cell lines, cells, or tissues.
  • RNA molecules may be modified to increase intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept can be extended in all of these molecules by the inclusion of nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine, which are not as easily recognized by endogenous endonucleases.
  • nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified forms of adenine, cytidine, guanine,
  • An alternative strategy for inhibiting nuclear receptor function using gene therapy involves intracellular expression of an anti-nuclear receptor antibody or a portion of an anti-nuclear receptor antibody.
  • the gene (or gene fragment) encoding a monoclonal antibody that specifically binds to a nuclear receptor polypeptide and inhibits its biological activity may be placed under the transcriptional control of a cell type-specific gene regulatory sequence.
  • the nuclear receptor sequences (Table 1) taught in the present invention facilitate the design of novel transcription factors for modulating nuclear receptor expression in native cells and animals, and cells transformed or transfected with nuclear receptor polynucleotides.
  • the CYS2-HiS2 zinc fmger proteins which bind DNA via their zinc finger domains, have been shown to be amenable to structural changes that lead to the recognition of different target sequences. These artificial zinc fmger proteins recognize specific target sites with high affinity and are able to act as gene switches to modulate gene expression.
  • Knowledge of the particular nuclear receptor target sequence of the present invention facilitates the engineering of zinc finger proteins specific for the target sequence using known methods such as a combination of structure-based modeling and screening of phage display libraries (Segal et al, Proc. Nat. Acad. Sci. USA 96:2758-2763 (1999); Liu et al, Proc. Nat. Acad. Sci.
  • Each zinc finger domain usually recognizes three or more base pairs. Since a recognition sequence of 18 base pairs is generally sufficient in length to render it unique in any known genome, a zinc finger protein consisting of 6 tandem repeats of zinc fingers would be expected to ensure specificity for a particular sequence (Segal et al.).
  • the artificial zinc finger repeats designed based on nuclear receptor sequences, are fused to activation or repression domains to promote or suppress nuclear receptor expression (Liu et al.).
  • the zinc fmger domains can be fused to the TATA box-binding factor with varying lengths of linker region between the zinc fmger peptide and the TBP to create either transcriptional activators or repressors (Kim et aL, Proc. Nat. Acad. Sci. USA 94:3616-3620 (1997).
  • transcriptional activators or repressors Kim et aL, Proc. Nat. Acad. Sci. USA 94:3616-3620 (1997).
  • Such proteins and polynucleotides that encode them have utility for modulating nuclear receptor expression in vivo in both native cells, animals and humans; and/or cells transfected with nuclear receptor -encoding sequences.
  • the novel transcription factor can be delivered to the target cells by transfecting constructs that express the transcription factor (gene therapy), or by introducing the protein.
  • Engineered zinc finger proteins can also be designed to bind RNA sequences for use in therapeutics as alternatives to antisense or catalytic RNA methods (McColl et aL, Proc. Natl. Acad. Sci. USA 96:9521- 9526 (1997); Wu et aL, Proc. Natl. Acad. Sci. USA 92:344-348 (1995)).
  • the present invention contemplates methods of designing such transcription factors based on the gene sequence of the invention, as well as customized zinc fmger proteins, that are useful to modulate nuclear receptor expression in cells (native or transformed) whose genetic complement includes these sequences.
  • An alternative strategy for inhibiting nuclear receptor function using gene therapy involves intracellular expression of an anti- nuclear receptor antibody or a portion of an anti- nuclear receptor antibody.
  • the gene (or gene fragment) encoding a monoclonal antibody that specifically binds to a nuclear receptor polypeptide and inhibits its biological activity may be placed under the transcriptional confrol of a cell type-specific gene regulatory sequence.

Abstract

The present invention features nuclear receptor polypeptides, polynucleotides, recombinant materials, and transgenic mice, as well as methods for their production. The polypeptides and polynucleotides are useful, for example, in methods of diagnosis and treatment of diseases and disorders. The invention also provides methods for identifying compounds (e.g., agonists or antagonists) using the nuclear receptor polypeptides and polynucleotides of the invention, and for treating conditions associated with nuclear receptor dysfunction with the nuclear receptor polypeptides, polynucleotides, or identified compounds. The invention also provides diagnostic assays for detecting diseases or disorders associated with inappropriate nuclear receptor activity or levels.

Description

NUCLEAR RECEPTOR-BASED DIAGNOSTIC, THERAPEUTIC, AND SCREENING METHODS
Background of the Invention
The invention relates to the fields of medicine and drug discovery. Mammalian nuclear receptors constitute a superfamily of diverse proteins with more than fifty human members (Table 1). Nuclear receptors act as intracellular receptors for a multitude of diverse, usually small lipophilic ligands. Known ligands for the nuclear receptor superfamily include cortisol, estradiol, thyroxine, testosterone, vitamin D3, retinoic acid, progesterone, aldosterone, palmitic acid, stearic acid, and eicosapentaenoic acid. Ligands to nuclear receptors have a number of biological effects and are known to influence human reproduction and sexuality, development, behavior, inflammation, growth, and homeostasis. Generally, in the absence of ligand, nuclear receptors are localized in either the cytoplasm or nucleus in an inactive state. Upon interaction of the nuclear receptor with a ligand, the nuclear receptor adopts an active conformation and, in conjunction with coregulators, acts as a transcriptional regulator. There are currently at least ten drugs on the market that target nuclear receptors, which indicates the biological and therapeutic importance of this receptor family.
Nuclear receptors are composed of four independent but interacting functional modules, the modulator domain, DNA-binding domain, hinge region, and ligand-binding domain. The modulator domain usually contains the transcriptional activation function, and is also known to interact with co-regulators to enhance the activity of the receptor complex. The DNA-binding domain is typically the most conserved domain among nuclear receptors and is involved in DNA interaction. The hinge region is a flexible region that is believed to serve as a hinge between the DNA-binding and ligand-binding domains. The ligand-binding domain is a multifunctional domain that mediates ligand binding, nuclear receptor dimerization, nuclear localization, and interaction with repressor molecules or transcriptional regulators.
Although many of the nuclear receptors have a known physiological ligand, there are nuclear receptors that have no known biological ligand; these nuclear receptors are referred to as orphan receptors (see, e.g., Table 2). There is a need to study members of this receptor family for nuclear receptor polypeptides, polynucleotides, antibodies, genetic models, and modulating compounds for use in the treatment and diagnosis of a wide variety of disorders and diseases.
Summary of the Invention
The present invention provides nuclear receptor polypeptides and polynucleotides, recombinant materials, and transgenic mice, as well as methods for their production. The polypeptides and polynucleotides are useful, for example, in methods of diagnosis and treatment of diseases and disorders. The invention also provides methods for identifying compounds (e.g., agonists or antagonists) using the nuclear receptor polypeptides and polynucleotides of the invention, and for treating conditions associated with nuclear receptor dysfunction with the nuclear receptor polypeptides, polynucleotides, or identified compounds. The invention also provides diagnostic assays for detecting diseases or disorders associated with inappropriate nuclear receptor activity or levels.
In one aspect, the invention features a method of preventing or treating a neurological disease or disorder, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a neurological disease or disorder, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a neurological disease or disorder. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder. The nuclear receptor polypeptide can be in a cell or may be in a cell-free assay system.
In yet another aspect, the invention features another method for determining whether a candidate compound is a compound that may be useful for the treatment of a neurological disease or disorder. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a neurological disease or disorder. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the nuclear receptor polypeptide in the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a neurological disease or disorder. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in any one of Tables 3-14, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder. In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a neurological disease or disorder. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction between the candidate compound and the polypeptide. Interaction between the compound and the polypeptide indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a neurological disease or disorder. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein a change in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder. Preferably, the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a neurological disease or disorder. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in one of Tables 3-14, wherein presence of the mutation indicates that the patient has an increased risk for developing a neurological disease or disorder.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a neurological disease or disorder. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in any one of Tables 3-14, wherein presence of the polymorphism indicates that the patient has an increased risk for developing a neurological disease or disorder. In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the expression level or biological activity of the polypeptide. In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a neurological disease or disorder. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in any one of Tables 3-14, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a neurological disease or disorder.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a neurological disease or disorder. The method includes the step of measuring the patient's expression level of a polypeptide listed in any one of Tables 3-14, wherein an alteration in the expression, relative to normal, indicates that the patient has an increased risk for developing a neurological disease or disorder. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA. Preferred neurological diseases or disorders that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include, without limitation, abetalipoproteinemia, abnormal social behaviors, absence (petit mal) epilepsy, absence seizures, abulia, acalculia, acidophilic adenoma, acoustic neuroma, acquired aphasia, acquired aphasia with epilepsy (Landau- Kleffner syndrome) specific reading disorder, acquired epileptic aphasia, acromegalic neuropathy, acromegaly, action myoclonus-renal insufficiency syndrome, acute autonomic neuropathy, acute cerebellar ataxia in children, acute depression, acute disseminated encephalomyelitis, acute idiopathic sensory neuronopathy, acute intermittent porphyria, acute mania, acute mixed episode, acute pandysautonomia, acute polymorphic disorder with symptoms of schizophrenia, acute polymorphic psychotic disorder without symptoms of schizophrenia, acute purulent meningitis, addiction, Addison syndrome, adenovirus serotypes, adjustment disorders, adrenal hyperfunction, adrenal hypofunction, adrenoleukodystrophy, adrenomyeloneuropathy, advanced sleep- phase syndrome, affective disorder syndromes, agenesis of the corpus callosum, agnosia, agoraphobia, agraphia, agyria, agyria-pachygyria, ahylognosia, Aicardi syndrome, AIDS, akathisia, akinesia, akinetic mutism, akinetopsia, alcohol abuse, alcohol dependence syndrome, alcohol neuropathy, alcohol related disorders, alcoholic amblyopia, alcoholic blackouts, alcoholic cerebellar degeneration, alcoholic dementia, alcoholic hallucinosis, alcoholic polyneuropathy, alcohol-induced anxiety disorders, alcohol-induced dementia, alcohol-induced mood disorders, alcohol-induced psychosis, alcoholism, Alexander's syndrome, alexia, alexia with agraphia, alexia without agraphia, alien hand syndrome, Alper's disease, altered sexuality syndromes, alternating hemiplagia, Alzheimer's disease, Alzheimer-like senile dementia, Alzheimer-like juvenile dementia, amenorrea, aminoacidurias, amnesia, amnesia for offences, amok- type reactions, amorphognosia, amphetamine addiction, amphetamine or amphetaminelike related disorders, amphetamine withdrawal, amyloid neuropathy, amyotrophic lateral sclerosis, anencephaly, aneurysms, angioblastic meningiomas, Angleman's syndrome, anhidrosis, anisocoria, anomia, anomic aphasia, anorexia nervosa, anosmia, anosognosia, anterior cingulate syndrome, anterograde amnesia, antibiotic-induced neuromuscular blockade, antisocial personality disorder, Anton's syndrome, anxiety and obsessive-compulsive disorder syndromes, anxiety disorders, apathy syndromes, aphasia, aphemia, aplasia, apnea, apraxia, arachnoid cyst, archicerebellar syndrome, Arnold-Chiari malformation, arousal disorders, arrhinencephaly, arsenic poisoning, arteriosclerotic Parkinsonism, arteriovenous aneurysm, arteriovenous malformations, aseptic meningeal reaction, Asperger's syndrome, astereognosis, asthenia, astrocytomas, asymbolia, asynergia, ataque de nervios, ataxia, ataxia telangiectasia, ataxic cerebral palsy, ataxic dysarthria, athetosis, atonia, atonic seizures, attention deficit disorder, attention-deficit and disruptive behavior disorders , attention-deficit hyperkinetic disorders, atypical Alzheimer's disease, atypical autism, autism, autism spectrum disorder, avoidant personality disorder, axial dementias, bacterial endocarditis, bacterial infections, Balint's syndrome, ballism, balo disease, basophilic adenoma, Bassen- Kornzweig syndrome, Batten disease, battered woman syndrome, Behcet syndrome, Bell' palsy, benign essential tremor, benign focal epilepsies of childhood, benign intracranial hypertension, benxodiazepine dependence, bilateral cortical dysfunction, Binswanger's disease, bipolar disorder, bipolar type 1 disorder, bipolar type 2 disorder, blepharospasm, body dysmorphic disorder, Bogaert-Bertrand disease, Bogarad syndrome, borderline personality disorder, botulism, Bouffee Delirante-type reactions, brachial neuropathy, bradycardia, bradykinesia, brain abscess, brain edema, brain fag, brain stem glioma, brainstem encephalitis, brief psychotic disorder, broca's aphasia, brucellosis, bulimia, bulimia nervosa, butterfly glioma, cachexia, caffeine related disorders, California encephalitis, callosal agenesis, Canavan's syndrome, cancer pain, cannabis dependence, cannabis flashbacks, cannabis psychosis, cannabis related disorders, carcinoma-associated retinopathy, cardiac arrest, cavernous malformations, cellular (cytotoxic) edema, central facial paresis, central herniation syndrome, central neurogenic hyperventilation, central pontine myelinolysis, central post-stroke syndrome (thalamic pain syndrome), cerebellar hemorrhage, cerebellar tonsillar herniation syndrome, cerebral amyloid (congophilic) angiopathy, cerebral hemorrhage, cerebral malaria, cerebral palsy, cerebral subdural empyema, cerebrotendinous xanthomatosis, cerebrovascular disorders, cervical tumors, cestodes, Charcot-Carie-tooth disease, Chediak-Cigashi disease, Cheiro-oral syndrome, chiari malformation with hydrocephalus, childhood disintegrative disorder, childhood feeding problems, childhood sleep problems, cholesteatomas, chordomas, chorea, chorea gravidarum, choreoathetosis, chromophobe adenoma, chromosomal disorders, chronic biplar major depression, chronic bipolar disorder, chronic demyelinating polyneuritis, chronic depression, chronic fatigue syndrome, chronic gm2 gangliosidosis, chronic idiopathic sensory neuropathy, chronic inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, chronic pain, chronic paroxysmal hemicrania, chronic sclerosing panencephalitis, chronic traumatic encphalopathy, chronobiological disorders, circadian rhythm disorder, circadian rhythm disorders, Claude's syndrome, clonic seizures, cluster headache, cocaine addiction, cocaine withdrawal, cocaine-related disorders, Cockayne's syndrome, colloid cysts of the third ventricle, Colorado tick fever, coma, communicating hydrocephalus, communication disorders, complex partial seizures, compression neuropathy, compulsive buying disorder, conceptual apraxia, conduct disorders, conduction aphasia, conduction apraxia, congenital analgesia, congenital cytomegalovirus disease, congenital hydrocephalus, congenital hypothyroidism, congenital muscular dystrophy, congenital myasthenia, congenital myotonic dystrophy, congenital rubella syndrome, congophilic angiopathy, constipation, coprophilia, cornedlia de lange syndrome, cortical dementias, cortical heteropias, corticobasal degeneration, corticobasal ganglionic degeneration, coxsackievirus, cranial meningoceles, craniopharyngioma, craniorachischisis, craniosynostosis, cranium bifidum, cretinism, Creutzfeldt- Jakob disease, Cri-du-Chat syndrome, cruciate hemiplegia, cryptococcal granulomas, cryptococcosis, culturally related syndromes, culturally stereotyped reactions to extreme environmental conditions (arctic hysteria), Cushing syndrome, cyclothymia, cysticercosis, cytomegalovirus, Dandy- Walker malformation, deafness, defects in the metabolism of amino acids, dehydration, Dejerine-Roussy syndrome, Dejerine-Sottas disease, delayed and advanced sleep phase syndromes, delayed ejaculation, delayed puberty, delayed-sleep-phase syndrome, delerium due to alcohol, delerium due to intoxication, delerium due to withdrawal, delirium, dementia, and amnestic and other cognitive disorders, delusional disorder, delusional disorder: erotomania subtype, delusional disorder: grandiose subtype, delusional disorder :jealousy subtype, delusional misidentification syndromes, dementia due to HIV disease, dementia pugilistica, dementias, dementias associated with extrapyramidal syndrome, dentatorubral-pallidoluysian atrophy, dependent personality disorder, depersonalization disorder, depression, depressive personality disorder, dermoids, developmental speech and language disorder, devic syndrome, devivo disease, diabetes, diabetes insipidus, diabetic neuropathy, dialysis demential, dialysis dysequilibrium syndrome, diencephalic dementias, diencephalic dysfunction, diencephalic syndrome of infancy, diencephalic vascular dementia, diffuse sclerosis, digestive disorders, diphtheria, diplopia, disarthria, disassociation apraxia, disorders of carbohydrate metabolism, disorders of excessive somnolence, disorders of metal metabolism, disorders of purine metabolism, disorders of sexual arousal, disorders of sexual aversion, disorders of sexual desire, disorders of the sleep-wake schedule, dissociative disorders, dorsolateral tegmental pontine syndrome, Down syndrome, Down syndrome with dementia, drug dependance, drug overdose, drag-induced myasthenia, Duchenne muscular dystrophy, dwarfism, dysarthria, dysdiadochokinesia, dysembryoplastic neuroepithelial tumor, dysexecutive syndrome, dysgraphia, dyskinesia, dyskinetic cerebral palsy, dyslexia, dysmetria, dysomnia, dysosmia, dyspareunia, dysphagia, dysphasia, dysphonia, dysplasia, dyspnea, dysprosody, dyssomnia, dyssynergia, dysthesia, dysthymia, dystonia, dystrophinopathies, early adolescent gender identity disorder, early infantile epileptic encephalopthy (Ohtahara syndrome, early myoclonic epileptic encephalopathy, Eaton-Lambert syndrome, echinococcus (hydatid cysts), echolalia, echo virus, eclampsia, Edward's syndrome, elimination disorders, embolismintracerebral hemorrhage, Emery-Dreifuss muscular dystrophy, encephalitis lethargica, encephaloceles, encephalotrigeminal angiomatosis, enophthalmos, enteroviras, enuresis, eosinophilic meningitis, ependymoma, epidural spinal cord compression, epilepsy, episodic ataxia, epstein-barr, equine encephalomyelitis, erectile dysfunction, essential thrombocythemia, essential tremor, esthesioneuroblastoma, excessive daytime somnolence, excessive secretion of antidiuretic hormone, excessive sleepiness, exhibitionism, expressive language disorder, extramedullary tumors, extrasylvian aphasias, extratemporal neocortical epilepsy, fabry's disease, facioscapulohumeral muscular dystrophy, factitious disorder, factitious disorders, false memories, familial dysautonomia, familial periodic paralysis, familial spastic paraparesis, familial spastic paraplegias, fear disorders, feeding and eating disorders of infancy or early childhood, female sexual arousal disorder, fetal alcohol syndrome, fetishism, flaccid dysarthria, floppy infant syndrome, focal inflammatory demyelinating lesions with mass effect, focal neonatal hypotonia, folie a deux, foramen magnum tumors, Foville's syndrome, fragile-x syndrome, Freidrich 's ataxia, Frolich syndrome, frontal alexia, frontal convexity syndrome, frontotemporal dementia, frontotemporal dementias, frotteurism, fungal infection, galactocerebroside lipidosis, galactorrhea, ganglioneuroma, Gaucher disease, gaze palsy, gender identity disorder, generalized anxiety disorder, genital shrinking syndrome (Kotro, Suo-Yang), germ cell tumors, Gerstmann's syndrome, Gerstmann-Straύssler syndrome, Gerstmann-Straussler- Schenker disease, gestational substance abuse syndromes, giant axonal neuropathy, gigantism, Gilles de la Tourette syndrome, glioblastoma multiforme, gliomas, gliomatosis cerebri, global aphasia, glossopharyngeal neuralgia, glycogen storage diseases, gml-gangliosidosis, gm2-gangliosidoses, granular cell tumor, granulocytic brain edema, granulomas, granulomatous angiitis of the brain, Grave's disease, growild typeh hormone deficit , growild typeh-hormone secreting adenomas, guam-Parkinson complex dementia, Guillain-Barre syndrome, Hallervorden-Spatz disease, hallucinogen persisting perception disorder, hallucinogen related disorders, hartnup disease, headache, helminthic infections (trichinellosis), hemangioblastomas, hemangiopericytomas, hemiachromatopsia, hemianesthesia, hemianopsia, hemiballism, hemiballismus, hemihypacusis, hemihypesthesia, hemiparesis, hemispatial neglect, hemophilus influenza meningitis, hemorrhagic cerebrovascular disease, hepatic coma, hepatic encephalopathy, hepatolenticular degeneration (Wilson disease), hereditary amyloid neuropathy, hereditary ataxias, hereditary cerebellar ataxia, hereditary neuropathies, hereditary nonprogressive chorea, hereditary predisposition to pressure palsies, hereditary sensory autonomic neuropathy, hereditary sensory neuropathy, hereditary spastic paraplegia, hereditary tyrosinemia, hermichorea, hermifacial spasm, herniation syndromes, herpes encephalitis, herpes infections, herpes zoster, herpres simplex, heterotopia, hexacarbon neuropathy, histrionic personality disorder, HIV, Holmes- Adie syndrome, homonymous quadrantaposia, Homer's syndrome, human β-mannosidosis, Hunter's syndrome, Huntington's chorea, Huntington's disease, Hurler's syndrome, Hwa-Byung, hydraencephaly, hydrocephalus, hyper thyroidism, hyperacusis, hyperalgesia, hyperammonemia, hypereosinophilic syndrome, hyperglycemia, hyperkalemic periodic paralysis, hyperkinesia, hyperkinesis, hyperkinetic dysarthria, hyperosmia, hyperosmolar hyperglygemic nonketonic diabetic coma, hyperparathyroidism, hyperphagia, hyperpituitarism, hyperprolactinemia, hypersexuality, hypersomnia, hypersomnia secondary to drug intake, hypersomnia- sleep-apnea syndrome, hypersomnolence, hypertension, hypertensive encephalopathy, hyperthermia, hyperthyroidism (Graves disease), hypertonia, hypnagogic (predormital) hallucinations, hypnogenic paroxysmal dystonia, hypoadrenalism, hypoalgesia, hypochondriasis, hypoglycemia, hypoinsulinism, hypokalemic periodic paralysis, hypokinesia, hypokinetic dysarthria, hypomania, hypoparathyroidism, hypophagia, hypopituitarism, hypoplasia, hyposmia, hyposthenuria, hypotension, hypothermia, hypothyroid neuropathy, hypothyroidism, hypotonia, Hyrler syndrome, hysteria, ideational apraxia, ideomotor apraxia, idiopathic hypersomnia, idiopathic intracranial hypertension, idiopathic orthostatic hypotension, immune mediated neuropathies, impersistence, impotence, impulse control disorders, impulse dyscontrol and aggression syndromes, impulse-control disorders, incontinence, incontinentia pigmenti, infantile encephalopathy with cherry-red spots, infantile neuraxonal dystrophy, infantile spasms, infantilism, infarction, infertility, influenza, inhalant related disorders, insomnias, insufficient sleep syndrome, intention tremor, intermittent explosive disorder, internuclear ophthalmoplegia, interstitial (hydrocephalic) edema, intoxication, intracranial epidural abscess, intracranial hemorrhage, intracranial hypotension, intracranial tumors, intracranial venous-sinus thrombosis, intradural hematoma, intramedullary tumors, intravascular lymphoma, ischemia, ischemic brain edema, ischemic cerebrovascular disease, ischemic neuropathies, isolated inflammatory demyelinating CNS syndromes, Jackson-Collet syndrome, Jakob-Creutzfeld disease, Japanese encephalitis, jet lag syndrome, Joseph disease, Joubert's syndrome, juvenile neuroaxonal dystrophy, Kayak-Svimmel, Kearns-Sayre syndrome, kinky hair disease (Menkes syndrome), Kleine-Levin syndrome, kleptomania, Klinefelter's syndrome, Kluver-Bucy syndrome, Koerber-Salus-Elschnig syndrome, Korsakoffs syndrome, krabbe disease, krabbe leukodystrophy, Kugelberg-Welander syndrome, kuru, Lafora's disease, language deficits, language related disorders, latah-type reactions, lateral mass herniation syndrome, lateropulsation, lathyrism, Laurence-Moon Biedl syndrome, Laurence-Moon syndrome, lead poisoning, learning disorders, leber hereditary optic atrophy, left ear extinction, legionella pneumophilia infection, Leigh's disease, Lennoc- Gastaut syndrome, Lennox-Gastaut's syndrome, leprosy, leptospirosis, Lesch-Nyhan syndrome, leukemia, leukodystrophies, Levy-Roussy syndrome, lewy body dementia, lewy body disease, limb girdle muscular dystrophies, limbic encephalitis, limbic encephalopathy, lissencephaly, localized hypertrophic neuropathy, locked-in syndrome, logoclonia, low pressure headache, Lowe syndrome, lumbar tumors, lupus anticoagulants, lyme disease, lyme neuropathy, lymphocytic choriomeningitis, lymphomas, lysosomal and other storage diseases, macroglobinemia, major depression with melancholia, major depression with psychotic features, major depression without melancholia, major depressive (unipolar) disorder, male orgasmic disorder, malformations of septum pellucidum, malignant peripheral nerve sheath tumors, malingers, mania, mania with psychotic features, mania without psychotic features, maple syrup urine disease, Marchiafava-Bignami syndrome, Marcus Gunn syndrome, Marie-Foix syndrome, Marinesco-Sjogren syndrome, Maroteaux-Lamy syndrome, masochism, masturbatory pain, measles, medial frontal syndrome, medial medullary syndrome, medial tegmental syndrome, medication-induced movement disorders, medullary dysfunction, medulloblastomas, medulloepithelioma, megalencephaly, melanocytic neoplasms, memory disorders, memory disturbances, meniere syndrome, meningeal carcinomatosis, meningeal sarcoma, meningial gliomatosis, meningiomas, meningism, meningitis, meningococcal meningitis, mental neuropathy (the numb chin syndrome), mental retardation, mercury poisoning, metabolic neuropathies, metachromatic leukodystrophy, metastatic neuropathy, metastatic tumors, metazoal infections, microcephaly, microencephaly, micropolygyria, midbrain dysfunction, midline syndrome, migraine, mild depression, Millard-Gubler syndrome, Miller-Dieker syndrome, minimal brain dysfunction syndrome, miosis, mitochondrial encephalopathy with lactic acidosis and stroke (melas), mixed disorders of scholastic skills, mixed dysarthrias, mixed transcortical aphasia, Mδbius syndrome, Mollaret meningitis, monoclonal gammopathy, mononeuritis nultiplex, monosymptomatic hypochondriacal psychosis, mood disorders, Moritz Benedikt syndrome, Morquio syndrome, Morton's neuroma, motor neuron disease, motor neurone disease with dementia, motor neuropathy with multifocal conduction block, motor skills disorder , mucolipidoses, mucopolysaccharide disorders, mucopolysaccharidoses, multifocal eosinophilic granuloma, multiple endocrine adenomatosis, multiple myeloma, multiple sclerosis, multiple system atrophy, multiple systems atrophy, multisystemic degeneration with dementia, mumps, Munchausen syndrome, Munchausen syndrome by proxy, muscular hypertonia, mutism, myasthenia gravis, mycoplasma pneumoniae infection, myoclonic seizures, myoclonic-astatic epilepsy (doose syndrome), myoclonus, myotonia congenita, myotonic dystrophy, myotonic muscular dystrophy, nacolepsy, narcissistic personality disorder, narcolepsy, narcolepsy-cataplexy syndrome, necrophilia, nectrotizing encephalomyelopathy, Nelson's syndrome, neocerebellar syndrome, neonatal myasthenia, neonatal seizures, nervios, nerves, neurasthenia, neuroacanthocytosis, neuroaxonal dystrophy, neurocutaneous disorders, neurofibroma, neurofibromatosis, neurogenic orthostatic hypotension, neuroleptic malignant syndrome, neurologic complications of renal transplantation, neuromyelitis optica, neuromyotonia (Isaacs syndrome), neuronal ceroid lipofuscinoses, neuro-ophthalamic disorders, neuropathic pain , neuropathies associated with infections, neuropathy associated with cryoglobulins, neuropathy associated with hepatic diseases, neuropathy induced by cold, neuropathy produced by chemicals, neuropathy produced by metals, neurosyphilis, new variant Creutzfeldt- Jakob disease, nicotine dependence, nicotine related disorders, nicotine withdrawal, niemann-pick disease, nocturnal dissociative disorders, nocturnal enuresis, nocturnal myoclonus, nocturnal sleep-related eating disorders, noecerbellar syndrome, non-alzherimer frontal-lobe degeneration, nonamyloid polyneuropathies associated with plasma cell dyscrasia, non-lethal suicidal behavior, nonlocalizing aphasic syndromes, normal pressure hydrocephalus, Nothnagel's syndrome, nystagmus, obesity, obsessive- compulsive (anankastic) personality disorder, obsessive-compulsive disorder, obstetric factitious disorder, obstructive hyrocephalus, obstructive sleep apnea, obstructive sleep apnoea syndrome, obstructive sleep hypopnoea syndrome, occipital dementia, occlusive cerebro vascular disease, oculocerebrorenal syndrome of lowe, oculomotor nerve palsy, oculopharyngeal muscular dystrophy, oligodendrogliomas, olivopontocerebellar atrophy, ondine's curse, one and a half syndrome, onychophagia, opiate dependance, opiate overdose, opiate withdrawal, opioid related disorders, oppositional defiant disorder, opsoclonus, orbitofrontal syndrome, orgasmic anhedonia, orgasmic disorders, osteosclerotic myeloma, other disorders of infancy, childhood, or adolescence, other medication-induced movement disorders, pachygyria, paedophilia, pain, pain syndromes, painful legs-moving toes syndrome, paleocerebellar syndrome, palilalia, panhypopituitarism, panic disorder, panic disorders, papillomas of the choroid plexus, paraganglioma, paragonimiasis, paralysis, paralysis agitans (shaking palsy), paramyotonia congenita, paraneoplastic cerebellar degeneration, paraneoplastic cerebellar syndrome, paraneoplastic neuropathy, paraneoplastic syndromes, paranoia, paranoid personality disorder, paranoid psychosis, paraphasia, paraphilias, paraphrenia, parasitic infections, parasomnia, parasomnia overlab disorder, parenchymatous cerebellar degeneration, paresis, paresthesia, parinaud's syndrome, Parkinson's disease, Parkinson-dementia complex of guam, Parkinsonism, Parkinsonism-plus syndromes, Parkinson's disease, paroxysmal ataxia, paroxysmal dyskinesia, partial (focal) seizures, partialism, passive-aggressive (negativistic) personality disorder, Patau's syndrome, pathological gambling, peduncular hallucinosis, Pelizaeus-Merzbacher disease, perineurioma, peripheral neuropathy, perisylvian syndromes, periventricular leukomalacia, periventricular white matter disorder, periventricular-inrraventricular hemorrhage, pernicious anemia, peroneal muscular atrophy, peroxisomal diseases, perseveration, persistence of cavum septi pellucidi, persistent vegetative state, personality disorders, pervasive developmental disorders , phencyclidine (or phencyclidine-like) related disorders, phencyclidine delirium, phencyclidine psychosis, phencyclidine-induced psychotic disorder, phenylketonuria, phobic anxiety disorder, phonic tics, photorecepto degeneration, pibloktoq, Pick's disease, pineal cell tumors, pineoblastoma, pineocytoma, pituitary adenoma, pituitary apoplexy, pituitary carcinoma, pituitary dwarfism, placebo effect, Plummer's disease, pneumococcal meningitis, poikilolthermia, polio, polycythemia vera, polydipsia, polyglucosan storage diseases, polymicrogyria, polymyositis, polyneuropathy with dietary deficiency states, polysubstance related disorder, polyuria, pontine dysfunction, pontosubicular neuronal necrosis, porencephaly, porphyric neuropathy, portal-systemic encephalopathy, postcoital headaches, postconcussion syndrome, postencephalic Parkinson syndrome, posthemorrhagic hydrocephalus, postinflammatory hydrocephalus, postpartum depression, postpartum psychoses, postpolio syndrome, postpsychotic depression, post- stroke hypersomnia, post-traumatic amnesia, post-traumatic epilepsy, post-traumatic hypersomnia, post-traumatic movement disorders, post-traumatic stress disorder, post- traumatic syndromes, Prader-Willi syndrome, precocious puberty, prefrontal dorsolateral syndrome, prefrontal lobe syndrome, premenstrual stress disorder, premenstrual syndrome, primary amebic meningoencephalitis, primary CNS lymphoma, primary idiopathic thrombosis, primary lateral sclerosis, primitive neuroectodermal tumors, prion disease, problems related to abuse or neglect, progressive bulbar palsy, progressive frontal lobe dementias, progressive multifocal leukoencephalopathy, progressive muscular atrophy, progressive muscular dystrophies, progressive myoclonic epilepsies, progressive myoclonus epilepsies, progressive non-fluent aphasia, progressive partial epilepsies, progressive rubella encephalitis, progressive sclerosing poliodystrophy (Alpers disease), progressive subcortical gliosis, progressive supranuclear palsy, progressive supranuclear paralysis, progrssive external ophthalmoplegia, prolactinemia , prolactin-sectreting adenomas, prosopagnosia, protozoan infection, pseudobulbar palsy, pseudocyesis, pseudodementia, psychic blindness, psychogenic excoriation, psychogenic fugue, psychogenic pain syndromes, psychological mutism, psychosis after brain injury, psychotic syndromes, ptosis, public masturbation, puerperal panic, pulmonary edema, pure word deafness, pyromania, quadrantanopsia, rabies, radiation neuropathy, Ramsay Hunt syndrome, rape traume syndrome, rapid cycling disorder, rapid ejaculation, Raymond-Cestan-Chenais syndrome, receptive language disorder, recovered memories, recurrent bipolar episodes, recurrent brief depression, recurrent hypersomnia, recurrent major depression, refsum disease, reiterative speech disturbances, relational problems, rem sleep behavior disorder, rem sleep behavioral disorder, repetitive self-mutilation, repressed memories, respiratory dysrhythmia, restless legs syndrome, Rett syndrome, Reye syndrome, rhythmic movement disorders, rocky mountain spotted fever, rostral basal pontine syndrome, rubella, Rubinstein-Taybi syndrome, sadistic personality disorder, salla disease, Sandhoff disease, Sanfilippo syndrome, sarcoid neuropathy, sarcoidosis, scapuloperoneal syndromes, schistosomiasis (bilharziasis), schizencephaly, schizoaffective disorder, schizoid personality disorder, schizophrenia, schizophrenia and other psychotic disorders, schizophrenia-like psychosis, schizophreniform disorder, schizotypal personality disorder, school-refusal anxiety disorder, schwannoma, scrub typhus, seasonal depression, secondary spinal muscular atrophy, secondary thrombosis, sedative hypnotic or anxiolytic-related disorders, seizure disorders, selective mutism, self-defeating (masochistic) personality disorder, semen-loss syndrome (shen-k'uei, dhat, jiryan, sukra prameha), senile chorea, senile dementia, sensory perineuritis, separation anxiety disorder, septal syndrome, septo-optic dysplasia, severe hypoxia, severe myoclonic epilepsy, sexual and gender identity disorders, sexual disorders, sexual dysfunctions, sexual pain disorders, sexual sadism, Shapiro syndrome, shift work sleep disorder, Shy-Drager syndrome, sialidosis, sialidosis type 1 , sibling rivalry disorder, sickle cell anemia, Simmonds disease, simple partial seizures, simultanagnosia, sleep disorders, sleep paralysis, sleep terrors, sleep-related enuresis, sleep-related gastroesophageal reflux syndrome, sleep-related headaches, sleep-wake disorders, sleepwalking, Smith-Magenis syndrome, social anxiety disorder, social phobia, social relationship syndromes, somatoform disorders, somnambulism, Sotos syndrome, spasmodic dysphonia, spasmodic torticollis (wry neck), spastic cerebral palsy, spastic dysarthria, specific developmental disorder of motor function, specific developmental disorders of scholastic skills, specific developmental expressive language disorder, specific developmental receptive language disorder, specific disorders of arithmetical skills, specific phobia, specific speech articulation disorder, specific spelling disorder, speech impairment, spina bifida, spinal epidural abcess, spinal muscular atrophies, spinocerebellar ataxias, spirochete infections, spongiform encephalopathies, spongy degeneration of the nervous system, St. Louis encephalitis, stammer, staphylococcal meningitis, startle syndromes, status marmoratus, steele-richardson-olszewski syndrome, stereotypic movement disorder, stereotypies, stiff-man syndrome, stiff-person syndrome, stimulant psychosis, Strachan syndrome (nutritional neuropathy), streptococcal meningitis, striatonigral degeneration, stroke, strongyloidiasis, sturge-weber disease (Krabbe-Weber-Dimitri disease), stutter, subacute combined degeneration of the spinal cord, subacute motor neuronopathy, subacute necrotic myelopathy, subacute sclerosing panencephalitis, subacute sensory neuronopathy, subarachniod hemorrhage, subcortical aphasia, subfalcine herniation syndrome, substance abuse, substance related disorders, sudanophilic leukodystrophis, sudden infant death syndrome, suicide, sulfatide lipidosis, susto, espanto, meido, sydenham chorea, symmetric neuropathy associated with carcinoma, sympathotonic orthostatic hypotension, syncope, syndromes related to a cultural emphasis on learnt dissociation, syndromes related to a cultural emphasis on presenting a physical appearance pleasing to others (taijin-kyofu reactions), syndromes related to acculturative stress, syringobulbia , syringomyelia, systemic lupus erythematosus, tachycardia, tachypnea, Tangier disease, tardive dyskinesia, Tay-sachs disease, telangiectasia, telencephalic leukoencephalopathy, telephone scatologia, temporal lobe epilepsy, temporoparietal dementia, tension-type headache, teratomas, tetanus, tetany, thalamic syndrome, thallium poisoning, thoracic tumors, thrombotic thrombocytopenic purpura, thyroid disorders, tic disorders, tick paralysis, tick-borne encephalitis, tinnitis, tomaculous neuropathy, tonic seizures, tonic-clonic seizures, torticollis, Tourette syndrome, toxic neuropathies, toxoplasmosis, transcortical motor aphasia, transcortical sensory aphasia, transient epileptic amnesia, transient global amnesia, transitional sclerosis, transvestic fetishism, traumatic brain injury, traumatic neuroma, traumiatic mutism, tremors, trichinosis, trichotillomania, trigeminal neuralgia, trochlear nerve palsy, tropical ataxic neuropathy, tropical spastic paraparesis, trypanosomiasis, tuberculomas, tuberculous meningitis, tuberous sclerosis, tumors,
Turner's syndrome, typhus fever, ulegyria, uncinate fits, Unverricht-Lundborg's disease, upper airway resistance syndrome, upward transtentorial herniation syndrome, uremic encephalopathy, uremic neuropathy, urophilia, vaccinia, varicella-zoster, vascular dementia, vascular malformations, vasculitic neuropathies, vasogenic edema, velocardiofacial syndrome, venous malformations, ventilatory arrest, vertigo, vincristine toxicity, viral infections, visuospatial impairment, Vogt-Koyanagi-Harada syndrome, Von Hippel-Lindau disease, Von Racklinghousen disease, voyeurism, Waldenstrδm's macroglobulinemia, Walker- Warburg syndrome, Wallenburg's syndrome, Walleyed syndrome, Weber's syndrome, Wenicke's encephalopathy, Werdnig-Hoffmann disease, Wernicke's encephalopathy, Wernicke-Korsakoff syndrome, Wernicke's aphasia, West's syndrome, whipple disease, Williams syndrome, Wilson disease, windigo, witiko, witigo, withdrawal with grand mal seizures, withdrawal with perceptual disturbances, withdrawal without complications, Wolman disease, xeroderma pigmentosum, xyy syndrome, Zellweger syndrome. Neurological diseases and disorders that are treated or diagnosed by methods of the invention or for which candidate therapeutic compounds are identified preferably involve at least one of the following neurological tissues: hypothalamus, amygdala, pituitary, nervous system, brainstem, cerebellum, cortex, frontal cortex, hippocampus, striatum, and thalamus or other regions of the central or peripheral nervous system.. In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14. In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14. In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14. In another aspect, the invention features a method of preventing or treating a disease of the adrenal gland including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15 operably linked to a promoter. In still another aspect, the invention features a method of treating or preventing a disease of the adrenal gland including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the adrenal gland. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the adrenal gland. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the adrenal gland. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 15, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the adrenal gland. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system; In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 15, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the adrenal gland.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 15, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the adrenal gland.
In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide. In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 15, wherein increased or decreased levels in the nuclear receptor biological, activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the adrenal gland.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 15, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the adrenal gland. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the adrenal gland that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include 11-hydroxylase deficiency, 17-hydroxylase deficiency, 3β-dehydrogenase deficiency, acquired immune deficiency syndrome, ACTH-dependent adrenal hyperfunction (Cushing disease), ACTH-independent adrenal hyperfunction, acute adrenal insufficiency, adrenal abscess, adrenal adenoma, adrenal calcification, adrenal cysts, adrenal cytomegaly, adrenal dysfunction in glycerol kinase deficiency, adrenal hematoma, adrenal hemorrhage, adrenal histoplasmosis, adrenal hyperfunction, adrenal hyperplasia, adrenal medullary hyperplasia, adrenal myelolipoma, adrenal tuberculosis, adrenocortical adenoma, adrenocortical adenoma with primary hyperaldosteronism
(Conn's syndrome), adrenocortical carcinoma, adrenocortical carcinoma with Cushing's syndrome, adrenocortical hyperfunction, adrenocortical insufficiency, adrenocortical neoplasms, adrenoleukodystrophy, amyloidosis, anencephaly, autoimmune Addison's disease, Beckwith-Wiedemann syndrome, bilateral adrenal hyperplasia, chronic insufficiency of adrenocortical hormone synthesis, complete 21-hydroxylase deficiency, congenital adrenal hyperplasia, congenital adrenal hypoplasia, cortical hyperplasia, desmolase deficiency, ectopic ACTH syndrome, excess aldosterone secretion, excess cortisol secretion (Cushing's syndrome), excess secretion of adrenocortical hormones, excess sex hormone secretion, familial glucocorticoid deficiency, functional "black" adenomas, ganglioneuroblastoma, ganglioneuroma, glucocorticoid remediable hyperaldosteronism, herpetic adrenalitis, hyperaldosteronism, idiopathic Addison's disease, idiopathic hyperaldosteronism with bilateral hyperplasia of zona glomerulosa, latrogenic hypercortisolism, lysosomal storage diseases, macronodular hyperplasia, macronodular hyperplasia with marked adrenal enlargement, malignant lymphoma, malignant melanoma, metastatic carcinoma, metastatic tumors, micronocular hyperplasia, multiple endocrine neoplasia syndromes, multiple endocrine neoplasia type 1 (Wermer syndrome), multiple endocrine neoplasia type 2a (Sipple syndrome), multiple endocrine neoplasia type 2b, neuroblastoma, Niemann-Pick disease, ovarian thecal metaplasia, paraganglioma, partial 21-hydroxylase deficiency, pheochromocytoma, primary aldosteronism (Conn's syndrome), primary chronic adrenal insufficiency (Addison's disease), primary hyperaldosteronism, primary mesenchymal tumors, primary pigmented nodular adrenocortical disease, salt- wasting congenital adrenal hyperplasia, secondary Addison's disease, secondary hyperaldosteronsim, selective hypoaldosteronism, simple virilizing congenital adrenal hyperplasia, Waterhouse- Friderichsen syndrome, and Wolman's disease.
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15. In another aspect, the invention features a method of preventing or treating a disease of the colon including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16, operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the colon including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the colon. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the colon. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the colon. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the colon. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 16, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the colon. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the colon. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the colon. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system. In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the colon. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 16, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the colon. In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the colon. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed, in Table 16, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the colon.
In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide. In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the colon. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 16, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the colon.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the colon. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 16, wherem altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the colon. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA. Diseases of the colon that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute self-limited infectious colitis, adenocarcinoma, adenoma, adenoma-carcinoma sequence, adenomatous polyposis coli, adenosquamous carcinomas, allergic (eosinophilic) proctitis and colitis, amebiasis, amyloidosis, angiodysplasia, anorectal malformations, blue rubber bleb nevus syndrome, brown bowel syndrome, Campylobacter fetus infection, carcinoid tumors, carcinoma of the anal canal, carcinoma of the colon and rectum, chlamidial proctitis, Crohn's disease, clear cell carcinomas, Clostridium difficile pseudomembranous enterocolitis, collagenous colitis, colonic adenoma, colonic diverticulosis, colonic inertia, colonic ischemia, congenital atresia, congenital megacolon (Hirschsprung's disease), congenital stenosis, constipation, Cowden's syndrome, cystic fibrosis, cytomegalovirus colitis, diarrhea, dieulafor lesion, diversion colitis, diverticulitis, diverticulosis, drug-induced diseases, dysplasia and malignancy in inflammatory bowel disease, Ehlers-Danlos syndromes, enterobiasis, familial adenomatous polyposis, familial polyposis syndromes, Gardner's syndrome, gastrointestinal stromal neoplasms, hemangiomas and vascular anomalies, hemorrhoids, hereditary hemorrhagic telangiectasia, herpes colitis, hyperplastic polyps, idiopathic inflammatory bowel disease, incontinence, inflammatory bowel syndrome, inflammatory polyps, inherited adenomatous polyposis syndromes, intestinal hamartomas, intestinal pseudo-obstruction, irritable bowel syndrome, ischemic colitis, juvenile polyposis, juvenile polyps, Klippel-Trenaunay- Weber syndrome, leiomyomas, lipomas, lymphocytic (microscopic) colitis, lymphoid hyperplasia and lymphoma, malakoplakia, malignant lymphoma, malignant neoplasms, malrotation, metastatic neoplasms, mixed hyperplastic and adenomatous polyps, mucosal prolapse syndrome, neonatal necrotizing enterocolitis, neuroendocrine cell tumors, neurogenic tumors, neutropenic enterocolitis, non-neoplastic polyps, Peutz-Jeghers syndrome, pneumatosis cystoides intestinalis, polyposis coli, pseudomembranous colitis, pseudoxanthoma elasticum, pure squamous carcinomas, radiation colitis, schistosomiasis, Shigella colitis (bacilliary dysentery), spindle cell carcinomas, spirochetosis, stercolar ulcers, stromal tumors, systemic sclerosis and CREST syndrome, trichuriasis, tubular adenoma (adenomatous polyp, polypoid adenoma), Turcot's syndrome, Turner's syndrome, ulcerative colitis, villous adenoma, and volvulus.
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16. In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
In another aspect, the invention features a method of preventing or treating cardiovascular disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17 operably linked to a promoter. In still another aspect, the invention features a method of treating or preventing cardiovascular disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a cardiovascular disease or disorder. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a cardiovascular disease or disorder. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a cardiovascular disease or disorder. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a cardiovascular disease or disorder. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 17, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder. In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a cardiovascular disease or disorder. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a cardiovascular disease or disorder. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 17, wherein presence of the mutation indicates that the patient may have an increased risk for developing a cardiovascular disease or disorder. In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 17, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a cardiovascular disease or disorder.
In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide. In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 17, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a cardiovascular disease or disorder.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 17, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a cardiovascular disease or disorder. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
One preferred cardiovascular disease that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified is coronary artery disease. Others include acute coronary syndrome, acute idiopathic pericarditis, acute rheumatic fever, American trypanosomiasis (Chagas' disease), angina pectoris, ankylosing spondylitis, anomalous pulmonary venous connection, anomalous pulmonary venous drainage, aortic atresia, aortic regurgitation, aortic stenosis, aortic valve insufficiency, aortopulmonary septal defect, asymmetric septal hypertrophy, asystole, atrial fibrillation, atrial flutter, atrial septal defect, atrioventricular septal defect, autoimmune myocarditis, bacterial endocarditis, calcific aortic stenosis, calcification of the cental valve, calcification of the valve ring, carcinoid heart disease, cardiac amyloidosis, cardiac arrest, cardiac arrhythmia, cardiac failure, cardiac myxoma, cardiac rejection, cardiac tamponade, cardiogenic shock, cardiomyopathy of pregnancy, chronic adhesive pericarditis, chronic constrictive pericarditis, chronic left ventricular failure, coarctation of the aorta, complete heart block, complete transposition of the great vessels, congenital bicuspid aortic valves, congenital narrowing of the left ventricular outflow tract, congenital pulmonary valve stenosis, congenitally corrected transposition of the great arteries, congestive heart failure, constrictive pericarditis, cor pulmonale, coronary artery origin from pulmonary artery, coronary atherosclerosis, dilated (congestive) cardiomyopathy, diphtheria, double inlet left ventricle, double outlet right ventricle, Ebstein's malformation, endocardial fibroelastosis, endocarditis, endomyocardial fibrosis, eosinophilic endomyocardial disease (Loffler endocarditis), fibroma, glycogen storage diseases, hemochromatosis, hypertensive heart disease, hyperthyroid heart disease, hypertrophic cardiomyopathy, hypothyroid heart disease, idiopathic dilated cardiomyopathy, idiopathic myocarditis, infectious myocarditis, infective endocarditis, ischemic heart disease, left ventricular failure, Libman-Sachs endocarditis, lupus erythematosus, lyme disease, marantic endocarditis, metastatic tumors, mitral insufficiency, mitral regurgitation, mitral stenosis, mitral valve prolapse, mucopolysaccharidoses, multifocal atrial tachycardia, myocardial infarction, myocardial ischemia, myocardial rupture, myocarditis, myxomatuos degeneration, nonatheromatous coronary artery disease, nonbacterial thrombotic endocarditis, noninfectious acute pericarditis, nonviral infectious pericarditis, oblitaerative cardiomyopathy, patent ductus arteriosus, pericardial effusion, pericardial tumors, pericarditis, persistent truncus arteriosis, premature ventricular contraction, progressive infarction, pulmonary atresia with intact ventricular septum, pulmonary atresia with vertricular septal defect, pulmonary insufficiency, pulmonary regurgitation, pulmonary stenosis, pulmonary valve lesions, pulmonary valve stenosis, pyogenic pericarditis, Q fever, radiations myocarditis, restrictive cardiomyopathy, rhabdomyoma, rheumatic aortic stenosis, rheumatic heart disease, rocky mountain spotted fever, rupture of the aortic valve, sarcoid myocarditis, scleroderma, shingolipidoses, sinus brachycardia, sudden death syndrome, syphilis, systemic embolism from mural thrombi, systemic lupus erythematosus, tetralogy of fallot, thiamine deficiency (Beriberi) heart disease, thoracic outlet syndrome, Torsade de Pointes, toxic cardiomyopathy, toxic myocarditis, toxoplasmosis, trichinosis, tricuspid atresia, tricuspid insufficiency, tricuspid regurgitation, tricuspid stenosis, tricuspid valve lesions, tuberculuos pericarditis, typhus, ventricular aneurysm, ventricular fibrillation, ventricular septal defect, ventricular tachycardia, ventriculoarterial septal defect, viral pericarditis, and Wolff-Parkinson- White syndrome. In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
In another aspect, the invention features a method of preventing or treating a disease of the intestine including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the intestine including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the intestine. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the intestine. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the intestine. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the intestine. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 18, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine. In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the intestine. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Tables 18; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine.
In still another aspect, the invention features another method for determining „ whether a candidate compound may be useful for the treatment of a disease or disorder of the intestine. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the intestine. Preferably the nuclear receptor polypeptide is in a cell or a.cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 18, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the intestine.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 18, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the intestine. In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide. In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 18, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the intestine.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 18, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the intestine. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA. Diseases of the intestine that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abdominal hernia, abetalipoproteinemia, abnormal rotation, acute hypotensive hypoperfusion, acute intestinal ischemia, acute small intestinal infarction, adenocarcinoma, adenoma, adhesions, amebiasis, anemia, arterial occlusion, atypical mycobacteriosis, bacterial diarrhea, bacterial overgrowild typeh syndromes, botulism, Campylobacter fetus infection, Campylobacter jejuni, carbohydrate absorption defects, carcinoid tumors, celiac disease (nontropical sprue, gluten-induced enteropathy), cholera, Crohn's disease, chronic intestinal ischemia, Clostridium difficile pseudomembranous enterocolitis, Clostridium perfringens, congenital umbilical hernia, Cronkite-Canada syndrome, cytomegalovirus enterocolitis, diarrhea, diarrhea caused by invasive bacteria, diverticulitits, diverticulosis, dysentery, enteroinvasive and enterohemorrhagic Escherichia coli infection, eosinophilic gastroenteritis, failure of peristalsis, familial polyposis syndromes, food poisoning, fungal enteritis, gangliocytic paragangliomas, Gardner's syndrome, gastrointestinal stromal neoplasms, giardiasis, hemorroids, hernia, hyperplastic polyps, idiopathic inflammatory bowel disease, ileus, imperforate anus, intestinal (abdominal ischemia), intestinal atresia, intestinal cryptosporidiosis, microsporidiosis & isosporiasis in AIDS, intestinal hamartomas, intestinal helminthiasis, intestinal hemorrhage, intestinal infiltrative disorders, intestinal lymphangiectasia, intestinal obstruction, intestinal perforation, intestinal reduplication, intestinal stenosis, intestinal tuberculosis, intussusception, jejunal diverticulosis, juvenile polyposis, juvenile retention polyps, lactase deficiency, lymphomas, malabsorption syndrome, malignant lymphoma, malignant neoplasms, malrotations, mechanical obstruction, Meckel's diverticulum, meconium ileus, mediterranean lymphoma, mesenchymal tumors, mesenteric vasculitis, mesenteric vein thrombosis, metastatic neoplasms, microvillus inclusion disease, mixed hyperplastic and adenomatous polyps, neonatal necrotizing enterocolitis, nodular duodenum, nonocclusive intestinal ischemia, nonspecific duodenitis, nontyphoidal salmonellosis, omphalocele, parasitic infections, peptic ulcer disease, Peutz-Jeghers syndrome, pneumatosis cystoides intestinalis, poorly differentiated neuroendocrine carcinomas, primary lymphoma, protein-losing enteropathy, Salmonella gastroenteritis, sarcoidosis, sarcomas, shigellosis, staphlococcal food poisoning, steatorrhea, sugar intolerance, thrombosis of the mesenteric veins, toxigenic diarrhea, toxigenic Escherichia coli infection, tropical sprue, tubular adenoma (adenomatous polyp, polypoid adenoma), typhoid fever, ulcers, vascular malformations, villous adenoma, viral enteritis, viral gastroenteritis, visceral myopathy, visceral neuropathy, vitelline duct remnants, volvulus, Western-type intestinal lymphoma, Whipple's disease (intestinal lipopystrophy), Yersinia enterocolitica & Yersinia pseudotuberculosis infection, and Zollinger-EUison syndrome. In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
In another aspect, the invention features a method of preventing or treating a disease of the kidney including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the kidney including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the kidney. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the kidney. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney. hi yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the kidney. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the kidney. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 19, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the kidney. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the kidney. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1 , wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the kidney.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the kidney. In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 19, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the kidney. In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 19, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the kidney. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the kidney that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acquired cystic disease, acute (postinfectious) glomerulonephritis, acute infectious interstitial nephritis, acute interstitial nephritis, acute pyelonephritis, acute renal failure, acute transplant failure, acute tubular necrosis, adult polycystic kidney disease, AL amyloid, analgesic nephropathy, anti-glomerular basement membrane disease (Goodpasture's Syndrome), asymptomatic hematuria, asymptomatic proteinuria, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bence Jones cast nephropathy, benign familial hematuria, benign nephrosclerosis and atheromatous embolization, bilateral cortical necrosis, chronic glomerulonephritis, chronic interstitial nephritis, chronic pyelonephritis, chronic renal failure, chronic transplant failure, circulating immune complex nephritis, crescentic glomerulonephritis, cryoglobulinemia, cystic renal dysplasia, diabetic glomerulosclerosis, diabetic nephropathy, dialysis cystic disease, drug induced (allergic) acute interstitial nephritis, ectopic kidney, Fabry's disease, familial juvenile nephronophthisis-medullary cystic disease complex, focal glomerulosclerosis (segmental hyalinosis), glomeralocystic disease, glomeralonephritis, glomerulonephritis associated with bacterial endocarditis, glomerulosclerosis, hemolytic-uremic syndrome, Henoch- Schonlein purpura, hepatitis-associated glomerulonephritis, hereditary nephritis (Alport syndrome), horseshoe kidney, hydronephrosis, IgA nephropathy, infantile polycystic kidney disease, ischemic acute tubular necrosis, light-chain deposit disease, malignant nephrosclerosis, medullary cystic disease, membranoproliferative (mesangiocapiUary) glomeralonephritis, membranous glomeralonephritis, membranous nephropathy, mesangial proliferative glomerulonephritis (includes Berger's Disease), minimal change glomeralar disease, minimal change nephrotic syndrome, nephritic syndrome, nephroblastoma (Wilms tumor), nephronophthisis (medullary cystic disease complex), nephrotic syndrome, plasma cell dyscrasias (monoclonal immunoglobulin-induced renal damage), polyarteritis nodosa, proteinuria, pyelonephritis, rapidly progressive (crescentic) glomeralonephritis, renal agenesis, renal amyloidosis, renal cell carcinoma, renal dysgenesis, renal dysplasia, renal hypoplasia, renal infection, renal osteodystrophy, renal stones (urolithiasis), renal tubular acidosis, renal vasculitis, renovascular hypertension, scleroderma (progressive systemic sclerosis), secondary acquired glomeralonephritis, simple renal cysts, systemic lupus erythematosus, thin basement membrane nephropathy, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, toxic acute tubular necrosis, tubular defects, tubulointerstitial disease in multiple myeloma, urate nephropathy, urinary obstruction, and vasculitis. In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19. In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19. In another aspect, the invention features, a method of preventing or treating a disease of the liver including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the liver including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the liver. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the liver. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the liver. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the liver. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 20, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the liver. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the liver. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the liver. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the liver. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 20, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the liver.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the liver. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 20, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the liver. In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the liver. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 20, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the liver. In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the liver. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 20, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the liver. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the liver that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute alcoholic hepatitis (acute sclerosing hyaline necrosis of the liver), acute graft- versus-host disease, acute hepatitis, acute hepatocellular injury associated with infectious diseases other than viral hepatitis., acute liver failure, acute viral hepatitis, adenovirus hepatitis, Alagille syndrome, alcoholic cirrhosis, alcoholic hepatitis, alcoholic liver disease, alphal-antitrypsin deficiency, amebic abscess, angiolmyolipoma, angiosarcoma, ascending cholangitis, autoimmune chronic active hepatitis (lupoid hepatitis), bile duct adenoma, bile duct cystadenocarcinoma, bile duct cystadenoma, biliary atresia, biliary cirrhosis, biliary papillomatosis, bridging necrosis, Budd-Chiari syndrome, Byler disease, cardiac fibrosis of the liver, Caroli disease, cavernous hemangioma, l cholangiocarcinoma, cholangitic abcess, choleostasis, cholestatic viral hepatitis, chronic active hepatitis, chronic alcoholic liver disease, chronic graft-versus-host disease, chronic hepatic venous congestion, chronic hepatitis, chronic liver failure, chronic passive congestion, chronic viral hepatitis, cirrhosis, combined hepatocellular and cholangiocarcinoma, confluent hepatic necrosis, congenital hepatic fibrosis, Crigler- Najjar syndrome, cryptogenic cirrhosis, cystic fibrosis, defects of coagulation, delta hepatitis, Dubin- Johnson syndrome, epithelioid hemangioendothelioma, erythrohepatic protoporphyria, extrahepatic biliary obstruction (primary biliary cirrhosis), fatty change, fatty liver, focal necrosis, focal nodular hyperplasia, fulminant viral hepatitis, galactosemia, Gilbert's syndrome, glycogen storage diseases, graft-versus-host disease, granulomatous hepatitis, hemangioma, hemangiosarcoma, hemochromatosis, hepatic adenoma, hepatic amebiasis, hepatic encephalopathy, hepatic failure, hepatic schistosomiasis, hepatic veno-occlusive disease, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, hepatoblastoma, hepatocellular adenoma, hepatocellular carcinoma, hepatocellular necrosis, hepatorenal syndrome, hereditary fructose intolerance, hereditary hemochromatosis, herpesvirus hepatitis, hydatid cust, hyperplastic lesions, hypoalbuminenia, infantile hemangioendothelioma, infarction of the liver, infectious mononucleosis hepatitis, inflammatory pseudotumor of the liver, intrahepatic cholangiocarcinoma, intrahepatic cholestasis, intrahepatic protal hypertension, ischemic necrosis (ischemic hepatitis), isoniazid-induced necrosis, jaundice, leptospirosis, liver cell adenoma, liver manifestations of Rocky Mountain spotted fever, macronodular cirrhosis, macrovesicular steatosis, malignant vascular neoplasts, mass lesions, massive hepatocellular necrosis, massive necrosis, mesenchymal hamartoma, metastatic tumors, micronodular cirrhosis, microvesicular steatosis, neonatal (physiologic) jaundice, neonatal hepatitis, neoplastic lesions, nodular transformation (nodular regenerative hyperplasia, nonsuppurative infections, nutritional cirrhosis, nutritional liver disease, oriental cholangiohepatitis, parasitic infestation of the liver, peliosis hepatis, porphyria cutaneo tarda, portal hypertension, portal vein thrombosis, posthepatic portal hypertension, predictable (dose-related) toxicity, prehepatic portal hypertension, primary biliary cirrhosis, primary sclerosing cholangitis, pyogenic liver abcess, Q-fever hepatitis, Rotor's syndrome, sclerosing bile duct adenoma, sclerosing cholangitis, secondary hemochromatosis, submassive necrosis, syphilis, toxic liver injury, tyrosinemia, undifferentiated sarcoma, unpredictable (idiosyncratic) toxicity, vascular lesions, virus-induced cirrhosis, Wilson's disease, and zonal necrosis.
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20. In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
In another aspect, the invention features a method of preventing or treating lung disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21 operably linked to a promoter. In still another aspect, the invention features a method of treating or preventing lung disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a lung disease or disorder. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a lung disease or disorder. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the lung. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the lung.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the lung. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the lung. In still, another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a lung disease or disorder. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 21, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a lung disease or disorder. In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a lung disease or disorder. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a lung disease or disorder.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a lung disease or disorder. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a lung disease or disorder. Preferably, the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a lung disease or disorder. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 21, wherein presence of the mutation indicates that the patient may have an increased risk for developing a lung disease or disorder.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a lung disease or disorder. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 21, wherem presence of the polymorphism indicates that the patient may have an increased risk for developing a lung disease or disorder.
In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a lung disease or disorder. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 21 , wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a lung disease or disorder.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a lung disease or disorder. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 21, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a lung disease or disorder. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Preferred lung diseases (including those of the traches) that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abnormal diffusion, abnormal perfusion, abnormal ventilation, accelerated silicosis, actinomycosis, acute air space pneumonia (acute bacterial pneumonia), acute bronchiolitis, acute congestion, acute infections of the lung, acute interstitial pneumonia, acute necrotizing viral pneumonia, acute organic dust toxic syndrome, acute pneumonia, acute radiation pneumonitis, acute rheumatic fever, acute silicosis, acute tracheobronchitis, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adenovirus, adult respiratory distress syndrome (shock . lung), agenesis, AIDS, air embolism, allergic bronchopulmonary mycosis, allergic granulomatosis and angiitis (Churg-Strauss), allograft rejection, aluminum pneumoconiosis, alveolar microlithiasis, alveolar proteinosis, amebic lung abscess, amniotic fluid embolism, amyloidosis of the lung, anomalies of pulmonary vasculature, anomalous pulmonary venous return, aspiration pneumonia, aplasia, asbestosis, asbestos-related diseases, aspergillosis, asthma, atelectasis, atriovenous fistulas, atypical mycobacterial infection, bacteremia, bacterial pneumonia, benign clear cell tumor, benign epithelial tumors, benign fibrous mesothelioma, berylliosis, blastomycosis, bromchial atresia, bronchial asthma, bronchial carcinoid tumor, bronchial isomerism, bronchial obstruction, bronchial stenosis, bronchiectasis, bronchiolalveolar carcinoma, bronchiolitis, bronchiolitis obliterans-organizing pneumonia, bronchocentric granulomatosis, bronchogenic cyst, bronchopneumonia, bronchopulmonary dysplasia, bronchopulmonary sequestration, bullae, bullous emphysema, cancer, carcinoid tumors, carcinoma of the lung (bronchogenic carcinoma), central (bronchogenic) carcinoma, central cyanosis, centriacinar emphysema, cetrilobular emphysema, chest pain, Chlamydial pneumonia, chondroid hamartoma, chronic airflow obstruction, chronic bronchitis, chronic diffuse interstitial lung disease, chronic idiopathic pulmonary fibrosis, chronic lung abscess, chronic obstructive pulmonary diseases, chronic radiation pneumonitis, chronic silicosis, chylothorax, ciliary dyskinesia, coal worker's pneumoconiosis (anthracosis), coccidioidomycosis, collagen-vascular diseases, common cold, compensatory emphysema, congenital acinar dysplasia, congenital alveolar capillary dysplasia, congenital bronchobiliary fistula, congenital bronchoesophageal fistula, congenital cystic adenomatoid malformation, congenital pulmonary lymphangiectasis, congenital pulmonary overinflation (congenital emphysema), congestion, cough, cryptococcosis, cyanosis, cystic fibrosis, cysticercosis, cytomegalovirus, desquamative interstitial pneumonitis, destructive lung disease, diatomaceous earth pneumoconiosis, diffuse alveolar damage, diffuse pulmonary hemorrhage, diffuse septal amyloidosis, diffuse panbronchiolitis, Dirofilaria immitis, diseases of the pleura, distal acinar (paraceptal) emphysema, drag-induced asthma, drug- induced diffuse alveolar damage, dyspnea, ectopic hormone syndromes, emphysema, empyemnia, eosinophilic pneumonias, exercise-induced asthma, extralobar sequestration, extrinsic allergic asthma, fat emboli, focal dust emphysema, follicular bronchiolitis, follicular bronchitis, foreign-body embolism, Fuller's earth pneumoconiosis, functional resistance to arterial flow (vasoconstriction), fungal granulomas of the lung, fungal infections, Goodpasture's syndrome, graphite pneumoconiosis, gray hepatization, hamartomas, hard metal disease, hemoptysis, hemothorax, herniation of lung tissue, herpes simplex, heterotopic tissues, high-altitude pulmonary edema, histoplasmosis, horseshoe lung, humidifier fever, hyaline membrane disease, hydatid cysts, hydrothorax, hypersensitivity pneumonitis (extrinsic allergic alveolitis), hypoxic vascular remodeling, iatrogenic drug-, chemical-, or radiation- induced interstitial fibrosis, idiopathic interstitial pneumonia, idiopathic organizing pneumonia, idiopathic pulmonary fibrosis (fibrosing alveolitis, Hamman-Rich syndrome, acute interstitial pneumonia), idiopathic pulmonary hemosiderosis, immunologic interstitial fibrosis, immunologic interstitial pneumonitis, immunologic lung disease, infections causing chronic granulomatous inflammation, infections causing chronic suppurative inflammation, infections of the air passages, infiltrative lung disease, inflammatory lesions, inflammatory pseudotumors, influenza, interstitial diseases of uncertain etiology, interstitial lung disease, interstitial pneumonitis in connective tissue diseases, intralobar sequestration of the lung (congenital), intrinsic (nonallergic) asthma, invasive pulmonary aspergillosis, kaolin pneumoconiosis, Kartagner's syndrome, Klebsiella pneumonia, Langerhans' cell histiocytosis (histiocytosis X), large cell undifferentiated carcinoma, larval migration of Ascaris lumbricoides, larval migration of Strongyloides stercoralis, left pulmonary artery "sling", Legionella pneumonia, lipid pneumonia, lobar pneumonia, localized emphysema, long-standing bronchial obstruction, lung abscess, lung collapse, lung fluke, lung transplantation implantation response, lymphangiomyomatosis, lymphocytic interstitial pneumonitis (pseudolymphoma, lymphoma, lymphomatoid granulomatosis, malignant mesothelioma, massive pulmonary hemorrhage in the newborn, measles, meconium aspiration syndrome, mesenchymal cystic hamartomas, mesenchymal tumors, mesothelioma, metal-induced lung diseases, metastatic calcification, metastatic neoplasms, metastatic ossification, mica pneumoconiosis, mixed dust fibrosis, mixed epithelial-mesenchymal tumors, mixed type neoplasms, mucoepidermoid tumor, mucoviscidosis (fibrocystic disease of the pancreas), mycoplasma pneumoniae, necrotizing bacterial pneumonia, necrotizing sarcoid granulomatosis, neonatal respiratory distress syndrome, neoplasms of the pleura, neuromuscular syndromes, nocardiosis, nondestructive lung disease, North American blastomycosis, occupational asthma, organic dust disease, panacinar emphysema, Pancoast's syndrome, paracoccidioidomycosis, parainfluenza, paraneoplastic syndromes, paraseptal emphysema (paracicatricial), parasilicosis syndromes, parasitic infections of the lung, peripheral cyanosis, peripheral lung carcinoma, persistent pulmonary hypertension of the newborn, pleural diseases, pleural effusion, pleural plaques, pneumococcal pneumonia, pneumoconioses (inorganic dust diseases), Pneumocystis carinii pneumonia, pneumocystosis, pneumonitis, pneumothorax, precapillary pulmonary hypertension, primary (childhood) tuberculosis, primary (idiopathic) pulmonary hypertension, primary mesothelial neoplasms, primary pulmonary hypertensions, progressive massive fibrosis, psittacosis, pulmonary actinomycosis, pulmonary air-leak syndromes, pulmonary alveolar proteinosis, pulmonary arteriovenous malformation, pulmonary blastoma, pulmonary capillary hemangiomatosis, pulmonary carcinosarcoma, pulmonary edema, pulmonary embolism, pulmonary eosinophilia, pulmonary fibrosis, pulmonary hypertension, pulmonary hypoplasia, pulmonary infarction, pulmonary infiltration and eosinophilia, pulmonary interstitial air (pulmonary interstitial emphysema), pulmonary lesions, pulmonary nocardiosis, pulmonary parenchymal anomalies, pulmonary thromboembolism, pulmonary tuberculosis, pulmonary vascular disorders, pulmonary vasculitides, pulmonary veno-occlusive disease, pyothorax, radiation pneumonitis, recurrent pulmonary emboli, red hepatization, respiration failure, respiratory syncytial virus, Reye's syndrome, rheumatoid lung disease, Rickettsial pneumonia, rupture of pulmonary arteries, sarcoidosis, scar cancer, scimitar syndrome, scleroderma, sclerosing hemangioma, secondary (adult) tuberculosis, secondary bacterial pneumonia, secondary pleural neoplasms, secondary pulmonary hypertension, senile emphysema, siderosis, silicate pneumoconiosis asbestosis, silicatosis, silicosis, simple nodular silicosis, Sjόgren's syndrome, small airway lesions, small cell carcinoma, small cell undifferentiated'(oat cell) carcinoma, spontaneous pneumothorax, sporotrichosis, sputum production, squamous (epidermoid) carcinoma, stannosis, staphlococcal pneumonia, suppuration (abscess formation), systemic lupus erythematosus, talcosis, tension pneumothorax, tracheal agenesis, tracheal stenosis, tracheobronchial amyloidosis, tracheobronchomegaly, tracheoesophageal fistula, transient tachypnea of the newborn (neonatal wet lung), tungsten carbide pneumoconiosis, usual interstitial pneumonia, usual interstitial pneumonitis, varicella, viral pneumonia, visceral pleural thickening, Wegener's granulomatosis, and whooping cough (pertussis). In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21. In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21. In another aspect, the invention features a method of preventing or treating muscular disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing muscular disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a muscular disease or disorder. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a muscular disease or disorder. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a muscular disease or disorder. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a muscular disease or disorder. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 22, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a muscular disease or disorder. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a muscular disease or disorder. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a muscular disease or disorder. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 22, wherein presence of the mutation indicates that the patient may have an increased risk for developing a muscular disease or disorder. In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a muscular disease or disorder. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 22, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a muscular disease or disorder.
In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a muscular disease or disorder. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 22, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a muscular disease or disorder.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a muscular disease or disorder. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 22, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a muscular disease or disorder. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Preferred muscular diseases that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abnormalities of ion channel closure, acetylcholine receptor deficiency, acetylcholinesterase deficiency, acid maltase deficiencies (type 2 glycogenosis), acquired myopathies, acquired myotonia, adult myotonic dystrophy, alveolar rhabdomyosarcoma, aminoglycoside drags, amyloidosis, amyotrophic lateral sclerosis, antimyelin antibodies, bacteremic myositis, Batten's disease (neuronal ceroid lipofuscinoses), Becker's muscular dystrophy, benign neoplasms, Bomholm disease, botulism, branching enzyme deficiency (type 4 glycogenosis), carbohydrate storage diseases, carnitine deficiencies, carnitine palmitoyltransferase deficiency, central core disease, centronuclear (myotubular) myopathy, Chagas' disease, chondrodystrophic myotonia, chronic renal disease, congenital fiber type disproportion, congenital muscular dystrophy, congenital myopathies, congenital myotonic dystrophy, congenital paucity of synaptic clefts, cysticercosis, cytoplasmic body myopathy, debranching enzyme deficiency (type 3 glycogenosis), defect in acetylcholine synthesis, denervation, dermatomyositis, diabetes mellitus, diphtheria, disorders of glycolysis, disorders of neuromuscular junction, distal muscular dystrophy, drag induced inflammatory myopathy, Duchenne muscular dystrophy, embryonal rhabdomyosarcoma, Emery- Dreifuss muscular dystrophy, exotoxic bacterial infections, facioscapulohumeral muscular dystrophy, failure of neuromuscular transmission, fiber necrosis, fibromyalgia, fingerprint body myopathy, Forbe's disease, gas gangrene, Guillain-Barre syndrome, inclusion body myositis, infantile spinal muscular atrophies, infectious myositis, inflammatory myopathies, influenza, Isaac's syndrome, ischemia, Kearns-Sayre syndrome, lactase dehydrogenase deficiency, Lambert-Eaton syndrome, Leigh's disease, leukodystrophies, limb girdle muscular dystrophy, lipid storage myopathies, Luft's disease, lysosomal glycogen storage disease with normal acid maltase activity, malignant neoplasms, malignant hyperthermia, McArdle's disease, MELAS syndrome (mitochondrial myopathy, encephalopathy, lacticacidosis, and strokes), MERRF syndrome (myoclonus epilepsy with ragged-red fibers), metabolic myopathies, microfϊber myopathy, mitochondrial myopathies, multicore disease (minicore disease), multisystem triglyceride storage disease, muscle wasting from diabetes, muscular dystrophies, myasthenia gravis, myasthenic syndrome (Eaton-Lambert syndrome), myoadenylate deaminase deficiency, myoglobinuria, myopathies, myophosphorylase deficiency (type 5 glycogenosis), myositis, myositis ossificans, myotonia congenita, myotonic muscular dystrophy, nemaline myopathy, ocular muscular dystrophy, oculopharyngeal muscular dystrophy, paramyotonia, parasitic myopathies, periodic paralysis, peripheral neuropathies, phosphofructokinase deficiency (type 7 glycogenosis), phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, pleomorphic rhabdomyosarcoma, polymyositis, Pompe's disease, progressive muscular atrophy, progressive systemic sclerosis, reducing body myopathy, Refsum' s disease, rhabdomyolysis, rhabdomyoma, rhabdomyosarcoma, sarcoidosis, sarcoma botryoides, sarcotubular myopathy, secondary congenital myopathies, slow channel syndrome, spasmodic torticollis, spheroid body myopathy, spinal muscular atrophy, steroid myopathy, stiff-person syndrome, systemic lupus erythematosus, Tauri's disease, tick paralysis, toxic myopathies, toxoplasmosis, trichinosis, trilaminar fiber myopathy, type 2 myofiber atrophy, typhoid fever, vasculitis, viral myositis, and zebra body myopathy. In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22. In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
In another aspect, the invention features a method of preventing or treating a disease of the ovary including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the ovary including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the ovary. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be usefubfor the treatment of disease or disorder of the ovary. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the ovary. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherem altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the ovary. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 23, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary. In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the ovary. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the ovary. This .method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the ovary. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 23, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the ovary. In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 23, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a disease or disorder of the ovary.
In either of these two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide. In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 23, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the ovary.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 23, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the ovary. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the ovary that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include autoimmune oophoritis, brenner tumors, choriocarcinoma, clear cell adenocarcinoma, clear cell carcinoma, corpus luteal cysts, decidual reaction, dysgerminoma, embryonal carcinoma, endometrioid tumors, endometriosis, endometriotic cysts, epithelial inclusion cysts, fibrothecoma, follicular cysts, gonadoblastoma, granulosa-stroma cell tumors, granulosa-theca cell tumor, gynandroblastoma, hilum cell hypeφlasia, luteal cysts, luteal hematomas, luteoma of pregnancy, massive ovarian edema, metastatic neoplasm, mixed germ cell tumors, monodermal tumors, mucinous tumors, neoplastic cysts, ovarian changes secondary to cytotoxic drags and radiation, ovarian fibroma, polycystic ovary syndrome, pregnancy luteoma, premature follicle depletion, pseudomyxoma peritonei, resistant ovary, serous tumors, Sertoli-Leydig cell tumor, sex-cord tumor with annular tubules, steroid (lipid) cell tumor, stromal hyperplasia, stromal hyperthecosis, teratoma, theca lutein cysts, thecomas, transitional cell carcinoma, undifferentiated carcinoma, and yolk sac carcinoma (endodermal sinus tumor).
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23. In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
In another aspect, the invention features a method of preventing or treating blood disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing blood disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a blood disease or disorder. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor, polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a blood disease or disorder. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a blood disease or disorder. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a blood disease or disorder In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a blood disease or disorder. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a blood disease or disorder.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a blood disease or disorder. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 24, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a blood disease or disorder.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a blood disease or disorder. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a blood disease or disorder. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a blood disease or disorder. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the , polypeptide not contacted with the compound, ndicates that the candidate compound may be useful for the treatment of a blood disease or disorder. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system. In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a blood disease or disorder. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 24, wherein presence of the mutation indicates that the patient may have an increased risk for developing a blood disease or disorder. In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a blood disease or disorder. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Table 24, wherein presence of the polymorphism indicates that the patient may have an increased risk for developing a blood disease or disorder.
In either of these'.two methods, the mutation or polymorphism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a blood disease or disorder. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 24, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a blood disease or disorder.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a blood disease or disorder. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 24, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a blood disease or disorder. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA. Preferred blood diseases that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abnormal hemoglobins, abnormalities in granulocyte count, abnormalities in lymphocyte count, abnormalities in monocyte count, abnormalities of blood platelets, abnormalitites of platelet function, acanthocytosis, acquired neutropenia, acute granulocytic leukemia, acute idiopathic thrombocytopenic puφura, acute infections, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloblastic leukemia, acute myelocytic leukemia, acute myeloid leukemia, acute pyogenic bacterial infections, acute red cell aplasia, acute response to endotoxin, adult T-cell leukemial/lymphoma, afibrinogenemia, alpha thalassemia, altered affinity of hemoglobin for oxygen, amyloidosis, anemia, anemia due to acute blood loss, anemia due to chronic blood loss, anemia of chronic disease, anemia of chronic renal failure, anemias associated with enzyme deficiencies, anemias associated with erythrocyte cytoskeletal defects, anemias caused by inherited disorders of hemoglobin synthesis, angiogenic myeloid metaplasia, aplastic anemia, ataxia-telangiectasia, Auer rods, autoimmune hemolytic anemias, B-cell chronic lymphocytic leukemia, B-cell chronic lymphoproliferative disorders, Bernard-Soulier disease, beta thalassemia, Blackfan-Diamond disease, brucellosis, Burkitt's lymphoma, Chediak-Higashi syndrome, cholera, chronic acquired pure red cell aplasia, chronic granulocytic leukemia, chronic granulomatous disease, chronic idiopathic myelofibrosis, chronic idiopathic thrombocytopenic puφura, chronic lymphocytic leukemia, chronic lymphoproliferative disorders, chronic myelocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, congenital dyserythropoietic anemias, congenital dysfibrinogenemia, congenital neutropenia, corticosteriods, cyclic neutropenia, cytoplasmic maturation defect, deficiency of coagulation factors, delta-beta thalassemia, diphtheria, disorders of blood coagulation, disseminated intravascular coagulation & fibrinolysis, Dohle bodies, drag & chemical- induced hemolysis, drug-induced thrombocytopenia, drags that suppress granulopoiesis, E. coli, early preleukemic myeloid leukemia, eosinophilia, eosinophilic granuloma, erythrocute enzyme deficiency, erythrocyte membrane defects, essential thrombocythemia, factor 7 deficiency, familial cyclic neutropenia, Felty's syndrome, fibrinolytic activity, folate antagonists, folic acid deficiency, Gaucher disease, Glanzmann's thrombasthenia, glucose-6-phosphate dehydrogenase deficiency, granulated T-cell lymphocyte leukemia, granulocytic sarcoma, granulocytosis, Hageman trait, hairy cell leukemia (leukemic reticuloendotheliosis), Hand-Schϋller-Christian disease, heavy-chain disease, hemoglobin C disease, hemoglobin constant spring, hemoglobin S, hemoglobinopathies, hemolysis caused by infectious agents, hemolytic anemia, hemolytic anemia secondary to mechanical erythrocyte destruction, hemolytic blood transfusion reactions, hemolytic disease of the newborn, hemophagocytic disorders, hemophilia A, hemophilia B (Christmas disease, factor 9 deficiency, hepatitis, hereditary elliptocytosis, hereditary spherocytosis, heterozygous beta thalassemia (Cooley's trait), homozygous beta thalassemia (Cooley's anemia), hypereosinophilic syndrome, hypoxia, idiopathic cold hemagglutinin disease, idiopathic thrombocytopenic puφura, idiopathic warm autoimmune hemolytic anemia, immune drag induced hemolysis, immune-mediated hemolytic anemias, immunodeficiency disease, infantile neutropenia (Kostmann), instability of the hemoglobin molecule, iron deficiency anemia, isoimmune hemolytic anemia, juvenile chronic myeloid leukemia, Langerhans cell histiocytosis, large granular lymphocyte leukemia, lazy leukocyte syndrome, Letterer-Siwe disease, leukemias, leukemoid reaction, leukoerythroblastic anemia, lipid storage diseases, lymphoblastosis, lymphocytopenia, lymphocytosis, lymphoma, lymphopenia, macroangiopathic hemolytic anemia, malaria, marrow aplasia, May- Hegglin anomaly, measles, megaloblastic anemia, metabolic diseases, microangiopathic hemolytic anemia, microcytic anemia, miliary tuberculosis, mixed phenotupe aςute leukemia, monoclonal gammopathy of undetermined significance, monocytic leukemia, monocytosis, mucopolysaccharidosis, multiple myeloma, myeloblastic leukemia, myelodysplastic syndromes, myelofibrosis (agnogenic myeloid metaplasia), myeloproliferative diseases, myelosclerosis, neonatal thrombocytopenic puφura, neoplasms of hematopoietic cells, neutropenia, neutrophil dysfunction syndromes, neutrophil leukocytosis, neutrophilia, Niemann-Pick disease, nonimmune drug-induced hemolysis, normocytic anemia, nuclear maturation defects, parahemophilia, paroxysmal cold hemoglominuria, paroxysmal nocturnal hemoglobinuria, Pelger-Hϋet anomaly, pernicious (Addisonian) anemia, plasma cell leukemia, plasma cell neoplasia, polycythemia, polycythemia rabra vera, presence of circulating anticoagulants, primary (idiopathic) thrombocythemia, primary neoplasms, prolymphocytic leukemia, Proteus, Pseudomonas, pure red cell aplasia, pyogenic bacterial infection, pyruvate kinase deficiency, radiation, red cell aplasia, refractory anemias, ricketsial infections, Rosenthal's syndrome, secondary absolute polycythemia, septicemia, severe combined immunodeficiency disease, Sezary syndrome, sickle cell disease, sickle cell-beta thalassemia, sideroblastic anemia, solitary plasmacytoma, storage pool disease, stress, structural hemoglobin variants, systemic lupus erythematosus, systemic mastocytosis, tart cell, T-cell chronic lymphoproliferative disorders, T-cell prolymphocytic leukemia, thalassemias, thrombocytopenia, thrombotic thrombocytopenic puφura, toxic granulation, toxic granules in severe infection, typhus, vitamm B12 deficiency, vitamin K deficiency, Von Willebrand's disease, Waldenstrorn macroglobulinemia, and Wiskott- aldrich syndrome.
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptpr polypeptide substantially identical to a polypeptide listed in Table 24.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24. In another aspect, the invention features a method of preventing or treating a disease of the prostate including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25 operably linked to a promoter. In still another aspect, the invention features a method of treating or preventing a disease of the prostate including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the prostate. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the prostate. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a blood disease or disorder of the prostate. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the prostate. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 25, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the prostate. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the prostate. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the prostate. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 25, wherem presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the prostate.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 25, wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the prostate.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 25, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the prostate.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 25, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the prostate. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the prostate that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute bacterial prostatitis, acute prostatitis, adenoid basal cell tumor (adenoid cystic-like tumor), allergic (eosinophilic) granulomatous prostatitis, atrophy, atypical adenomatous hypeφlasia, atypical basal cell hypeφlasia, basal cell adenoma, basal cell hypeφlasia, BCG-induced granulomatous prostatitis, benign prostatic hypeφlasia, benign prostatic hypertrophy, blue nevus, carcinosarcoma, chronic abacterial prostatitis, chronic bacterial prostatitis, cribriform hypeφlasia, ductal (endometrioid) adenocarcinoma, granulomatous prostatitis, hematuria, iatrogenic granulomatous prostatitis, idiopathic (nonspecific) granulous prostatitis, impotence, infectious granulomatous prostatitis, inflammatory pseudotumor, leiomyosarcoma, leukemia, lymphoepithelioma-like carcinoma, malakoplakia, malignant lymphoma, mucinous (colloid) carcinoma, nodular hypeφlasia (benign prostatic hypeφlasia), nonbacterial prostatitis, obstruction of urinary outflow, phyllodes tumor, postatrophic hypeφlasia, postirradiation granulomatous prostatitis, postoperative spindle cell nodules, postsurgical granulomatous prostatitis, prostatic adenocarcinoma, prostatic carcinoma, prostatic intraepithelial neoplasia, prostatic melanosis, prostatic neoplasm, prostatitis, rhabdomyosarcoma, sarcomatoid carcinoma of the prostate, sclerosing adenosis, signet ring cell carcinoma, small-cell, undifferentiated carcinoma (high-grade neuroendocrine carcinoma), squamous cell carcinoma of the prostate, stromal hypeφlasia with atypia, transitional cell carcinoma of the prostate, xanthogranulomatous prostatitis, and xanthoma. In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
In another aspect, the invention features a method of preventing or treating skin disease, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing skin disease, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a skin disease or disorder. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a skin disease or disorder. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a. compound that may be useful for the treatment of a skin disease or disorder. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a skin disease or disorder
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a skin disease or disorder. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease skin disease or disorder.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a skin disease or disorder. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 26, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a skin disease or disorder.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a skin disease or disorder. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a skin disease or disorder. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a skin disease or disorder. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a skin disease or disorder. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a skin disease or disorder. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 26, wherein presence of the mutation indicates that the . patient may have an increased risk for developing a skin disease or disorder.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a skin disease or disorder. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 26, wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a skin disease or disorder.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a skin disease or disorder. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 26, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a skin disease or disorder.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a skin disease or disorder. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 26, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a skin disease or disorder. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA. Preferred skin diseases that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acanthosis nigricans, acne vulgaris, acquired epidermolysis bullosa, acrochordons, acrodermatitis enteropathica, acropustulosis, actinic keratosis, acute cutaneous lupus erythematosus, age spots, allergic dermatitis, alopecia areata, angioedema, angiokeratoma, angioma, anthrax, apocrine tumors, arthropid-bite reactions, atopic dermatitis, atypical fibroxanthoma, Bart's syndrome, basal cell carcinoma (basal cell epithelioma), Bateman's puφura, benign familial pemphigus (Hailey-Hailey disease), benign keratoses, Berloque dermatitis, blue nevus, borderline leprosy, Borrelia infection (lyme disease), Bowen's disease (carcinoma in situ), bullous pemphigoid, Cafe-au-lait spot, calcification, cellular blue nevus, cellulitis, Chagas' disease, chickenp'ox
(varicella), chloasma, chondrodermatitis nodularis helicis, chondroid syringoma, chronic actinic dermatitis, chronic cutaneous lupus erythematosus, chronic discoid lesions, cicatricial pemphigoid, collagen abnormalities, compount melanocytic nevus, congenital melanocytic nevus, connective tissue nevus, contact dermatitis, cutaneous leishmaniasis, cutis laxa, cysts of the skin, dandruff, Darier's disease (keratosis follicularis), deep fungal infections, delayed-hypersensitivity reaction, dermal Spitz's nevus, dermatitis, dermatitis heφetifoπnis, deraiatofibroma (cutaneous fibrous histiocytoma), dermatofibrosarcoma protuberans, dermatomyositis, dermatophyte infections, dermatophytid reactions, dermoid cyst, dermotropic ricketsial infections, dermotropic viral infections., desmoplastic melanoma, discoid lupus erythematosus, dominant dystrophic epidermolysis bullosa, Dowling-Meara epidermolysis bullosa, dyshidrotic dermatitis, dysplastic nevi, eccrine tumors, ecthyma, eczema, elastic tissue abnormalities, elastosis perforans seφiginosa, eosinophilic fasciitis, eosinophilic folliculitis, ephelides (freckles), epidermal cysts, epidermolysis bullosa, epidermolysis bullosa simplex, epidermotropic T-cell lymphoma, epidermotropic viruses, erysipelas, erythema multiforme, erythema nodosum, erythema nodosum leprosum, fibrotic disorders, fibrous tumors, follicular mucinosis, Fordyce's condition, fungal infections, genodermatoses, graft-versus-host disease, granuloma annulare, granulomatous vasculitis, Grover's disease, hair follicle infections, hair follicle tumors, hair loss, halo nevus, heφes simplex, heφes zoster (shingles), hidradenitis suppurativa, histiocytic lesions, HIV infections, hives, human papilloma virus, hyperhydrosis, ichthyosis, idiopathic skin diseases, impetigo, incontinentia pigmenti, intraepidermal spongiotic vesicles and bullae, invasive malignant melanoma, invasive squamous cell carcinoma, junctional epidermolysis bullosa, junctional melanocytic nevus, juvenile xanthogranuloma, Kaposi's sarcoma, keloids, keratinocytic lesions, keratinocytic tumors, keratoacanthoma, keratoderma blennorrhagicum, keratosis pilaris, leiomyoma, lentigo, lentigo maligna (Hutchinson's freckle), lepromatous leprosy, leprosy (Hansen's disease), leukocytoclastic vasculitis, lichen planus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen striatus, lichenoid disorders, lichenoid drug reactions, light eruptions, linear bullous IgA dermatitis, lipoma, Lucio's phenomenon, lupus erythematosus, lymphatic filariasis, lymphocytic vasculitis, lymphocytoma cutis, lymphoid lesions, lymphomatoid papulosis, malignant blue nevus, malignant lymphomas, malignant melanoma, malignant melanoma in situ (noninvasive malignant melanoma), mast cell neoplasms, mastocytosis, measles, melanocyte disorders, melanocytic lesions, melanocytic neoplasms, melanocytic nevus, melanocytic nevus with dysplasia, melanotic macule, reactive type, melasma, merkel cell (neuroendocrine) carcinoma, metastatic melanoma, miliara, mixed connective tissue disease, molluscum contagiosum, moφhea, mucin deposition, mucocutaneous leishmaniasis, mycetoma, mycobacterial infection, Mycobacterium marinum, Mycobacterium ulcerans, mycosis fungoides (cutaneous T cell lymphoma), myxoid cyst, necrobiosis lipoidica, necrobiosis lipoidica diabeticoram, necrolytic migratory erythema, necrotizing fasciitis, neoplasms of dermal mesenchymal cells, neoplasms of keratinocytes, neoplasms of skin appendages, neoplasms of the epidermis, neural tumors, neuroendocrine carcinoma of the skin, neurothekeoma, nevocellular nevus (melanocytic nevus), nummular dermatitis, obliterative vasculitis, onchocerciasis, Paget's disease, pale cell acanthoma of Degos, palisaded encapsulated neuroma, papillomaviras infections, paraneoplastic pemphigus, parasitic infections, pemphigoid gestationis, pemphigus, pemphigus foliaceus, pemphigus vulgaris, perivascular infiltrates, pilar cysts, pinta, pityriasis alba, pityriasis lichenoides chronica (of Juliusberg), pityriasis lichenoides et varioliformis acuta, pityriasis rosea, pityriasis rabra pilaris, plantar warts, porokeratosis, pressure necrosis, progressive systemic sclerosis, protozoal infections, pruritic urticarial papules and plasques of pregnancy, pruritis ani, pseudofolliculitis barbae, pseudoxanthoma elasticum, psoriasis vulgaris, pyogenic granuloma, radial growild typeh phase melanoma, recessive dystrophic epidermolysis bullosa, Reiter's syndrome, ringworm, Rochalimaea henselae infection, rosacea, rubella, sarcoidosis, scabies, Schamberg's disease, scleroderma, sebaceous hypeφlasia, sebaceous tumors, seborrheic dermatitis, seborrheic keratosis, Sezary syndrome, skin manifestations of systemic diseases, small plaque parapsoriasis, smallpox (variola), solitary mastocytoma, spirochetal infections, Spitz's nevus, Spitz's nevus junctional type, squamous cell carcinoma, stasis dermatitis, Stevens- Johnson syndrome, subacute cutaneous lupus erythematosus, subcorneal pustular dermatosis, superficial fungal infections, superficial spreading melanoma in situ, syphilis, syringoma, systemic lupus erythematosus, systemic mastocytosis, tinea (dermatophytosis, tinea versicolor, toxic epidermal necrolysis, transient acantholytic dermatosis, tuberculoid leprosy, tuberculosis, urticaria, urticaria pigmentosa, urticarial vasculitis, vascular tumors, verruca vulgaris (common wart), vertical growild typeh phase melanoma, visceral leishmaniasis, vitiligo, warty dyskeratoma, Weber-Cockayne epidermolysis bullosa, Woringer-Kolopp disease, xanthomas, xeroderma pigmentosum, xerosis, and yaws. In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that-includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26. In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
In another aspect, the invention features a method of preventing or treating a disease of the spleen including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the spleen including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the spleen. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the spleen. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the spleen. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the spleen. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 27, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted With the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
In another aspect, the invention features yet another method for determining whether a candidate compound maybe useful for the treatment of a disease or disorder of the spleen. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the spleen. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the spleen. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 27, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the spleen.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 27, wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the spleen.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 27, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the spleen. In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 27, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the spleen. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the spleen that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abnormal immunoblastic proliferations of unknown origin, acute infections, acute parasitemias, agnogenic myeloid metaplasia, amyloidosis, angioimmunoblastic lymphadenopathy, antibody-coated cells, asplenia, autoimmune diseases, autoimmune hemolytic anemias, B-cell chronic lymphocytic leukemia and prolymphocytic leukemia, babesiosis, bone marrow involvement by carcinoma, brucellosis, carcinoma, ceroid histiocytosis, chronic alcoholism, chronic granulomatous disease, chronic hemolytic anemias, chronic hemolytic disorders, chronic immunologic inflammatory disorders, chronic infections, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic parasitemias, chronic uremia, cirrhosis, cold agglutinin disease, congestive splenomegaly, cryoglobulinemia, disseminated tuberculosis, dysproteinemias, endocrine disorders, erythroblastic leukemia, erythropoiesis, essential thrombocythemia, extramedullary hematopoiesis, Felty syndrome, fibrocongestive splenomegaly, fungal infections, gamma heavy-chain disease, Gaucher's disease, graft rejection, granulomatous infiltration, hairy cell leukemia, hamartomas, Hand-Schϋller-Christian disease, hemangiomas, hemangiosarcomas, hematologic disorders, hemoglobinopathies, hemolytic anemias, hereditary elliptocytosis, hereditary spherocytosis, histiocytic medullary reticulosis, histiocytosis X, Hodgkin's disease, hypersensitivity reactions, hypersplenism, hyposplenism, idiopathic thrombocytopenic puφura, IgA deficiency, immune granulomas, immune thrombocytopenia, immune thrombocytopenic puφura, immunodeficiency disorders, infection associated hemophagocytic syndrome, infectious granulomas, infectious mononucleosis, infective endocarditis, infiltrative splenomegaly, inflammatory pseudotumors, leishmaniasis, Leterer-Siwe disease, leukemia, lipogranulomas, lymphocytic leukemias, lymphoma, malabsoφtion syndromes, malaria, malignant lymphoma, megakaryoblastic leukemia, metastatic tumor, monocytic leukemias, mucopolysaccharidoses, multicentric Castleman's disease, multiple myeloma, myelocytic leukemias, myelofibrosis, myeloproliferative syndromes, neoplasms, Niemann-Pick disease, non-Hodgkin's lymphoma, parasitic disorders, parasitized red blood cells, peliosis, polycythemia rabra vera, portal vein congestion, portal vein stenosis, portal vein thrombosis, portal venous hypertension, rheumatoid arthritis, right-sided cardiac failure, sarcoidosis, sarcoma, secondary amyloidosis, secondary myeloid metaplasia, serum sickness, sickle-cell disease, splenic cysts, splenic infarction, splenic vein hypertension, splenic vein stenosis, splenic vein thrombosis, splenomegaly, storage diseases, systemic lupus erythematosus, systemic vasculitides, T- cell chronic lymphocytic leukemia, thalasemia, thrombocytopenic puφura, thyrotoxicosis, trapping of immature hematologic cells, tuberculosis, tumorlike conditions, typhoid fever, vascular tumors, vasculitis, and viral infections.
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27. In another aspect, the invention features a method of preventing or treating a disease of the stomach including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the stomach including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the stomach. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the stomach. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the stomach. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the stomach. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 28, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the stomach. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the stomach. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the stomach. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system. In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 28, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the stomach.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 28, wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the stomach.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 28, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the stomach.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 28, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the stomach. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the stomach that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute erosive gastropathy, acute gastric ulcers, adenocarcinomas, adenomas, adenomatous polyps, advanced gastric cancer, ampullary carcinoma, atrophic gastritis, bacterial gastritis, carcinoid tumors, carcinoma of the stomach, chemical gastritis, chronic (nonerosive) gastritis, chronic idiopathic gastritis, chronic nonatrophic gastritis, Cronkite-Canada syndrome, congenital cysts, congenital diaphragmatic hernias, congenital diverticula, congenital duplications, congenital pyloric stenosis, congestive gastropathy, cyclic vomiting syndrome, decreased mucosal resistance to acid, diffuse or infiltrating adenocarcinoma, early gastric cancer, emphysematous gastritis, endocrine cell hypeφlasia, environmental gastritis, eosinophilic gastritis, eosinophilic gastroenteritis, epithelial polyps, erosive (acute) gastritis, fundic gland polyps, fungal gastritis, gangliocytic paragangliomas, gastral antral vascular ectasia, gastric adenocarcinoma, gastric outlet obstruction (pyloric stenosis), gastric ulcers, gastritis, gastroesophageal reflux, gastroparesis, granulomatous gastritis, H. Pylori infection, hamartomatous polyps, heterotopias, heterotopic pancreatic tissue, heterotopic polyps, hypeφlastic gastropathy, hypeφlastic polyps, hypersecretion of acid, infectious gastritis, inflammatory lesions of the stomach, inflammatory polyps, intestinal metaplasia, invasive carcinoma, ischemia, leiomyoma, linitis plastica, luminally acting toxic chemicals, lymphocytic gastritis, lymphomas, malignant gastric stromal neoplasms, malignant lymphoma, malignant transformation of a benign gastric ulcer, Menentrier's disease (hypertrophic gastritis, rugal hypertrophy), mesenchymal neoplasms, metastatic tumors, mucosal polyps, myoepithelial adenomas, myoepithelial hamartomas, neoplasms, neuroendocrine hypeφlasias, neuroendocrine tumors, nonerosive gastritis and stomach cancer, nonneoplastic polyps, parasitic gastritis, peptic ulcer disease, phlegmonous gastritis, plasma cell gastritis, polypoid (fungating) adenocarcinoma, poorly differentiated neuroendocrine carcinomas, precancerous lesions, Puetz-Jeghers syndrome, pyloric atresia, rapid gastric emptying, reflux of bile, stress ulcers, stromal tumors, superficial gastritis, type A chronic gastritis (autoimmune gastritis and pernicious anemia), type B chronic gastritis (chronic antral gastritis, H. Pylori gastritis), ulcerating adenocarcinoma, vasculitis, viral gastritis, xanthomatous gastritis, and Zollinger-Ellison syndrome. In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
In another aspect, the invention features a method of preventing or treating a disease of the testes including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the testes including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the testes. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder, of the testes. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the testes. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the testes. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the testes. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 29, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the testes. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the testes. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the testes. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the testes. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 29, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the testes.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the testes. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 29, wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the testes. In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the testes. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 29, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the testes. In still another aspect, the invention features yet another method for detemiining whether a patient has an increased risk for developing a disease or disorder of the testes. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 29, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the testes. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the testes that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include aberrant ducts of Haller, abnormal productions of hormones, abnormalities of testicular descent, acute epididymoorhcitis, adenomatoid tumor, adenomatous hypeφlasia of the rete testis, adenovirus, administration of estrogens, adrenal rests, alcoholic cirrhosis, amyloidosis, anorchism, appendix testes, bacterial infections, Bracella, cachexia, carcinoma in situ, carcinoma of the rete testis, chlamydia, choriocarcinoma, choristomas, chronic fibrosing epididymoorchitis, coxsackie virus B, cryptorchidism, cystic dysplasia of the rete testis, cytomegalovirus, dystopia, E. coli, Echinococcus granulosus, ectopic testes, embryonal carcinoma, epididymoorchitis, Fournier's scrotal gangrene, fungal infection, germ cell aplasia, germ cell neoplasms, gonadal dysgenesis, gonadal stromal neoplasms, granulomatous orchitis, granulosa cell tumors, Haemophilus influenzae, HIV, hypergonadism, hypogonadotropic hypogonadism, hypopituitarism, hypospermatogenesis, hyrocele, idiopathic granulomatous orchitis, incomplete maturation arrest, infarction, infertility, inflammatory diseases, inflammatory lesions, interstitial (Leydig) cell tumors, Klinefelter's syndrome, latrogenic lesions, Leydig cell tumors, malakoplakia, malignant lymphoma, malnutrition, maturation arrest of spermatogenesis, metastatic tumors, mixed germ cell tumors, monorchism, mumps orchitis, mycobacteria, Neisseria gonorrhoeae, neoplasms, obstruction to outflow of semen, orchitis, parasitic infection, polyorchidism, radiation, Salmonella, sarcoidosis, Schistosoma haematobium, seminoma, Sertoli cell tumors, sex cord stromal tumors, sperm granuloma, spermatocytic seminoma, syphilis, teratocarcinoma, teratoma, testicular atrophy, testicular neoplasms, testicular torsion, Treponema pallidum, tuberculous epididymoorchitis, tumors of nonspecific stroma, undescended testes, uropathogens, varicocele, vascular disturbances, vasculitis, viral infection, Wuchereria bancrofti, and yolk sac carcinoma. In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
In another aspect, the invention features a method of preventing or treating a disease of the thymus including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the thymus including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thymus. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thymus. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor . polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thymus. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thymus. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 30, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thymus. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thymus. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thymus. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 30, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the thymus.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 30, wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the thymus. In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 30, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the thymus. In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 30, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the thymus. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the thymus that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include accidental involution, acute accidental involution, acute lymphoblastic leukemia of T cell type, agenesis, age-related involution, anaplastic carcinoma, ataxia telangiectasia, atrophy, bacterial infections, bacterial mediastinitis, basaloid carcinoma, bone marrow transplantation, Braton's agammaglobulinemia, carcinosarcoma, chronic accidental involution, clear cell carcinoma, cortical thymoma, cytomegalovirus, DiGeorge syndrome, dysgenesis, dysplasia with pattern similar to severe atrophy, dysplasia with pseudoglandular appearance, dysplasia with stromal conticomedullary differentiation, ectopia, germ cell tumors, Grave's disease, histiocytosis X, HIV, Hodgkin's disease, hypeφlasia, infectious mononucleosis, involution, lymphoblastic lymphoma of T-cell type, lymphoepithelioma-like carcinoma, lymphofollicular thymitis, maldescent, malignant lymphomas, malignant thymoma, measles giant cell pneumonia, medullary thymoma, mixed (composite) thymoma, mucoepidermoid carcinoma, myasthenia gravis, neonatal syphilis, neoplasms, Omenn's syndrome, predominantly cortical (organoid) thymoma, primary mediastinal B-cell lymphoma of high-grade malignancy, sarcomatoid carcinoma, seminoma, severe combined immunodeficiency, short limb dwarfism, simple dysplasia, small cell carcinoma, small-cell B-cell lymphoma of MALT type, squamous cell carcinoma, systemic lupus erythematosus, teratoma, thymic carcinoid, thymic carcinoma, thymic cysts, thymic epithelial cysts, thymic epithelial tumor, thymic neoplasms, thymitis with diffuse B-cell infiltrations, thymolipoma, thymoma, true thymic hypeφlasia, varicella-zoster, viral infections, well differentiated thymic carcinoma, and Wiscott-Aldrich syndrome.
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30. In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
In another aspect, the invention features a method of preventing or treating a disease of the thyroid including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 operably linked to a promoter. In still another aspect, the invention features a method of treating or preventing a disease of the thyroid including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thyroid. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thyroid. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of transgenic non-human mammal, wherein altered biological activity, relative to that of the nuclear receptor transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thyroid. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thyroid. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 31, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thyroid. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the thyroid. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the thyroid. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.,
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 31, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the thyroid.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 31, wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the thyroid.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 31 , wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the thyroid.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 31, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the thyroid. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the thyroid that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include aberrant thyroid glands, accessory thyroid glands, adenoma with bizarre nuclei, agenesis, amphicrine variant of medullary carcinoma, anaplastic (undifferentiated) carcinoma, aplasia, atrophic thyroiditis, atypical adenoma, autoimmune thyroiditis, carcinoma, C-cell hypeφlasia, clear cell tumors, clear cell variant of medullary carcinoma, colloid adenoma, columnar variant of papillary carcinoma, congenital hypothyroidism (cretinism), diffuse nontoxic goiter, diffuse sclerosing variant of papillary carcinoma, dyshormonogenic goiter, embryonal adenoma, encapsulated variant of papillary carcinoma, endemic cretinism, endemic goiter, enzyme deficiency, fetal adenoma, follicular adenoma, follicular carcinoma, follicular variant of medullary carcinoma, follicular variant of papillary carcinoma, fungal infection, giant cell variant of medullary carcinoma, goiter induced by antithyroid agents, goitrous hypothyroidism, Graves' disease, Hashimoto's autoimmune thyroiditis, Hϋrthle cell (oncocytic) adenoma, hyalinized trabecular adenoma, hyperthyroidism, hypothyroid cretinism, hypothyroidism, iodine deficiency, juvenile thyroiditis, latrogenic hypothyroidism, lingual thyroid glands, malignant lymphoma, medullary carcinoma, melanocytic variant of medullary carcinoma, mesenchymal tumors, metastatic tumors, minimally invasive follicular carcinoma, mixed medullary and follicular carcinoma, mixed medullary and papillary carcinoma, mucinous carcinoma, mucoepidermoid carcinoma, multinodular goiter, myxedema, neoplasms, neurologic cretinism, nonspecific lymphocytic (simple chronic) thyroiditis, oncocytic variant of medullary carcinoma, palpation thyroiditis, papillary carcinoma, papillary microcarcinoma, papillary variant of medullary carcinoma, partial agenesis, pituitary thyrotropic adenoma, poorly differentiated carcinoma, primary hypothyroidism, pseudopapillary variant of medullary carcinoma, Riedel's thyroiditis, sclerosing mucoepidermoid carcinoma with eosinophilia, silent thyroiditis, simple adenoma, small cell variant of medullary carcinoma, solitary thyroid nodule, sporadic goiter, squamous cell carcinoma, squamous variant of medullary carcinoma, subacute thyroiditis (DeQuervain, granulomatous, giant cell thyroiditis), tall cell variant of papillary carcinoma, tertiary syphilis, thyroglossal duct cyst, thyroid agenesis, thyroid nodules, thyroiditis, thyrotoxicosis, toxic adenoma, toxic multinodular goiter, toxic nodular goiter (Plummer's disease), tuberculosis, tubular variant of medullary carcinoma, and widely invasive follicular carcinoma.
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31. In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
In another aspect, the invention features a method of preventing or treating a disease of the uterus including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the uterus including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the uterus. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the uterus. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non- human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the uterus. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non- human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uteras.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the uterus. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 32, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the uterus. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus . In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the uterus. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the uterus. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the uterus. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 32, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the uteras.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the uteras. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 32, wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the uterus.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the uterus. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 32, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicate that the patient may have an increased risk for developing a disease or disorder of the uterus.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the uterus. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 32, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the uterus. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the uterus that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute cervicitis, acute endometritis, adenocanthoma, adenocarcinoma, adenocarcinoma in situ, adenoid cystic carcinoma, adenomatoid tumor, adenomyoma, adenomyosis (endometriosis interna), adenosquamous carcinoma, amebiasis, arias-Stella phenomenon, atrophy of the endometrium, atypical hypeφlasia, benign polypoid lesions, benign stromal nodule, carcinoid tumors, carcinoma in situ, cervical intraepithelial neoplasia, chlamydia, chronic cervicitis, chronic nonspecific endometritis, ciliated (tubal) metaplasia, clear cell adenocarcinoma, clear cell carcinoma, clear cell metaplasia, complex hypeφlasia with atypia, complex hypeφlasia without atypia, condyloma aduminatum, congenital abnormalities, coφus cancer syndrome, cystic hypeφlasia, dysfunctional uterine bleeding, dysmenorrhea, dysplasia of the cervix (cervical intraepithelial neoplasia, squamous intraepithelial lesion), endocervical adenocarcinoma, endocervical polyp, endolymphatic stromal myosis, endometrial adenocarcinoma, endometrial carcinoma, endometrial hypeφlasia, endometrial polyps, endometrial stromal neoplasms, endometriosis, endometritis, endometroid (pure) adenocarcinoma of the endometrium, endometroid adenocarcinoma with squamous differentiation, eosinophilic metaplasia, epimenorrhea, exogenous progestational hormone effect, extrauterine endometriosis (endometriosis externia), gestational trophoplastic disease, gonorrhea, hemangioma, heφes simplex virus type 2, high-grade squamous intraepithelial lesion, human papillomaviras, hypeφlasia, inadequate luteal phase, infertility, inflammatory cervical lesions, inflammatory lesions of the endometrium, intravenous leiomyomatosis, invasive carcinoma of cervix, invasive squamous cell carcinoma, leiomyoma, leiomyosarcoma, lipoma, low-grade squamous intraepithelial lesion, malignant mixed mesodermal (Mύllerian) tumor, menorrhagia, metaplasia, metastasizing leiomyoma, metastatic carcinoma, microglandular hypeφlasia, microinvasive carcinoma, microinvasive squamous cell carcinoma, mucinous adenocarcinoma, mucinous metaplasia, neoplasms of the cervix, neoplasms of the endometrium, neoplasms of the myometrium, nonneoplastic cervical proliferations, papillary synctial metaplasia, papilloma, pelvic inflammatory disease, peritoneal leiomyomatosis, persistent luteal phase, postmenopausal bleeding, serous papillary adenocarcinoma, simple hypeφlasia with atypia, simple hypeφlasia without atypia, spontaneous abortion, squamous carcinoma, squamous cell neoplasia, squamous intraepithelial lesions, squamous metaplasia, squamous metaplasia (acanthosis), stromal sarcoma, tuberculous endometritis, unopposed estrogen effect, uterine leiomyomata, verrucou carcinoma, vestigial and heterotopic structures, villoglandular papillary adenocarcinoma, and viral endometritis.
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32. In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
In another aspect, the invention features a cell from a non-human mamirial having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
In another aspect, the invention features a method of preventing or treating a disease of the pancreas including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the pancreas including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the pancreas. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the pancreas. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disraption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the pancreas. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the pancreas. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1, the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the pancreas. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pancreas.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the pancreas. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the pa creas. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system. In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the pancreas. t In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the pancreas.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide. In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the pancreas. hi still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1 , wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the pancreas. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA. Diseases of the pancreas that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include ACTHoma, acute pancreatitis, adult onset diabetes, annulare pancreas, carcinoid syndrome, carcinoid tumors, carcinoma of the pancreas, chronic pancreatitis, congenital cysts, Cushing's syndrome, cystadenocarcinoma, cystic fibrosis (mucoviscidosis, fibrocystic disease), diabetes mellitus, ectopic pancreatic tissue, gastinoma, gastrin excess, glucagon excess, glucagonomas, GRFomas, hereditary pancreatitis, hyperinsulinism, impaired insulin release, infected pancreatic necrosis, insulin resistance, insulinomas, islet cell hypeφlasia, islet cell neoplasms, juvenile onset diabetes, macroamylasemia, maldevelopment of the pancreas, maturity-onset diabetes of the young, metastatic neoplasms, mucinous cystadenoma, neoplastic cysts, nonfunctional pancreatic endocrine tumors, pancreas divisum, pancreatic abcess, pancreatic cancer, pancreatic cholera, pancreatic cysts, pancreatic endocrine tumor causing carcinoid syndrome, pancreatic endocrine tumor causing hypercalcemia, pancreatic endocrine tumors, pancreatic exocrine insufficiency, pancreatic pleural effusion, pancreatic polypeptide excess, pancreatic pseudocyst, pancreatic trauma, pancreatogenous ascites, serous cystadenoma, Shwachman's syndrome, somatostatin excess, somatostatinoma syndrome, traumatic pancreatitis, type 1 (insulin-dependent) diabetes, type 2 (non-insulin-dependent) diabetes, vasoactive intestinal polypeptide excess, VIPomas, Zollinger-EUison syndrome.
In another aspect, the invention features a non-human mammal (e.g., a mouse), having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
In yet another aspect, the invention features a non-human mammal (e.g., a mouse), having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1. In another aspect, the invention features a method of preventing or treating a disease of the bone and joints including introducing into a human an expression vector that includes a nucleic acid molecule .encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a disease of the bone and joints including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the bone and joints. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the bone and joints. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the bone and joints. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the. nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the bone and joints. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1 , the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the bone and joints. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the bone and joints. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the bone and joints. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the bone and joints.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the bone and joints.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in . Table 1, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the bone and joints. In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the bone and joints. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the bone and joints that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include achondroplasia, acute bacterial arthritis, acute pyogenic osteomyelitis, Albright's syndrome, alkaptonuria (ochronosis), aneurysmal bone cyst, ankylosing spondylitis, arthritic, arthropathies associated with hemoglobinopathies, arthropathy of acromegaly, arthropathy of hemochromatosis, bone cysts, calcium hydroxyapatite deposition disease, calcium pyrophosphate deposition disease, chondrocalcinosis, chondroma, chondrosarcoma, chostochondritis, chrondromblastoma, congenital dislocation of the hip, congenital disorders of joints, echondromatosis
(dyschondroplasia, Ollier's disease), erosive osteoarthritis, Ewing's sarcoma, Felty's syndrome, fibromyalgia, fibrous cortical defect, fibrous dysplasia (McCune-Albright syndrome, fungal arthritis, ganglion, giant cell tumor, gout, hematogenous osteomyelitis, hemophilic arthropathy, hereditary hypeφhosphatasia, hyperostosis, hyperostosis frontalis interna, hypeφarathyroidism (osteitis fibrosa cystica), hypertrophic osteoarthropathy, infections diseases of joints, juvenile rheumatoid arthritis (Still's disease), lyme disease, lymphoid neoplasms, melorheostosis, metabolic diseases of joints, metastatic carcinoma, metastatic neoplasms, monostatic fibrous dysplasia, multiple exostoses (diaphyseal aclasis, osteochondromatosis), neoplasms, neuropathic joint (Charcot's joint), osteoarthritis, osteoarthrosis, osteoblastoma, osteochondroma (exostosis), osteogenesis imperfecta (brittle bone disease), osteoid osteoma, osteoma, osteomalacia, osteomyelitis, osteomyelosclerosis, osteopefrosis (marbel bone disease, Albers-Schδnberg disease), osteopoikilosis, osteoporosis (osteopenia), osteosarcoma, osteosclerosis, Paget's disease of bone (osteitis deformans), parasitic arthritis, parosteal osteosarcome, pigmented villonodular synovitis, polyostotic fibrous dysplasia, postinfectious or reactive arthritis, progressive diaphyseal dysplasia (Camurati- Engelmann disease), pseudogout, psoriatic arthritis, pyknodysostosis, pyogenic arthritis, reflex sympathetic dystrophy syndrome, relapsing polychondritis, rheumatoid arthritis, rickets, senile osteoporosis, sickle cell disease, spondyloepiphyseal dysplasia, synovial chondromatosis, synovial sarcoma, syphilitic arthritis, talipes calcaneovalgus, talipes equinovaras, thalassemia, Tietze's syndrome, tuberculosis of bone, tuberculous arthritis, unicameral bone cyst (solitary bone cyst), viral arthritis. In another aspect, the invention features a method of preventing or treating a disease of the breast including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter.
In still another aspect, the invention, features a method of treating or preventing a disease of the breast including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the breast. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the breast. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding, a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the breast. This method includes the steps of (a) providing a transgenic non- human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the freatment of a disease or disorder of the breast.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the breast. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1 , the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the breast. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast. In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the breast. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the breast. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system. In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the breast. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the breast. In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the breast. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the ' polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the breast.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the breast. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1 , wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the breast.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the breast. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the breast. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA. Diseases of the breast that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include acute mastitis, breast abcess, carcinoma, chronic mastitis, congenital breast anomalies, cystic mastopathy, ductal carcinoma, ductal carcinoma in situ, ductal papilloma, fat necrosis, fibroadenoma, fibrocystic changes, fibrocystic disease, galactorrhea, granular cell tumor, gynecomastia, infiltrating ductal carcinoma, inflammatory breast carcinoma, inflammatory breast lesions, invasive lobular carcinoma, juvenile hypertrophy of the breast, lactating adenoma, lobular carcinoma in situ, neoplasms, Paget's disease of the nipple, phyllodes tumor (cystosarcome phyllodes), polymastia, polymazia, polythelia, silicone granuloma, supernumerary breast, and supernumerary nipples. In another aspect, the invention features a method of preventing or treating a disease of the immune system including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter. In still another aspect, the invention features a method of treating or preventing a disease of the immune system including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the immune system. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or disorder of the immune system. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the freatment of a disease or disorder of the immune system. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear.receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the immune system. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1 , the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter, activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the immune system. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the freatment of a disease or disorder of the immune system.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the immune system. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the immune system. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system.
In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a disease or disorder of the immune system.
In a related aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 1, wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a disease or disorder of the immune system.
In either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the immune system. In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1 , wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a disease or disorder of the immune system. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Diseases of the immune system that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include abnormal neutrophil function, acquired immunodeficiency, acute rejection, Addison's disease, advanced cancer, aging, allergic rhinitis, angioedema, arthras-type hypersensitivity reaction, ataxia-telangiectasia, autoimmune disorders, autoimmune gastritis, autosomal recessive agammaglobulinemia, blood transfusion reactions, Bloom's syndrome, Braton's congenital agammaglobulinemia, bullous pemphigoid, Chediak-Higashi syndrome, chronic active hepatitis, chronic granulomatous disease of childhood, chronic rejection, chronic renal failure, common variable immunodeficiency, complement deficiency, congenital (primary) immunodeficiency, contact dermatitis, deficiencies of immune response, deficiency of the vascular response, dermatomyositis, diabetes mellitus, disorders of mierobial killing, disorders of phagocytosis, Goodpasture's syndrome, graft rejection, graft-versus-host disease, granulocyt deficiency, granulocytic leukemia, Graves' disease, Hashimoto's thyroiditis, hemolytic anemia, hemolytic disease of the newborn, HIV infection (AIDS), Hodgkin's disease, hyperacute rejection, hyper-IgE syndrome, hypersensitivity pneumonitis, hypoparathyroidism, IgA deficiency, IgG subclass deficiencies, immunodeficiency with thymoma, immunoglobulin deficiency syndromes, immunologic hypersensitivity, immunosupressive drag therapy, infertility, insulin-resistant diabetes mellitus, interferon γ receptor deficiency, interleukin 12 receptor deficiency, iron deficiency, juvenile insulin-dependent diabetes mellitus, Kaposi's sarcoma, lazy leukocyte syndrome, localized type 1 hypersensitivity, lymphocytic leukemia, lymphoma, malignant B cell lymphoma, major histocompatibility complex class 2 deficiency, mixed connective tissue disease, multiple myeloma, myasthenia gravis, myeloperoxidase deficiency, neutropenia, nude syndrome, pemphigus vulgaris, pernicious anemia, postinfectious immunodeficiency, primary biliary cirrhosis, primary immunodeficiency, primary T cell immunodeficiency, progressive systemic sclerosis, protein-calorie malnutrition, purine nucleoside phosphorylation deficiency, rheumatic fever, rheumatoid arthritis, secondary immunodeficiency, selective (isolated) IgA deficiency, serum sickness type hypersensitivity reaction, severe combined immunodeficiency, Sjδgren's syndrome, sympathetic ophthalmitis, systemic lupus erythematosus, systemic mastocytosis, systemic type 1 hypersensitivity, T cell receptor deficiency, T lymphopenia (Nezelof s syndrome), thrombocytopenia, thymic hypoplasia (DiGeorge syndrome), thymic neoplasms, thymoma (Goode's syndrome), transient hypogammaglobulinemia of infancy, type 1 (immediate) hypersensitivity (atopy, anaphylaxis), type 2 hypersensitivity, type 3 hypersensitivity (immune complex injury), type 4 (delayed) hypersensitivity, urticaria, variable immunodeficiency, vitiligo,
Wiskott-Aldrich syndrom, x-linked agammaglobulinemia, x-linked immunodeficiency with hyper IgM, x-linked lymphoproliferative syndrome, zap70 tyrosine kinase deficiency.
In another aspect, the invention features a method of preventing or treating a metabolic or nutritive disease or disorder, including introducing into a human an expression vector that includes a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a promoter.
In still another aspect, the invention features a method of treating or preventing a metabolic or nutritive disease or disorder, including administering to an animal (e.g., a human) a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder. This method includes the steps of (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the nuclear receptor polypeptide with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide, wherein altered biological activity, relative to that of the nuclear receptor polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder. The nuclear receptor polypeptide can be in a cell or in a cell-free assay system. In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a knock-out mouse) having a disruption in a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
In yet another aspect, the invention features a method for determining whether a candidate compound is a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder. This method includes the steps of (a) providing a transgenic non-human mammal (e.g., a mouse) overexpressing a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the nuclear receptor polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the transgenic non-human mammal not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder. This method includes (a) providing a nucleic acid molecule comprising a promoter from a gene encoding a nuclear receptor polypeptide listed in Table 1 , the promoter operably linked to a reporter system; (b) contacting the nucleic acid molecule with the candidate compound; and (c) measuring reporter activity, wherein altered reporter activity, relative to a nucleic acid molecule not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
In another aspect, the invention features yet another method for determining whether a candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder. This method includes the steps of: (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring interaction of the candidate compound to the polypeptide. Interaction of the compound to the polypeptide indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder.
In still another aspect, the invention features another method for determining whether a candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder. This method includes (a) providing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 ; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, wherein an alteration in the half-life of the polypeptide, relative to that of the polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a metabolic or nutritive disease or disorder. Preferably the nuclear receptor polypeptide is in a cell or a cell free assay system. In another aspect, the invention features a method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder. The method includes the step of determining whether the patient has a mutation in a gene encoding a polypeptide listed in Table 1, wherein presence of the mutation indicates that the patient has an increased risk for developing a metabolic or nutritive disease or disorder.
In a related aspect, the invention features another method for detennining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder. This method includes the step of determining whether the patient has a polymoφhism in a gene encoding a polypeptide listed in Table 1 , wherein presence of the polymoφhism indicates that the patient may have an increased risk for developing a metabolic or nutritive disease or disorder. hi either of these two methods, the mutation or polymoφhism is preferably associated with an alteration (for example, a decrease) in the biological activity of the polypeptide.
In another aspect, the invention features another method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder. The method includes measuring biological activity of a nuclear receptor polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the nuclear receptor biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a metabolic or nutritive disease or disorder.
In still another aspect, the invention features yet another method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder. The method includes the step of measuring the patient's expression levels of a polypeptide listed in Table 1, wherein altered levels in the expression, relative to normal, indicate that the patient has an increased risk for developing a metabolic or nutritive disease or disorder. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
Prefened metabolic or nutritive diseases and disorders that can be treated or diagnosed using the methods of the invention or for which candidate therapeutic compounds may be identified include 5 , 10-methylenetefrahydrofolate reductase deficiency, achondrogenesis type IB, acid α-1,4 glucosidase deficiency, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Baπaquer-Simons syndrome), acute intermittent poφhyria, acute panniculitis, adenine phosphoribosyltransferase deficiency, adenosine deaminase deficiency, adenylosuccinate lyase deficiency, adiposis dolorosa (Dercum disease), ALA dehydratase-deficient poφhyria, albinism, alkaptonuria, amulopectinosis, Andersen disease, argininemia, argininosuccinic aciduria, astelosteogenesis type 2, Bartter's syndrome, benign familial neonatal epilepsy, benign fructosuria, benign recurrent and progressive familial intrahepatic cholestasis, biotin deficiency, branching enzyme deficiency, calcium deficiency, carnitine transport defect, choline deficiency, choline toxicity, chromium deficiency, chronic fat malabsoφtion, citrullinemia, classic branched-chain ketoaciduria, classic cystinuria, congenital chloridorrhea, congenital erythropoietic poφhyria, congenital generalized lipodystrophy, congenital myotonia, copper deficiency, copper toxicity, cystathionine β-synthase deficiency, cystathioninuria, cystic fibrosis, cystinosis, cystinuria, Darier disease, defect in transport of long-chain fatty acids, deficiency of cobalamin coenzyme deficiency, Dent's syndrome, diatrophic dysplasia, dibasic aminoaciduria, dicarboxylic aminoaciduria, dihydropyrimidine dehydrogenase deficiency, distal renal tubular acidosis, dry beriberi, Dubin- Johnson syndrome, dysbetalipoproteinemia, end-organ insensitivity to vitamin D, erythropoietic protopoφhyria, Fabry disease, failure of intestinal absoφtion, familial apoprotein C2 deficiency, familial combined hyperlipidemia, familial defective Apo B100, familial goiter, familial hypercholesterolemia, familial hypertriglyceridemia, familial hypophosphatemic rickets, familial lipoprotein lipase deficiency, familial partial lipodystrophy, Fanconi-Bickel syndrome, fluoride deficiency, folate malabsoφtiόn, folic adic deficiency, formiminoglutamic aciduria, fructose 1 ,6 diphosphatase deficiency, galactokinase deficiency, galactose 1 -phosphate uridyl transferase deficiency galactosemia, Gaucher disease, Gitelman's syndrome, globoid cell leukodystrophy, glucose-6-phosphatease deficiency, glucose-6-translocase deficiency, glucose-galactose malabsoφtion, glucose-transporter protein syndrome, glutaric aciduria, glycogen storage disease type 2, glycogen storage disease type lb, glycogen storage disease type ID, glycogen synthase deficiency, gout, Hartnup disease, hawkinsinuria, hemochromatosis, hepatic glycogenosis with renal fanconi syndrome, hepatic lipase deficiency, hepatic poφhyria, hereditary copropoφhyria, hereditary fructose intolerance, hereditary xanthinuria, Hers disease, histidinemia, histidinuria, HIV-1 protease inhibitor-induced lipodystrophy, homocitrallinuria, homocystinuria, homocystinuria, homocystinuria and methylmalonic acidemia, homocystinurias, Hunter syndrome, Hurler disease, Hurler- Scheie disease, hyophosphatemic rickets, hyperammonemia, hyperammonemia, hypercholesterolemia, hypercystinuria, hyperglycinemia, hyperhydroxyprolinemia, hyperkalemic periodic paralysis, hyperleucineisoleucinemia, hyperlipoproteinemias, hyperlysinemia, hypermagnesemia, hypeimetabolism, hypermethioninemia, hyperornithinemia, hyperoxaluria, hypeφhenylalaninemia with primapterinuria, hypeφhenylalaninemias, hypeφhosphatemia, hypeφrolinemia, hypertriglyceridemia, hyperaricemia, hypervalinemia, hypervitaminosis A, hypervitaminosis D, hypocholesterolemia, hypometabolism, hypophosphatemia, hypouricemia, hypovitaminosis A, hypoxanthine phosphoribosyltransferase deficiency, iminoglycinuria, iminopeptiduria, intermittent branched-chain ketoaciduria, intestinal malabsoφtion, iodine deficiency, iron deficiency, isovaleric acidemia, Jervell and Lange-Nielsen syndrome, juvenile pernicious anemia, keshan disease, Korsakoff s syndrome, kwashiorkor, leukodystrophies, Liddle's syndrome, lipodystrophies, lipomatosis, liver glycogenoses, liver phosphorylase kinase deficiency, long QT syndrome, lysinuria, lysosomal storage diseases, magnesium deficiency, malabsoφtive diseases, malignant hypeφhenylalaninemia, manganese deficiency, marasmus, Maroteaux-Lamy disease, McArdle disease, Menkes' disease, metachromatic leukodystrophy, methionine malabsoφtion, methylmalonic acidemia, molybdenum deficiency, monosodiumurate gout, Morquio syndrome, mucolipidoses, mucopolysaccharidoses, multiple carboxylase deficiency syndrome, multiple symmetric lipomatosis (Madelung disease, muscle glycogenoses, muscle phosphofructokinase deficiency, muscle phosphorylase deficiency, myoadenylate deaminase deficiency, neplirogenic diabetes insipidus, nesidioblastosis of pancreas, niacin deficiency, niacin toxicity, Niemann-Pick disease, obesity, orotic aciduria, osteomalacia, paramyotonia congenita, pellagra, Pendred syndrome, phenylketonuria, phenylketonuria type 1, phenylketonuria type 2, phenylketonuria type 3, phosphate deficiency, phosphoribosylpyrophosphate synthetase overactivity, polygenic hypercholesterolemia, Pompe disease, poφhyria cutanea tarda, poφhyrias, primary bile acid malabsoφtion, primary hyperoxaluria, primary hypoalphalipoproteinemia, propionic acidemia, protein- energy malnutrition, proximal renal tubular acidosis, purine nucleoside phosphorylase deficiency, pyridoxine deficiency, pyrimidine 5'-nucleotidase deficiency, renal glycosuria, riboflavin deficiency, rickets, Rogers' syndrome, saccharopinuria, Sandhoff disease, Sanfilippo syndromes, sarcosinemia, Scheie disease, scurvy (vitamin C deficiency), selenium deficiency, selenosis, sialic acid storage disease, S-sulfo-L- cysteine, sulfite, thiosulfaturia, Tarui disease, Tay-Sachs disease, thiamine deficiency, tryptophan malabsoφtion, tryptophanuria, type 1 pseudohypoaldosteronism, type 3 glycogen storage disease (debrancher deficiency, limit dextrinosis), tyrosinemia, tyrosinemia type 1, tyrosinemia type 2, tyrosinemia type 3, uridine diphosphate galactose 4-epimerase deficiency, urocanic aciduria, variegate poφhyria, vitamin B12 deficiency, vitamin C toxicity, vitamin D deficiency, vitamin D-resistant rickets, vitamin d-sensitive rickets, vitamin E deficiency, vitamin E toxicity, vitamin K deficiency, vitamin K toxicity, von Gierke disease, Wernicke's encephalopathy, wet beriberi, Wilson's disease, xanthurenic aciduria, X-linked sideroblastic anemia, zinc deficiency, zinc toxicity, α-ketoadipic aciduria, α-methylacetoacetic aciduria, β-hydroxy-β- methylglutaric aciduria, β-methylcrotonyl glycinuria.
In another aspect, the invention features a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1. The transgene may be operably linked, e.g., to an inducible, cell-type, or tissue-specific promoter. In one embodiment, the transgenic mouse has a mutation in a gene that is orthologous to the transgene. For example, the transgene encoding the human nuclear receptor polypeptide may entirely replace the coding sequence of the orthologous mouse gene or the transgene might complement a knock out of the orthologous mouse gene. In a related embodiment, the transgenic mouse has a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1.
In another aspect, the invention features an isolated cell or population of cells derived from a transgenic mouse either expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1 or has a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1.
The invention also features a method for identifying a compound that may be useful for the treatment of a disease or disorder described herein. The method includes the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a nuclear receptor polypeptide listed in Table 1 ; and determining whether the candidate compound decreases the biological activity of the nuclear receptor polypeptide, wherein a decrease in the biological activity of the nuclear receptor polypeptide identifies the candidate compound as a compound that may be useful for the treatment of a disease or disorder. In one embodiment, the transgenic mouse has a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1. In a related embodiment, the mouse has a mutation in the gene that is orthologous to the transgene.
In a related aspect, the invention features another method for identifying a compound that may be useful for the treatment of a disease or disorder described herein. This method includes the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a nuclear receptor polypeptide in a gene listed in Table 1, and having a disease or disorder caused by the expression of the transgene; and determining whether the candidate compound treats the disease or disorder. In a related aspect, the invention features another method for identifying a compound that may be useful for the treatment of a disease or disorder described herein. This method includes the steps of administering a candidate compound to a transgenic mouse fransgenic mouse containing a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1, and having a disease or disorder caused by gene disruption; and determining whether candidate compound treats the disease or disorder.
In still another aspect, the invention features a method for identifying a compound that may be useful for the treatment of a disease or disorder described herein. This method includes the steps of contacting a candidate compound with a cell from a transgenic mouse expressing a transgene encoding a nuclear receptor polypeptide in a gene listed in Table 1 ; and determining whether the candidate compound decreases the biological activity of the nuclear receptor polypeptide. A decrease in the biological . activity of the nuclear receptor polypeptide identifies the candidate compound as a compound that may be useful for the treatment of a disease or disorder. In one embodiment, the transgenic mouse from which the cell was derived has a mutation (e.g., a deletion, frameshift, insertion or a point mutation) in a gene listed in Table 1. In a related embodiment, the mouse has a mutation in the polypeptide that is orthologous to the nuclear receptor polypeptide encoded by the transgene. The invention also features a kit that includes a plurality of polynucleotides, wherein each polynucleotide hybridizes under high stringency conditions to a nuclear receptor polynucleotide of Table 1. At least 50 different polynucleotides, each capable of hybridizing under high stringency conditions to a different human nuclear receptor polynucleotide listed on Table 1, are present in the kit. The invention features another kit that includes a plurality of polynucleotides. In this kit, polynucleotides that hybridize under high stringency conditions, each to a different nuclear receptor polynucleotide listed on one of Tables 3-32, are present in the kit such that the kit includes polynucleotides that collectively hybridize to every nuclear receptor polynucleotide listed on one of Tables 3-32. The invention features another kit, this kit including a plurality of mice, each mouse having a mutation in a nuclear receptor polynucleotide of Table 1, wherein at least 50 mice, each having a mutation in a different nuclear receptor polynucleotide listed on Table 1, are present in the kit. This kit may optionally include a plurality of polynucleotides, wherein each polynucleotide hybridizes under high stringency conditions to a nuclear receptor polynucleotide of Table 1, wherein at least 50 different polynucleotides, each capable of hybridizing under high stringency conditions to a different mouse nuclear receptor polynucleotide listed on Table 1, are present in the kit. The invention features another kit that includes a plurality of mice having a mutation in a nuclear receptor polynucleotide. In this kit, mice having a mutation in each nuclear receptor polynucleotide listed on one of Tables 3-32 are present in the kit.
Definitions By "polypeptide" is meant any chain of more than two amino acids, regardless of post-translational modification such as glycosylation or phosphorylation.
By "substantially identical" is meant a polypeptide or nucleic acid exhibiting at least 50%, preferably 85%, more preferably 90%, and most preferably 95% identity to a reference amino acid or nucleic acid sequence. For polypeptides, the length of comparison sequences will generally be at least 16 amino acids, preferably at least
20 amino acids, more preferably at least 25 amino acids, and most preferably 35 amino acids or the full-length polypeptide. For nucleic acids, the length of comparison sequences will generally be at least 50 nucleotides, preferably at least 60 nucleotides, more preferably at least 75 nucleotides, and most preferably 110 nucleotides or the full- length polynucleotide.
Sequence identity is typically measured using a sequence analysis program (e.g., BLAST 2; Tatusova et al., FEMS Microbiol Lett. 174:247-250, 1999) with the default parameters specified therein.
By "high stringency conditions" is meant hybridization in 2X SSC at 40°C with a DNA probe length of at least 40 nucleotides. For other definitions of high stringency conditions, see F. Ausubel et al., Current Protocols in Molecular Biology, pp. 6.3.1- 6.3.6, John Wiley & Sons, New York, NY, 1994, hereby incoφorated by reference. "Substantially identical" polynucleotides also include those that hybridize under high stringency conditions. "Substantially identical" polypeptides include those encoded by polynucleotides that hybridize under high stringency conditions.
By "substantially pure polypeptide" is meant a polypeptide that has been separated from the components that naturally accompany it. Typically, the polypeptide is substantially pure when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. Preferably, the polypeptide is a nuclear receptor polypeptide that is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, pure. A substantially pure nuclear receptor polypeptide may be obtained, for example, by extraction from a natural source (e.g., a pancreatic cell), by expression of a recombinant nucleic acid encoding a nuclear receptor polypeptide, or by chemically synthesizing the polypeptide. Purity can be measured by any appropriate method, e.g., by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.
A polypeptide is substantially free of naturally associated components when it is separated from those contaminants that accompany it in its natural state. Thus, a polypeptide which is chemically synthesized or produced in a cellular system different from the cell from which it naturally originates will be substantially free from its naturally associated components. Accordingly, substantially pure polypeptides include those which naturally occur in eukaryotic organisms but are synthesized in E. coli, yeast or other microbial system.
By "purified antibody" is meant antibody that is at least 60%, by weight, free from proteins and naturally occurring organic molecules with which it is naturally associated. Preferably, the preparation is at least 75%, more preferably 90%, and most preferably at least 99%, by weight, antibody. A purified antibody may be obtained, for example, by affinity chromatography using recombinantly-produced protein or conserved motif peptides and standard techniques.
By "specifically binds" is meant any small molecule, peptide, antibody, or polypeptide that recognizes and binds, for example, a human nuclear receptor polypeptide but does not substantially recognize and bind other molecules in a sample, e.g., a biological sample, that naturally includes the protein.
By "polymorphism" is meant that a nucleotide or nucleotide region is characterized as occuπing in several different sequence forms. A "mutation" is a forai of a polymoφhism in which the expression level, stability, function, or biological activity of the encoded protein is substantially altered. By "nuclear receptor related polypeptide" is meant a polypeptide having substantial identity to any of the polypeptides listed in Table 1, including polymoφhic forms (e.g., sequences having one or more SNPs) and splice variants. By "nuclear receptor biological activity" is meant measurable effect or change in an organism or a cell resulting from the modulation of a nuclear receptor at the molecular, cellular, physiological or behavioral levels or alteration in the extent of activation or deactivation that can be elicited by an agonist or antagonist. "Dominant negative" means an effect of a mutant form of a gene product that dominantly interferes with the function of the normal gene product.
"Reporter system" means any gene, compound or polypeptide whose product can be assayed, measured or monitored. Examples include, but are not limited to neomycin (Kang et al., Mol Cells 1997; 7:502-8), luciferase (Welsh et al., Curr Opin Biotechnol 1997; 8:617-22), lacZ (Spergel et al, Prog Neurobiol 2001; 63:673-86), aequorin (Deo et al., J Anal Chem 2001; 369:258-66) and green fluorescent protein (Tsien, Annu Rev Biochem 1998; 67:509-44).
"Conditional mutant" is any gene, cell or organism for which the expression of the mutant phenotype can be controlled through alteration in the temperature, diet or other external conditions.
"Overexpression" means level of expression higher than the physiological level of expression.
"Isolated" or "purified" means altered from its natural state, i.e., if it occurs in nature, it has been changed or removed from its original environment, or both. For example, a polynucleotide or a polypeptide naturally present in a living organism is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated," as the term is employed herein. Moreover, a polynucleotide or polypeptide that is introduced into an organism by transformation, genetic manipulation, or by any other recombinant method is "isolated" even if it is still present in the organism.
"Polynucleotide" generally refers to any polyribonucleotide (RNA) or polydeoxribonucleotide (DNA), which may be unmodified or modified RNA or DNA. Polynucleotides include, without limitation, single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double- stranded or a mixture of single- and double-stranded regions. Polynucleotide can also refer to triple helix nucleic acids. "Variant" refers to a polynucleotide or polypeptide that differs from a reference polynucleotide or polypeptide, but retains the essential properties thereof. A typical variant of a polynucleotide differs in nucleotide sequence from the reference polynucleotide. Changes in the nucleotide sequence of the variant may or may not alter the amino acid sequence of a polypeptide encoded by the reference polynucleotide. Nucleotide changes may result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence, as discussed below. A typical variant of a polypeptide differs in amino acid sequence from the reference polypeptide. Generally, alterations are limited so that the sequences of the reference polypeptide and the variant are closely similar overall and, in many regions, identical. A variant and reference polypeptide may differ in amino acid sequence by one or more substitutions, insertions, or deletions in any combination. A substituted or inserted amino acid residue may or may not be one encoded by the genetic code. Typical conservative substitutions include Gly, Ala; Val, Ile, Leu; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe and Tyr. A variant of a polynucleotide or polypeptide may be naturally occurring such as an allele, or it may be a variant that is not known to occur naturally. Non-naturally occurring variants of polynucleotides and polypeptides may be made by mutagenesis techniques or by direct synthesis. Also included as variants are polypeptides having one or more post-translational modifications, for instance glycosylation, phosphorylation, methylation, ADP ribosylation and the like.
Embodiments include methylation of the N-terminal amino acid, phosphorylations of serines and threonines and modification of C-terminal glycines.
"Allele" refers to one of two or more alternative forms of a gene occuπing at a given locus in the genome. A "transgenic organism," as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection, transfection or by infection with a recombinant virus. The transgenic organisms contemplated in accordance with the present invention include mice, bacteria, cyanobacteria, fungi, plants and animals. The isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or fransconjugation.
A "transgenic mice," as used herein, is a mouse, in which one or more of the cells of the organism contains nucleic acid introduced by way of human intervention, such as by fransgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, by methods known in the art, for example microinjection, infection, transfection, or transformation.
"Transgene" is any exogenously added nucleic acid. "Antisense" or "Reverse complement" means a nucleic acid sequence complementary to the messenger RNA.
"Single nucleotide polymoφhism" or "SNP" refers to the occurrence of nucleotide variability at a single nucleotide position in the genome, within a population. An SNP may occur within a gene or within intergenic regions of the genome. SNPs can be assayed using Allele Specific Amplification (ASA). For this process, at least three primers are required. A common primer is used in reverse complement to the polymoφhism being assayed. This common primer can be between 50 and 1500 bps from the polymoφhic base. The other two (or more) primers are identical to each other except that the final 3' base wobbles to match one of the two (or more) alleles that make up the polymoφhism. Two (or more) PCR reactions are then conducted on sample DNA, each using the common primer and one of the Allele Specific Primers.
"Splice variant" as used herein refers to cDNA molecules produced from RNA molecules initially transcribed from the same genomic DNA sequence but which have undergone alternative RNA splicing. Alternative RNA splicing occurs when a primary RNA transcript undergoes splicing, generally for the removal of introns, which results in the production of more than one distinct mRNA molecules each of which may encode different amino acid sequences. The term splice variant also refers to the polypeptides encoded by the above mRNA molecules.
"Fusion protein" refers to a polypeptide encoded by two, often unrelated, fused genes or fragments thereof.
By "candidate compound" or "test compound" is meant a chemical, be. it naturally-occurring or artificially-derived, that is assayed for its ability to modulate gene activity or protein stability or binding, expression levels, or activity, by employing any standard assay method. Test compounds may include, for example, peptides, polypeptides, synthesized organic molecules, naturally occurring organic molecules, polynucleotide molecules, and components thereof.
By "promoter" is meant a minimal sequence sufficient to direct transcription. Also included in the invention are those promoter elements which are sufficient to render promoter-dependent gene expression controllable for cell type-specific, tissue- specific, temporal-specific, or inducible by external signals or agents; such elements may be located in the 5' or 3' or intron sequence regions of the native gene.
By "operably linked" is meant that a gene and one or more regulatory sequences are connected in such a way as to permit gene expression.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof and from the claims.
Detailed Description of the Invention
We have determined the expression pattern for nuclear receptors, providing functional information for these receptors (Table 1). In addition, we have indicated which nuclear receptors are oφhan, for which no physiological ligand has been identified for the nuclear receptor (Table 2). The nuclear receptor polypeptides and polynucleotides may be relevant for the treatment or diagnosis of various disease or disorders. In addition to the wild-type nuclear receptor polypeptide, polymoφhic, splice variant, mutagenzied, and recombinant forms of a nuclear receptor polypeptide may also be targets for treatment or diagnosis of diseases and disorders or for assaying for therapeutic compounds.
Table 1. Nuclear Receptors
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Table 2. Orphan Nuclear Receptors
Figure imgf000129_0002
Polypeptide Expression and Purification
' ' Recombinant nuclear receptor polypeptides may be produced using standard techniques known in the art. Such recombinant nuclear receptor polypeptides are, for example, useful in in vitro assays for identifying therapeutic compounds.
Accordingly, the present invention relates to expression systems that include a polynucleotide of the present invention, host cells that are genetically engineered with such expression systems, and production of polypeptides of the invention by recombinant techniques. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention. For recombinant production, host cells can be genetically engineered to incoφorate expression systems or portions thereof for any polynucleotide of the present invention. Polynucleotides may be introduced into host cells by methods described in standard laboratory manuals. Prefened methods of introducing polynucleotides into host cells include, for instance, calcium phosphate transfection, DEAE-dextran mediated transfection, transvection, microinjection, cationic lipid-mediated transfection, electroporation, transduction, ballistic introduction, infection or fusion with carriers such as liposomes, micelles, ghost cells, and protoplasts.
A great variety of expression systems can be used. These include, without limitation, chromosomal, episomal, and virus-derived systems such as vector derived bacterial plasmids, bacteriophage, transposons, yeast episomes, insertion elements, yeast chromosomal elements, viruses (such as baculoviruses, papova viruses, such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses, and retroviruses), and vectors derived from combinations .thereof, such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids. Prefened expression vectors include, but are not limited to, pcDNA3 (Invitrogen) and pSVL (Pharmacia Biotech). Other expression vectors include, but are not limited to, pSPORTTm vectors, pGEMTm vectors (Promega), pPROEXvectorsTm (LTI, Bethesda, MD), BIuescriptTm vectors (Stratagene), pQETm vectors (Qiagen), pSE420Tm (Invitrogen), and pYES2Tm (Invitrogen). The expression systems may contain control regions that regulate as well as engender expression. Generally, any system or vector that is able to maintain, propagate, or express a polynucleotide to produce a polypeptide in a host may be used. The appropriate polynucleotide may be inserted into an expression system by any of a variety of well-known and routine techniques, including transformation, transfection, electroporation, nuclear injection, or fusion with carriers such as liposomes, micelles, ghost cells, and protoplasts. Expression systems of the invention include bacterial, yeast, fungal, plant, insect, invertebrate, vertebrate, and mammalian cells systems.
If a eukaryotic expression vector is employed, then the appropriate host cell would be any eukaryotic cell capable of expressing the cloned sequence. Preferably, eukaryotic cells are cells of higher eukaryotes. Suitable eukaryotic cells include, but are not limited to, non-human mammalian tissue culture cells and human tissue culture cells. Prefened host cells include, but are not limited to, insect cells, HeLa cells, Chinese hamster ovary cells (CHO cells), African green monkey kidney cells (COS cells), human 293 cells, murine embryonal stem (ES) cells and murine 3T3 fibroblasts. Propagation of such cells in cell culture has become a routine procedure (see, Tissue Culture, Academic Press, Kruse and Patterson, eds. (1973), which is incoφorated herein by reference in its entirety). In addition, a yeast host may be employed as a host cell. Preferred yeast cells include, but are not limited to, the genera, Saccharomyces, Pichia, and Kluveromyces. Prefened yeast hosts are S. cerevisiae and P. pastoris. Prefened yeast vectors can contain an origin of replication sequence from a 2T yeast plasmid, an autonomously replication sequence (ARS), a promoter region, sequences for polyadenylation, sequences for transcription termination, and a selectable marker gene. Shuttle vectors for replication in both yeast and E. coli are also included herein.
Alternatively, insect cells may be used as host cells. In a prefened embodiment, the polypeptides of the invention are expressed using a baculovirus expression system (see, Luckow et al., BioTechnology, 1988, 6. and Baculovirus Expression Vectors: A Laboratory Manual, O'Rielly et al. (Eds.), W.H. Freeman and Company, New York, 1992, each of which is incoφorated herein by reference in its entirety). In addition, the Bac-to-BacTm complete baculovirus expression system (Invitrogen) can, for example, be used for production in insect cells.
Expression of proteins in prokaryotes is most often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three puφoses: 1) to increase expression of recombinant protein; 2) to increase the solubility of the recombinant protein; and 3) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protem from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase.
Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith, D.B. and Johnson, K.S. (1988) Gene 67:31 -40), pMAL (New England Biolabs, Beverly, MA) and pRIT5 (Pharmacia, Piscataway, NJ) which fuse glutathione S- transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.
If a polypeptide of the present invention is to be expressed for use in screening assays, it maybe produced at the surface of the cell. In this event, the cells may be harvested prior to use in the screening assay. If the polypeptide is secreted into the medium, the medium can be recovered in order to recover and purify the polypeptide. If produced intracellularly, the cells must first be lysed before the polypeptide is recovered.
Polypeptides of the present invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxyapatite chromatography and lectin chromatography. Most preferably, high perfoπnance liquid chromatography is employed for purification. Well- known techniques for refolding proteins may be employed to regenerate active conformation when the polypeptide is denatured during intracellular synthesis, isolation, and/or purification.
Expression of TR4 or other nuclear receptor listed in Table 1.
Recombinant expression of TR4 or other nuclear receptor encoding polynucleotide listed in Table 1 is expressed in a suitable host cell using a suitable expression vector by standard genetic engineering teclmiques. For example, the TR4 is subcloned into the commercial expression vector, for example pcDNA3.1 (Invitrogen, San Diego, CA) and transfected into Chinese Hamster Ovary (CHO) cells using the transfection reagent FuGENEό (Boehringer-Mannheim) and the transfection protocol provided in the product insert. Other eukaryotic cell lines, including human embryonic kidney (HEK293) and COS cells, are suitable as well. Cells stably expressing nuclear receptor are selected by growth in the presence of 100 μg/ml zeocin (Stratagene, LaJolla, CA). Optionally, nuclear receptors may be purified from the cells using standard chromatographic techniques. To facilitate purification, antisera, is raised against one or more synthetic peptide sequences that conespond to portions of the nuclear receptor amino acid sequence, and the antisera is used to affinity purify the nuclear receptor. TR4 also may be expressed in-frame with a tag sequence (e.g., polyhistidine, hemagluttinin, FLAG) to facilitate purification. Moreover, it will be appreciated that many of the uses for nuclear receptor polypeptides, such as assays described below, do not require purification of nuclear receptor from the host cell.
Expression of nuclear receptors in 293 cells. For expression of nuclear receptor polypeptides in mammalian cells HEK293 (transformed human, primary embryonic kidney cells), a plasmid bearing the relevant nuclear receptor coding sequence is prepared (Table 1), using vector pcDNA3.1 (Invitrogen). The forward primer for amplification of this nuclear receptor cDNA is determined by routine procedures and preferably contains a 5' extension of nucleotides to introduce the Hindlll cloning site and nucleotides matching the nuclear receptor sequence. The reverse primer is also determined by routine procedures and preferably contains a 5' extension of nucleotides to introduce an Xbal restriction site for cloning and nucleotides conesponding to the reverse complement of the nuclear receptor sequence. The PCR product is gel purified and cloned into the Hindlll-Xbal sites of the vector.
The expression vector containing the nuclear receptor gene is purified using Qiagen chromatography columns and transfected into 293 cells using DOTAPTm transfection media (Bochringer Mannheim, Indianapolis, IN). Transiently transfected cells are tested for expression after 24 hours of transfection, using western blots probed with anti-His and anti- nuclear receptor peptide antibodies. Permanently transfected cells are selected with Zeocin and propagated. Production of the recombinant protein is detected from both cells and media by western blots probed with anti-His, or anti- nuclear receptor peptide antibodies.
Expression of nuclear receptors in COS cells. For expression of the nuclear receptor in COS7 cells, a polynucleotide molecule having a sequence selected from the group consisting of polynucleotide sequences listed in Table 1, can be cloned into vector p3-CI or similar expression vector. This vector is a pUCl 8-derived plasmid that contains the HCMV (human cytomegalovirus) promoter-intron located upstream from the bGH (bovine growth hormone) polyadenylation sequence and a multiple cloning site. In addition, the plasmid contains the DHRF (dihydrofolate reductase) gene which provides selection in the presence of the drug methofrexane (MTX) for selection of stable transformants. The forward primer is determined by routine procedures and preferably contains a 5' extension which introduces an Xbal restriction site for cloning, followed by nucleotides which conespond to a sequence selected from the group consisting of sequences listed in Table 1. The reverse primer is also determined by routine procedures and preferably contains 5' extension of nucleotides which introduces a restriction cloning site followed by nucleotides which conespond to the reverse complement of a sequence selected from the group consisting of sequences listed in Table 1. The PCR reaction is perfonned as described in the manufactures instructions. The PCR product is gel purified and ligated into the p3-Cl or similar expression vector. This construct is transformed into E. coli cells for amplification and DNA purification. The expression vector containing the nuclear receptor polynucleotide sequence is purified with Qiagen chromatography columns and transfected into COS 7 cells using LipofectamineTm reagent from BRL, following the manufacturer's protocols. Forty-eight and 72 hours after transfection, the media and the cells are tested for recombinant protein expression. Nuclear receptor expressed from a COS cell culture can be purified by concentrating the cell- growth media to about 10 mg of protein/ml, and purifying the protein by chromatography.
Expression of nuclear receptors in Insect Cells. For expression of a nuclear receptor in a baculovirus system, a polynucleotide molecule having a sequence selected from the group consisting of sequences listed in Table 1, can be amplified by PCR. The forward primer is determined by routine procedures and preferably contains a 5' extension which adds the Ndel cloning site, followed by nucleotides which conespond to a sequence selected from the group consisting of sequences listed in Table 1. The reverse primer is also determined by routine procedures and preferably contains a 5' extension which introduces the Kpnl cloning site, followed by nucleotides which conespond to the reverse complement of a sequence selected from the group consisting of sequences listed in Table 1.
The PCR product is gel purified, digested with Ndel and Kpnl, and cloned into the conesponding sites of vector pACHTL-A (Pharmingen, San Diego, CA). The pAcHTL-A expression vector contains the strong polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus (AcMNPV), and a 6xHis tag upstream from the multiple cloning site. A protein kinase site for phosphorylation and a thrombin site for excision of the recombinant protein precede the multiple cloning site is also present. Of course, many other baculovirus vectors could be used in place of pAcHTL-A, such as pAc373, pVL941 and pAcIML. Other suitable vectors for the expression of nuclear receptor polypeptides can be used, provided that the vector construct includes appropriately located signals for transcription, translation, and trafficking, such as an in- frame AUG and a signal peptide, as required. Such vectors are described in Luckow et al., Virology 170:31-39, among others. The virus is grown and isolated using standard baculovirus expression methods, such as those described in Summers et al. (A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agricultural Experimental Station Bulletin No. 1555 (1987)).
In a prefened embodiment, pAcHLT-A containing a nuclear receptor gene is introduced into baculovirus using the "BaculoGoIdTm" transfection kit (Pharmingen, San Diego, CA) using methods established by the manufacturer. Individual virus isolates are analyzed for protein production by radiolabeling infected cells with 35S-methionine at 24 hours post infection. Infected cells are harvested at 48 hours post infection, and the labeled proteins are visualized by SDS-PAGE. Viruses exhibiting high expression levels can be isolated and used for scaled up expression.
For expression of a nuclear receptor polypeptide in a Sf9 cells, a polynucleotide molecule having a sequence selected from the group consisting of sequences listed in Table 1 , can be amplified by PCR using the primers and methods described above for baculovirus expression. The nuclear receptor cDNA is, cloned into vector pAcHLT-A (Pharmingen) for expression in Sf9 insect cells. The insert is cloned into the Ndel and Kpnl sites, after elimination of an internal Ndel site (using the same primers described above for expression in baculovirus). DNA is purified with Qiagen chromatography columns and expressed in Sf9 cells. Preliminary Western blot experiments from non- purified plaques are tested for the presence of the recombinant protein of the expected size which reacted with the nuclear receptor-specific antibody.
Nuclear Receptor Expression Profiles: Related Diseases and Disorders Expression profiles for nuclear receptors of the present invention were determined with human or mice tissues using RT-PCR and/or tissue in situ hybridization methods. Our findings are summarized below. Methods
RT-PCR
Tissue harvesting: 8-10 week old male or female 129Sl/SvIMJ mice (Jackson Laboratory) were used for tissue harvesting. Peripheral tissues were dissected fresh and stored in RNAlater at 4°C (Ambion). Some tissues were also purchased from PelFreez and kept frozen at -80°C until RNA extraction. Brains were removed and stored overnight at 4°C in RNAlater, then microdissected under a Leica MZ6 dissecting microscope into nine regions, using landmarks from a mouse atlas. RNA preparation: RNA was extracted using the Totally RNA kit (Ambion) including LiCl precipitation and DNAse (Epicenter) treatment. To test for genomic DNA contamination, infron/exon spanning PCR primers for several genes (ApoAI, Nunl, Actin, G3PDH and Blue opsin) were used in RT-PCRs, performed in the presence or absence of RT, with 200ng of input cDNA. RT reactions: 5μg of each RNA sample was reverse transcribed with random primers (Roche) in a 40μl reaction with 40U MMLV-RT (Roche) and 20U RNAse inhibitor (Roche). cDNAs were treated with RNAse H (Epicenter) and RNAse A (Ambion) and normalized with 18S RNA primer sets (Ambion).
PCRs: Gene amplification was carried out in 25μl reactions with 2ng, 20ng or 200ng of input cDNA, in the presence of 1.25 U of AmpliTaq Gold Polymerase
(Applied Biosystems) and 0.25uM of each primer. Cycling conditions were: 94°C for 5 minutes, followed by 37 or 40 cycles of 94°C / 0.5 minute - 65°C / 0.5 minute - 72°C / 1 minute. Subsequently to the final cycle, reactions were extended for 7 minutes at 72°C. All PCR products were analyzed on a 2% agarose gel containing ethidium bromide and visualized on an Alpha Imager. Scanning was performed on an Alpha Imager by the Alpha Ease Program (Alpha Innotech).
Primers: Primers were designed using the Oligo 6.0 program (Mol. Bio. Insights). Their specificity was evaluated by BLAST searches of the human and mouse genomes. Gene specific amplicons were and confirmed by sequencing the bands obtained from RT-PCR. In Situ Hybridization
Tissue dissection and sectioning: 8-10 week old male 129Sl/SvIMJ mice (Jackson Laboratory) were sacrificed and their brains were dissected, snap frozen on dry ice, and stored at-70°C. Brains were sectioned at 10-14 μm onto microscope slides. Sections were collected in series so that each gene was sampled at 100 μm intervals through the hypothalamus and amygdala, and at 500 μm intervals through the remainder of the brain. Riboprobe preparation: T3 (sense) and T7 (antisense) promoters were attached to either side of the gene of interest and amplified by PCR, using primers with the conesponding gene and promoter sequences. Transcription reactions were performed using Ambion Maxiscript kits. PCR generated templates (500ng) were added to 100 μCi of dried down 33P-UTP (Perkin Elmer) in lOμl reactions. Hybridization: Prehybridization and hybridization reactions were performed as previously described with modifications. Briefly, 33P labeled riboprobes (~5xl0 cpm/slide) were applied to slides overnight at 55°C. Slides were then digested with RNAse and rinsed in SSC, with a final rinse in 0.1X SSC at 70°C for 30min. Slides were subsequently dipped in NTB-2 emulsion, and developed after 3 weeks. Analysis: Specific mRNA distributions were determined by examination of two complete brains for each gene, with light and darkfield microscopy. An additional brain was examined for sense labeling, to assess sites of non-specific signal. Specific signal was scored as clusters of silver grains over discrete cells or brain regions, without conesponding signal in sense slides. Sections were counterstained with cresyl violet for contrast and regional identification. Images were captured with a Photometric CoolSnap camera and Universal Imaging MetaMoφh software (both Meridian Instruments).
Expression Profile Results
We have determined the expression pattern for nuclear receptors, providing functional information for these receptors (Table 1). The nuclear receptor polypeptides and polynucleotides may be relevant for the treatment or diagnosis of various disease br disorders, particularly behavioral disorders. In addition to the wild-type nuclear receptor polypeptide, polymoφhic, splice variant, mutagenzied, and recombinant forms of a nuclear receptor polypeptide may also be targets for treatment or diagnosis of diseases and disorders or for assaying for therapeutic compounds. Nervous System Tissues
Hypoihalamus. Nuclear receptors expressed in the hypothalamus are listed in Table 3. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the hypothalamus. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease involving the hypothalamus, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 3. Nuclear Receptors Expressed in the Hypothalamus
Figure imgf000138_0001
Amygdala. Nuclear receptors expressed in the amygdala are listed in Table 4. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the amygdala. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 4. Nuclear Receptors Expressed in the Amygdala
Figure imgf000138_0002
Pituitary. Nuclear receptors expressed in the pituitary are listed in Table 5. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the pituitary. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Figure imgf000139_0001
Brain. Nuclear receptors expressed in the female brain are listed in Table 6, and nuclear receptors expressed in the male brain are listed in Table 7. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the female or male nervous system. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the nervous system, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 6. Nuclear Receptors Expressed in the Female Brain
Figure imgf000139_0002
Figure imgf000140_0001
Brainstem and midbrain. Nuclear receptors expressed in the brainstem and midbrain are listed in Table 8. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the nervous system. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the nervous system, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 8. Nuclear Receptors Expressed in the Brainstem
Figure imgf000140_0002
Cerebellum. Nuclear receptors expressed in the cerebellum are listed in Table 9. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the cerebellum. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Figure imgf000141_0001
Cerebral cortex. Nuclear receptors expressed in the regions of the cerebral cortex other than the frontal cortex are listed in Table 10. These receptors are thus potential targets for therapeutic compounds that may modulate nuclear receptor activity, expression, or stability in the cerebral cortex. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder involving the cerebral cortex, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 10. Nuclear Receptors Expressed in the Cortex
Figure imgf000141_0002
Frontal cortex. Nuclear receptors expressed in the frontal cortex are listed in Table 11. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the frontal cortex. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder involving the frontal cortex, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 11. Nuclear Receptors Expressed in the Frontal Cortex
Figure imgf000142_0001
Hippocampus. Nuclear receptors expressed in the hippocampus are listed in Table 12. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the hippocampus. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the hippocampus, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 12. Nuclear Receptors Expressed in the Hippocampus
Figure imgf000142_0002
Striatum. Nuclear receptors expressed in the striatum are listed in Table 13. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the striatum. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the striatum, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 13. Nuclear Receptors Expressed in the Striatum
Figure imgf000143_0001
Thalamus. Nuclear receptors expressed in the thalamus are listed in Table 14. . These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the thalamus. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the thalamus, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 14. Nuclear Receptors Expressed in the Thalamus
Figure imgf000143_0002
Exemplary diseases and disorders of the nervous system include abetalipoproteinemia, abnormal social behaviors, absence (petit mal) epilepsy, absence seizures, abulia, acalculia, acidophilic adenoma, acoustic neuroma, acquired aphasia, acquired aphasia with epilepsy (Landau-Kleffher syndrome) specific reading disorder, acquired epileptic aphasia, acromegalic neuropathy, acromegaly, action myoclonus-renal insufficiency syndrome, acute autonomic neuropathy, acute cerebellar ataxia in children, acute depression, acute disseminated encephalomyelitis, acute idiopathic sensory neuronopathy, acute intermittent poφhyria, acute mania, acute mixed episode, acute pandysautonomia, acute polymoφhic disorder with symptoms of schizophrenia, acute polymoφhic psychotic disorder without symptoms of schizophrenia, acute purulent meningitis, addiction, Addison syndrome, adenovirus serotypes, adjustment disorders, adrenal hyperfunction, adrenal hypofunction, adrenoleukodystrophy, adrenomyeloneuropathy, advanced sleep-phase syndrome, affective disorder syndromes, agenesis of the coφus callosum, agnosia, agoraphobia, agraphia, agyria, agyria- pachygyria, ahylognosia, Aicardi syndrome, AIDS, akathisia, akinesia, akinetic mutism, akinetopsia, alcohol abuse, alcohol dependence syndrome, alcohol neuropathy, alcohol related disorders, alcoholic amblyopia, alcoholic blackouts, alcoholic cerebellar degeneration, alcoholic dementia, alcoholic hallucinosis, alcoholic polyneuropathy, alcohol-induced anxiety disorders, alcohol-induced dementia, alcohol-induced mood disorders, alcohol-induced psychosis, alcoholism, Alexander's syndrome, alexia, alexia with agraphia, alexia without agraphia, alien hand syndrome, Alper's disease, altered sexuality syndromes, alternating hemiplagia, Alzheimer's disease, Alzheimer-like senile dementia, Alzheimer-like juvenile dementia, amenonea, aminoacidurias, amnesia, amnesia for offences, amok-type reactions, amoφhognosia, amphetamine addiction, amphetamine or amphetamine-like related disorders, amphetamine withdrawal, amyloid neuropathy, amyotrophic lateral sclerosis, anencephaly, aneurysms, angioblastic meningiomas, Angleman's syndrome, anhidrosis, anisocoria, anomia, anomic aphasia, anorexia nervosa, anosmia, anosognosia, anterior cingulate syndrome, anterograde amnesia, antibiotic-induced neuromuscular blockade, antisocial personality disorder, Anton's syndrome, anxiety and obsessive-compulsive disorder syndromes, anxiety disorders, apathy syndromes, aphasia, aphemia, aplasia, apnea, apraxia, arachnoid cyst, archicerebellar syndrome, Arnold-Chiari malformation, arousal disorders, anhinencephaly, arsenic poisoning, arteriosclerotic Parkinsonism, arteriovenous aneurysm, arteriovenous malformations, aseptic meningeal reaction, Asperger's syndrome, astereognosis, asthenia, astrocytomas, asymbolia, asynergia, ataque de nervios, ataxia, ataxia telangiectasia, ataxic cerebral palsy, ataxic dysarthria, athetosis, atonia, atonic seizures, attention deficit disorder, attention-deficit and disruptive behavior disorders , attention-deficit hyperkinetic disorders, atypical Alzheimer's disease, atypical autism, autism, autism spectrum disorder, avoidant personality disorder, axial dementias, bacterial endocarditis, bacterial infections, Balint's syndrome, ballism, balo disease, basophilic adenoma, Bassen-Komzweig syndrome, Batten disease, battered woman syndrome, Behcet syndrome, Bell' palsy, benign essential tremor, benign focal epilepsies of childhood, benign intracranial hypertension, benxodiazepine dependence, bilateral cortical dysfunction, Binswanger's disease, bipolar disorder, bipolar type 1. disorder, bipolar type 2 disorder, blepharospasm, body dysmoφhic disorder, Bogaert-Bertrand disease, Bogarad syndrome, borderline personality disorder, botulism, Bouffee Delirante-type reactions, brachial neuropathy, bradycardia, bradykinesia, brain abscess, brain edema, brain fag, brain stem glioma, brainstem encephalitis, brief psychotic disorder, broca's aphasia, brucellosis, bulimia, bulimia nervosa, butterfly glioma, cachexia, caffeine related disorders, California encephalitis, callosal agenesis, Canavan's syndrome, cancer pain, cannabis dependence, cannabis flashbacks, cannabis psychosis, cannabis related disorders, carcinoma-associated retinopathy, cardiac anest, cavernous malformations, cellular (cytotoxic) edema, central facial paresis, central herniation syndrome, central neurogenic hyperventilation, central pontine myelinolysis, central post-stroke syndrome (thalamic pain syndrome), cerebellar hemonhage, cerebellar tonsillar herniation syndrome, cerebral amyloid (congophilic) angiopathy, cerebral hemonhage, cerebral malaria, cerebral palsy, cerebral subdural empyema, cerebrotendinous xanthomatosis, cerebrovascular disorders, cervical tumors, cestodes, Charcot-Carie-tooth disease, Chediak-Cigashi disease, Cheiro-oral syndrome, chiari malformation with hydrocephalus, childhood disintegrative disorder, childhood feeding problems, childhood sleep problems, cholesteatomas, chordomas, chorea, chorea gravidaram, choreoathetosis, chromophobe adenoma, chromosomal disorders, chronic biplar major depression, chronic bipolar disorder, chronic demyelinating polyneuritis, chronic depression, chronic fatigue syndrome, chronic gm2 gangliosidosis, chronic idiopathic sensory neuropathy, chronic inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, chronic pain, chronic paroxysmal hemicrania, chronic sclerosing panencephalitis, chronic traumatic encphalopathy, chronobiological disorders, circadian rhythm disorder, circadian rhythm' disorders, Claude's syndrome, clonic seizures, cluster headache, cocaine addiction, cocaine withdrawal, cocaine-related disorders, Cockayne's syndrome, colloid cysts of the third ventricle, Colorado tick fever, coma, communicating hydrocephalus, communication disorders, complex partial seizures, compression neuropathy, compulsive buying disorder, conceptual apraxia, conduct disorders, conduction aphasia, conduction apraxia, congenital analgesia, congenital cytomegalovirus disease, congenital hydrocephalus, congenital hypothyroidism, congenital muscular dystrophy, congenital myasthenia, congenital myotonic dystrophy, congenital rubella syndrome, congophilic angiopathy, constipation, coprophilia, cornedlia de lange syndrome, cortical dementias, cortical heteropias, corticobasal degeneration, corticobasal ganglionic degeneration, coxsackieviras, cranial meningoceles, craniopharyngioma, craniorachischisis, craniosynostosis, cranium bifidum, cretinism, Creutzfeldt- Jakob disease, Cri-du-Chat syndrome, cruciate hemiplegia, cryptococcal granulomas, cryptococcosis, culturally related syndromes, culturally stereotyped reactions to extreme environmental conditions (arctic hysteria), Gushing syndrome, cyclothymia, cysticercosis, cytomegalovirus, Dandy- Walker malformation, deafness, defects in the metabolism of amino acids, dehydration, Dejerine-Roussy syndrome, Dejerine-Sottas disease, delayed and advanced sleep phase syndromes, delayed ejaculation, delayed puberty, delayed-sleep-phase syndrome, delerium due to alcohol, delerium due to intoxication, delerium due to withdrawal, delirium, dementia, and amnestic and other cognitive disorders, delusional disorder, delusional disorder: erotomania subtype, delusional disorder: grandiose subtype, delusional disorder:jealousy subtype, delusional misidentification syndromes, dementia due to HIV disease, dementia pugilistica, dementias, dementias associated with extrapyramidal syndrome, dentatorabral- pallidoluysian atrophy, dependent personality disorder, depersonalization disorder, depression, depressive personality disorder, dermoids, developmental speech and language disorder, devic syndrome, devivo disease, diabetes, diabetes insipidus, diabetic neuropathy, dialysis demential, dialysis dysequilibrium syndrome, diencephalic dementias, diencephalic dysfunction, diencephalic syndrome of infancy, diencephalic vascular dementia, diffuse sclerosis, digestive disorders, diphtheria, diplopia, disarthria, disassociation apraxia, disorders of carbohydrate metabolism, disorders of excessive somnolence, disorders of metal metabolism, disorders of purine metabolism, disorders of sexual arousal, disorders of sexual aversion, disorders of sexual desire, disorders of the sleep-wake schedule, dissociative disorders, dorsolateral tegmental pontine syndrome, Down syndrome, Down syndrome with dementia, drag dependance, drag overdose, drag-induced myasthenia, Duchenne muscular dystrophy, dwarfism, dysarthria, dysdiadochokinesia, dysembryoplastic neuroepithelial tumor, dysexecutive syndrome, dysgraphia, dyskinesia, dyskmetic cerebral palsy, dyslexia, dysmetria, dysomnia, dysosmia, dyspareunia, dysphagia, dysphasia, dysphonia, dysplasia, dyspnea, dysprosody, dyssomnia, dyssynergia, dysthesia, dysthymia, dystonia, dystrophinopathies, early adolescent gender identity disorder, early infantile epileptic encephalopthy (Ohtahara syndrome, early myoclonic epileptic encephalopathy, Eaton- Lambert syndrome, echinococcus (hydatid cysts), echolalia, echovirus, eclampsia, Edward's syndrome, elimination disorders, embolismintracerebral hemonhage, Emery- Dreifuss muscular dystrophy, encephalitis lethargica, encephaloceles, encephalotrigeminal angiomatosis, enophthalmos, enterovirus, enuresis, eosinophilic meningitis, ependymoma, epidural spinal cord compression, epilepsy, episodic ataxia, epstein-ban, equine encephalomyelitis, erectile dysfunction, essential thrombocythemia, essential tremor, esthesioneuroblastoma, excessive daytime somnolence, excessive secretion of antidiuretic hormone, excessive sleepiness, exhibitionism, expressive language disorder, extramedullary tumors, extrasylvian aphasias, extratemporal neocortical epilepsy, fabry's disease, facioscapulohumeral muscular dystrophy, factitious disorder, factitious disorders, false memories, familial dysautonomia, familial periodic paralysis, familial spastic paraparesis, familial spastic paraplegias, fear disorders, feeding and eating disorders of infancy or early childhood, female sexual arousal disorder, fetal alcohol syndrome, fetishism, flaccid dysarthria, floppy infant syndrome, focal inflammatory demyelinating lesions with mass effect, focal neonatal hypotonia, folie a deux, foramen magnum tumors, Foville's syndrome, fragile-x syndrome, Freidrich 's ataxia, Frolich syndrome, frontal alexia, frontal convexity syndrome, frontotemporal dementia, frontotemporal dementias, frotteurism, fungal infection, galactocerebroside lipidosis, galactonhea, ganglioneuroma, Gaucher disease, gaze palsy, gender identity disorder, generalized anxiety disorder, genital shrinking syndrome (Koro, Suo-Yang), germ cell tumors, Gerstmann's syndrome, Gerstmann- Straϋssler syndrome, Gerstmann-Straussler-Schenker disease, gestational substance abuse syndromes, giant axonal neuropathy, gigantism, Gilles de la Tourette syndrome, glioblastoma multiforme, gliomas, gliomatosis cerebri, global aphasia, glossopharyngeal neuralgia, glycogen storage diseases, gml-gangliosidosis, gm2-gangliosidoses, granular cell tumor, granulocytic brain edema, granulomas, granulomatous angiitis of the brain, Grave's disease, growild typeh hormone deficit , growild typeh-hormone secreting adenomas, guam-Parkinson complex dementia, Guillain-Bane syndrome, Hallervorden- Spatz disease, hallucinogen persisting perception disorder, hallucinogen related disorders, hartnup disease, headache, helminthic infections (trichinellosis), hemangioblastomas, hemangiopericytomas, hemiacl romatopsia, hemianesthesia, hemianopsia, hemiballism, hemiballismus, hemihypacusis, hemihypesthesia, hemiparesis, hemispatial neglect, hemophilus influenza meningitis, hemonhagic cerebrovascular disease, hepatic coma, hepatic encephalopathy, hepatolenticular degeneration (Wilson disease), hereditary amyloid neuropathy, hereditary ataxias, hereditary cerebellar ataxia, hereditary neuropathies, hereditary nonprogressive chorea, hereditary predisposition to pressure palsies, hereditary sensory autonomic neuropathy, hereditary sensory neuropathy, hereditary spastic paraplegia, hereditary tyrosinemia, hermichorea, hermifacial spasm, herniation syndromes, heφes encephalitis, heφes infections, heφes zoster, heφres simplex, heterotopia, hexacarbon neuropathy, histrionic personality disorder, HIV, Holmes-Adie syndrome, homonymous quadrantaposia, Homer's syndrome, human β-mannosidosis, Hunter's syndrome, Huntington's chorea, Huntington's disease, Hurler's syndrome, Hwa-Byung, hydraencephaly, hydrocephalus, hyper thyroidism, hyperacusis, hyperalgesia, hyperammonemia, hypereosinophilic syndrome, hyperglycemia, hyperkalemic periodic paralysis, hyperkinesia, hyperkinesis, hyperkinetic dysarthria, hyperosmia, hyperosmolar hyperglygemic nonketonic diabetic coma, hypeφarathyroidism, hypeφhagia, hypeφituitarism, hypeφrolactinemia, hypersexuality, hypersomnia, hypersomnia secondary to drug intake, hypersomnia-sleep-apnea syndrome, hypersomnolence, hypertension, hypertensive encephalopathy, hyperthermia, hyperthyroidism (Graves disease), hypertonia, hypnagogic (predormital) hallucinations, hypnogenic paroxysmal dystonia, hypoadrenalism, hypoalgesia, hypochondriasis, hypoglycemia, hypoinsulinism, hypokalemic periodic paralysis, hypokinesia, hypokinetic dysarthria, hypomania, hypoparathyroidism, hypophagia, hypopituitarism, hypoplasia, hyposmia, hyposthenuria, hypotension, hypothermia, hypothyroid neuropathy, hypothyroidism, hypotonia, Hyrler syndrome, hysteria, ideational apraxia, ideomotor apraxia, idiopathic hypersomnia, idiopathic intracranial hypertension, idiopathic orthostatic hypotension, immune mediated neuropathies, impersistence, impotence, impulse control disorders, impulse dysconfrol and aggression syndromes, impulse-control disorders, incontinence, incontinentia pigmenti, infantile encephalopathy with cheny-red spots, infantile neuraxonal dystrophy, infantile spasms, infantilism, infarction, infertility, influenza, inhalant related disorders, insomnias, insufficient sleep syndrome, intention tremor, intermittent explosive disorder, internuclear ophthalmoplegia, interstitial (hydrocephalic) edema, intoxication, intracranial epidural abscess, intracranial hemonhage, intracranial hypotension, intracranial tumors, intracranial venous-sinus thrombosis, infradural hematoma, inframedullary tumors, intravascular lymphoma, ischemia, ischemic brain edema, ischemic cerebrovascular disease, ischemic neuropathies, isolated inflammatory demyelinating CNS syndromes, Jackson-Collet syndrome, Jakob-Creutzfeld disease, Japanese encephalitis, jet lag syndrome, Joseph disease, Joubert's syndrome, juvenile neuroaxonal dystrophy, Kayak-Svimmel, Kearns- Sayre syndrome, kinky hair disease (Menkes syndrome), Kleine-Levin syndrome, kleptomania, Klinefelter's syndrome, Kluver-Bucy syndrome, Knoerber-Salus-Elschnig syndrome, Korsakoff s syndrome, krabbe disease, krabbe leukodystrophy, Kugelberg- Welander syndrome, kuru, Lafora's disease, language deficits, language related disorders, latah-type reactions, lateral mass herniation syndrome, lateropulsation, lathyrism, Laurence-Moon Biedl syndrome, Laurence-Moon syndrome, lead poisoning, learning disorders, leber hereditary optic atrophy, left ear extinction, legionella pneumophilia infection, Leigh's disease, Lennoc-Gastaut syndrome, Lennox-Gastaut's syndrome, leprosy, leptospirosis, Lesch-Nyhan syndrome, leukemia, leukodystrbphies, Levy-Roussy syndrome, lewy body dementia, lewy body disease, limb girdle muscular dystrophies, limbic encephalitis, limbic encephalopathy, lissencephaly, localized hypertrophic neuropathy, locked-in syndrome, logoclonia, low pressure headache, Lowe syndrome, lumbar tumors, lupus anticoagulants, lyme disease, lyme neuropathy, lymphocytic choriomeningitis, lymphomas, lysosomal and other storage diseases, macroglobinemia, major depression with melancholia, major depression with psychotic features, major depression without melancholia, major depressive (unipolar) disorder, male orgasmic disorder, malformations of septum pellucidum, malignant peripheral nerve sheath tumors, malingers, mania, mania with psychotic features, mania without psychotic features, maple syrup urine disease, Marchiafava-Bignami syndrome, Marcus Gunn syndrome, Marie-Foix syndrome, Marinesco-Sjδgren syndrome, Maroteaux-Lamy syndrome, masochism, masturbatory pain, measles, medial frontal syndrome, medial medullary syndrome, medial tegmental syndrome, medication-induced movement disorders, medullary dysfunction, medulloblastomas, medulloepithelioma, megalencephaly, melanocytic neoplasms, memory disorders, memory disturbances, meniere syndrome, meningeal carcinomatosis, meningeal sarcoma, meningial gliomatosis, meningiomas, meningism, meningitis, meningococcal meningitis, mental neuropathy (the numb chin syndrome), mental retardation, mercury poisoning, metabolic neuropathies, metachromatic leukodystrophy, metastatic neuropathy, metastatic tumors, metazoal infections, microcephaly, microencephaly, micropolygyria, midbrain dysfunction, midline syndrome, migraine, mild depression, Millard-Gubler syndrome, Miller-Dieker syndrome, minimal brain dysfunction syndrome, miosis, mitochondrial encephalopathy with lactic acidosis and stroke (melas), mixed disorders of scholastic skills, mixed dysarthrias, mixed transcortical aphasia, Mόbius syndrome, Mollaret meningitis, monoclonal gammopathy, mononeuritis nultiplex, monosymptomatic hypochondriacal psychosis, mood disorders, Moritz Benedikt syndrome, Morquio syndrome, Morton's neuroma, motor neuron disease, motor neurone disease with dementia, motor neuropathy with multifocal conduction block, motor skills disorder , mucolipidoses, mucopolysaccharide disorders, mucopolysaccharidoses, multifocal eosinophilic granuloma, multiple endocrine adenomatosis, multiple myeloma, multiple sclerosis, multiple system atrophy, multiple systems atrophy, multisystemic degeneration with dementia, mumps, Munchausen syndrome, Munchausen syndrome by proxy, muscular hypertonia, mutism, myasthenia gravis, mycoplasma pneumoniae infection, myoclonic seizures, myoclonic-astatic epilepsy (doose syndrome), myoclonus, myotonia congenita, myotonic dystrophy, myotonic muscular dystrophy, nacolepsy, narcissistic personality disorder, narcolepsy, narcolepsy-cataplexy syndrome, necrophilia, nectrotizing encephalomyelopathy, Nelson's syndrome, neocerebellar syndrome, neonatal myasthenia, neonatal seizures, nervios, nerves, neurasthenia, neuroacanthocytosis, neuroaxonal dystrophy, neurocutaneous disorders, neurofibroma, neurofibromatosis, neurogenic orthostatic hypotension, neuroleptic malignant syndrome, neurologic complications of renal transplantation, neuromyelitis optica, neuromyotonia (Isaacs syndrome), neuronal ceroid lipofuscinoses, neuro-ophthalamic disorders, neuropathic pain , neuropathies associated with infections, neuropathy associated with cryoglobulins, neuropathy associated with hepatic diseases, neuropathy induced by cold, neuropathy produced by chemicals, neuropathy produced by metals, neurosyphilis, new variant Creutzfeldt- Jakob disease, nicotine dependence, nicotine related disorders, nicotine withdrawal, niemann-pick disease, nocturnal dissociative disorders, nocturnal enuresis, nocturnal myoclonus, nocturnal sleep-related eating disorders, noecerbellar syndrome, non-alzherimer frontal-lobe degeneration, nonamyloid polyneuropathies associated with plasma cell dyscrasia, non-lethal suicial behavior, nonlocalizing aphasic syndromes, normal pressure hydrocephalus, Nothnagel's syndrome, nystagmus, obesity, obsessive-compulsive (anankastic) personality disorder, obsessive-compulsive disorder, obstetric factitious disorder, obstructive hyrocephalus, obstructive sleep apnea, obstructive sleep apnoea syndrome, obstructive sleep hypopnoea syndrome, occipital dementia, occlusive cerebrovascular disease, oculocerebrorenal syndrome of lowe, oculomotor nerve palsy, oculopharyngeal muscular dystrophy, oligodendrogliomas, olivopontocerebellar atrophy, ondine's curse, one and a half syndrome, onychophagia, opiate dependance, opiate overdose, opiate withdrawal, opioid related disorders, oppositional defiant disorder, opsoclonus, orbitofrontal syndrome, orgasmic anhedonia, orgasmic disorders, osteosclerotic myeloma, other disorders of infancy, childhood, or adolescence, other medication-induced movement disorders, pachygyria, paedophilia, pain, pain syndromes, painful legs-moving toes syndrome, paleocerebellar syndrome, palilalia, panhypopituitarism, panic disorder, panic disorders, papillomas of the choroid plexus, paraganglioma, paragonimiasis, paralysis, paralysis agitans (shaking palsy), paramyotonia congenita, paraneoplastic cerebellar degeneration, paraneoplastic cerebellar syndrome, paraneoplastic neuropathy, paraneoplastic syndromes, paranoia, paranoid personality disorder, paranoid psychosis, paraphasia, paraphilias, paraphrenia, parasitic infections, parasomnia, parasomnia overlab disorder, parenchymatous cerebellar degeneration, paresis, paresthesia, parinaud's syndrome, Parkinson's disease, Parkinson-dementia complex of guam, Parkinsonism, Parkinsonism-plus syndromes, Parkinson's disease, paroxysmal ataxia, paroxysmal dyskinesia, partial (focal) seizures, partialism, passive-aggressive (negativistic) personality disorder, Patau's syndrome, pathological gambling, peduncular hallucinosis, Pelizaeus-Merzbacher disease, perineurioma, peripheral neuropathy, perisylvian syndromes, periventricular leukomalacia, periventricular white matter disorder, periventricular-intraventricular hemonhage, pernicious anemia, peroneal muscular atrophy, peroxisomal diseases, perseveration, persistence of cavum septi pellucidi, persistent vegetative state, personality disorders, pervasive developmental disorders , phencyclidine (or phencyclidine-like) related disorders, phencyclidine delirium, phencyclidine psychosis, phencyclidine-induced psychotic disorder, phenylketonuria, phobic anxiety disorder, phonic tics, photorecepto degeneration, pibloktoq, Pick's disease, pineal cell tumors, pineoblastoma, pineocytoma, pituitary adenoma, pituitary apoplexy, pituitary carcinoma, pituitary dwarfism, placebo effect, Plummer's disease, pneumococcal meningitis, poikilolthermia, polio, polycythemia vera, polydipsia, polyglucosan storage diseases, polymicrogyria, polymyositis, polyneuropathy with dietary deficiency states, polysubstance related disorder, polyuria, pontine dysfunction, pontosubicular neuronal necrosis, porencephaly, poφhyric neuropathy, portal-systemic encephalopathy, postcoital headaches, postconcussion syndrome, postencephalic Parkinson syndrome, posthemonhagic hydrocephalus, postinflammatory hydrocephalus, postpartum depression, postpartum psychoses, postpolio syndrome, postpsychotic depression, post- stroke hypersomnia, post-traumatic amnesia, post-traumatic epilepsy, post-traumatic hypersomnia, post-traumatic movement disorders, post-traumatic stress disorder, post- traumatic syndromes, Prader-Willi syndrome, precocious puberty, prefrontal dorsolateral syndrome, prefrontal lobe syndrome, premenstrual stress disorder, premenstrual syndrome, primary amebic meningoencephalitis, primary CNS lymphoma, primary idiopathic thrombosis, primary lateral sclerosis, primitive neuroectodermal tumors, prion disease, problems related to abuse or neglect, progressive bulbar palsy, progressive frontal lobe dementias, progressive multifocal leukoencephalopathy, progressive muscular atrophy, progressive muscular dystrophies, progressive myoclonic epilepsies, progressive myoclonus epilepsies, progressive non-fluent aphasia, progressive partial epilepsies, progressive rubella encephalitis, progressive sclerosing poliodystrophy (Alpers disease), progressive subcortical gliosis, progressive supranuclear palsy, progressive supranuclear paralysis, progrssive external ophthalmoplegia, prolactinemia , prolactin-sectreting adenomas, prosopagnosia, protozoan infection, pseudobulbar palsy, pseudocyesis, pseudodementia, psychic blindness, psychogenic excoriation, psychogenic fugue, psychogenic pain syndromes, psychological mutism, psychosis after brain injury, psychotic syndromes, ptosis, public masturbation, pueφeral panic, pulmonary edema, pure word deafness, pyromania, quadrantanopsia, rabies, radiation neuropathy, Ramsay Hunt syndrome, rape traume syndrome, rapid cycling disorder, rapid ejaculation,
Raymond-Cestan-Chenais syndrome, receptive language disorder, recovered memories, recunent bipolar episodes, recunent brief depression, recunent hypersomnia, recunent major depression, refsum disease, reiterative speech disturbances, relational problems, rem sleep behavior disorder, rem sleep behavioral disorder, repetitive self-mutilation, repressed memories, respiratory dysrhythmia, restless legs syndrome, Rett's syndrome, Reye syndrome, rhythmic movement disorders, rocky mountain spotted fever, rostral basal pontine syndrome, rubella, Rubinstein-Taybi syndrome, sadistic personality disorder, salla disease, Sandhoff disease, Sanfilippo syndrome, sarcoid neuropathy, sarcoidosis, scapuloperoneal syndromes, schistosomiasis (bilharziasis), schizencephaly, schizoaffective disorder, schizoid personality disorder, schizophrenia, schizophrenia and other psychotic disorders, schizophrenia-like psychosis, schizophreniform disorder, schizotypal personality disorder, school-refusal anxiety disorder, schwannoma, scrub typhus, seasonal depression, secondary spinal muscular atrophy, secondary thrombosis, sedative hypnotic or anxiolytic-related disorders, seizure disorders,- selective mutism, self-defeating (masochistic) personality disorder, semen-loss syndrome (shen-k'uei, dliat, jiryan, sukra prameha), senile chorea, senile dementia, sensory perineuritis, separation anxiety disorder, septal syndrome, septo-optic dysplasia, severe hypoxia, severe myoclonic epilepsy, sexual and gender identity disorders, sexual disorders, sexual dysfunctions, sexual pain disorders, sexual sadism, Shapiro syndrome, shift work sleep disorder, Shy-Drager syndrome, sialidosis, sialidosis type 1, sibling rivalry disorder, sickle cell anemia, Simmonds disease, simple partial seizures, simultanagnosia, sleep disorders, sleep paralysis, sleep tenors, sleep-related enuresis, sleep-related gastroesophageal reflux syndrome, sleep-related headaches, sleep-wake disorders, sleepwalking, Smith-Magenis syndrome, social anxiety disorder, social phobia, social relationship syndromes, somatoform disorders, somnambulism, Sotos syndrome, spasmodic dysphonia, spasmodic torticollis (wry neck), spastic cerebral palsy, spastic dysarthria, specific developmental disorder of motor function, specific developmental disorders of scholastic skills, specific developmental expressive language disorder, specific developmental receptive language disorder, specific disorders of arithmetical skills, specific phobia, specific speech articulation disorder, specific spelling disorder, speech impairment, spina bifida, spinal epidural abcess, spinal muscular atrophies, spinocerebellar ataxias, spirochete infections, spongiform encephalopathies, spongy degeneration of the nervous system, St. Louis encephalitis, stammer, staphylococcal meningitis, startle syndromes, status marmoratus, steele-richardson-olszewski syndrome, stereotypic movement disorder, stereotypies, stiff-man syndrome, stiff-person syndrome, stimulant psychosis, Strachan syndrome (nutritional neuropathy), streptococcal meningitis, striatonigral degeneration, stroke, strongyloidiasis, sturge-weber disease (Krabbe- Weber-Dimitri disease), stutter, subacute combined degeneration of the spinal cord, subacute motor neuronopathy, subacute necrotic myelopathy, subacute sclerosing panencephalitis, subacute sensory neuronopathy, subarachniod hemonhage, subcortical aphasia, subfalcine herniation syndrome, substance abuse, substance related disorders, sudanophilic leukodystrophis, sudden infant death syndrome, suicide, sulfatide lipidosis, susto, espanto, meido, sydenham chorea, symetric neuropathy associated with carcinoma, sympathotonic orthostatic hypotension, syncope, syndromes related to a cultural emphasis on learnt dissociation, syndromes related to a cultural emphasis on presenting a physical appearance pleasing to others (taijin-kyofu reactions), syndromes related to acculturative stress, syringobulbia , syringomyelia, systemic lupus erythematosus, tachycardia, tachypnea, Tangier disease, tardive dyskinesia, Tay-sachs disease, telangiectasia, telencephalic leukoencephalopathy, telephone scatologia, temporal lobe epilepsy, temporoparietal dementia, tension-type headache, teratomas, tetanus, tetany, thalamic syndrome, thallium poisoning, thoracic tumors, thrombotic thrombocytopenic puφura, thyroid disorders, tic disorders, tick paralysis, tick-borne encephalitis, tinnitis, tomaculous neuropathy, tonic seizures, tonic-clonic seizures, torticollis, Tourette syndrome, toxic neuropathies, toxoplasmosis, transcortical motor aphasia, transcortical sensory aphasia, transient epileptic amnesia, transient global amnesia, transitional sclerosis, transvestic fetishism, traumatic brain injury, traumatic neuroma, traumiatic mutism, tremors, trichinosis, trichotillomania, trigeminal neuralgia, trochlear nerve palsy, tropical ataxic neuropathy, tropical spastic paraparesis, trypanosomiasis, tuberculomas, tuberculous meningitis, tuberous sclerosis, tumors, Turner's syndrome, typhus fever, ulegyria, uncinate fits, Unvenicht-Lundborg's disease, upper airway resistance syndrome, upward transtentorial herniation syndrome, uremic encephalopathy, uremic neuropathy, urophilia, vaccinia, varicella-zoster, vascular dementia, vascular malformations, vasculitic neuropathies, vasogenic edema, velocardiofacial syndrome, venous malformations, ventilatory anest, vertigo, vincristine toxicity, viral infections, visuospatial impairment, Vogt-Koyanagi-Harada syndrome, Von Hippel-Lindau disease, Von Racklinghousen disease, voyeurism, Waldensfrom's macro globulinemia, Walker- Warburg syndrome, Wallenburg's syndrome, Walleyed syndrome, Weber's syndrome, Wenicke's encephalopathy, Werdnig-Hoffmann disease, Wernicke's encephalopathy, Wernicke-Korsakoff syndrome, Wernicke's aphasia, West's syndrome, whipple disease, Williams syndrome, Wilson disease, windigo, witiko, witigo, withdrawal with grand mal seizures, withdrawal with perceptual disturbances, withdrawal without complications, Wolman disease, xeroderma pigmentosum, xyy syndrome, Zellweger syndrome.
Behavioral Disorders
In humans, as in other animals, behaviors related to survival, avoidance of injury, maintenance of bodily function, and reproduction are in large part instinctive. These behaviors are caused by powerful drives, such as hunger, thirst, sleep, and sexual desire. Emotions, such as fear or joy, are also closely linked with the parts of our lives governed by instincts.
As behaviors begin to involve higher mental functions, they include a broader mixture of features related to both "nature" and "nurture." The impact of learning, experience, and environment then becomes layered upon such instinctive behaviors as curiosity, attention and pleasure.
The intensity of a particular drive or emotion is highly variable from one person to another. There is also variation in the extent to which different individuals experience particular drives and emotions. For instance, one person may experience hunger more frequently than another, or feel more anxious or stressed. - There also are differences in how one responds to drives and emotions. For example, anxiety in a stressful circumstance might motivate a person to gain control of the matter, while in another, the same feelings might cause a behavior directed at avoiding the situation altogether;
Basic drives and emotions are components of everyday life, and are important to one's physical and psychological well-being. Abnormalities in any of them may profoundly affect an individual's ability to think, feel and act. Behavioral problems are also very common. More individuals are afflicted every year by these conditions than by cancer and heart diseases combined.
Eating Disorders
Nearly one-quarter of the U.S. Population (60 million people) is now classified as obese. Despite the fact that Americans spend about $40 billion per year on weight- loss treatments, only a small percentage of people can lose weight and keep it off. Since obesity is a direct contributor to cardiovascular disease and diabetes, there is need to address the extreme forms of these behaviors as life-threatening conditions.
Eating disorders such as anorexia nervosa and bulimia nervosa affect over a million Americans. These disorders are characterized by a constant preoccupation with food and a fear of fatness. Cunent treatments for anorexia nervosa include hospitalization, high caloric diet, and psychological counseling. In the case of bulimia nervosa, psychiatric treatment and antidepressant medications are being prescribed. The success rate in both cases is low.
Sleep Disorders
The most common sleeping problems are insomnia and narcolepsy. Insomnia is the continued inability to fall asleep or stay asleep. Almost everyone occasionally suffers from short-term insomnia. However, for people who suffer chronically from the insomnia, the disease can severely disrupt their ability to function. Narcolepsy, on the other hand, is the sudden, inesistible daytime episodes of sleepiness. People with narcolepsy have frequent "sleep attacks" at various times of the day, even if they have had a normal amount of night-time sleep.
The main anti-insomniac drugs in use today are benzodiazepine products (sleeping pills). Benzodiazepines, although somewhat effective' for short-term insomnia, are not indicated for mild or severe insomnia, as they have several side effects and can cause physical dependence. For narcolepsy, there is presently no cure. Stimulants, like amphetamines, can help reduce the symptoms, but do not alleviate them entirely.
Sexual Disorders Tens of millions of men have some form of erectile dysfunction (impotence) — mild, moderate, severe, acute, or chronic. An even larger number of women are estimated to suffer from sexual arousal (inability to attain or maintain sexual excitement) and orgasmic (lack of orgasm during sex) disorders. Several million American men and women have symptoms of compulsive sexual disorder (sex addiction). Sexual disorders can be caused by either physical or psychological factors.
There are effective medicines today (such as VIAGRA™) to treat certain disorders associated with physical factors. This is not the case, however, for individuals suffering from sexual disorders involving libido. There are no drags available to help another 5-6 million men with impotency, who do not benefit from VIAGRA™, or millions of other with sexual arousal, orgasmic, or compulsive sexual disorders.
Anxiety Disorders Personal anxieties and fears are part of everyday life. For millions of individuals, however, anxieties and fears are overwhelming and persistent, often drastically interfering with daily life. These people suffer from anxiety disorders, a widespread group of illnesses that can be terrifying and crippling. These conditions include panic disorder, phobias, obsessive-compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder.
Cunent pharmacologic treatments for anxiety include tranquilizers or anxiolytic drug (e.g., valium, and tranxene) and antidepressants. While these medications can be effective at relieving anxiety symptoms, they also cany undesirable side effects such as sedation, fatigue, weight gain, sexual difficulties, and withdrawal reactions.
Mood Disorders
Depression is the most commonly diagnosed emotional problem. Each year, millions of people will suffer from a depressive illness, such as major depression, or bipolar disorder. As many as one in five Americans will have at least one episode of depression during their lifetime. Many of them will be incapacitated for weeks or months.
The treatment of depression today is not much different than it was many years ago. The cunent antidepressants are no more efficacious than the older ones. They are improved in terms of certain side effects, but they still cause sexual dysfunction, require an extended period to become effective, and cannot be mixed with several other commonly used medications.
Memory Impairments
Over a million Americans suffer from memory deficits beyond that expected for their age. These people are suffering from mild cognitive impairment or from dementia.
Memory loss, particularly of recent events, is the prevailing symptom of mild cognitive impairment. Dementia is a more severe condition. People with dementia suffer from short-term memory loss, inability to think through or complete complex tasks without step-by-step instructions, confusion, difficulty concentrating, and paranoid, inappropriate, or bizane behavior. Cunently, there are no medications available to treat or prevent memory impairments.
Attention Disorders
As many as a million school-age children in the U.S. are claimed to suffer from attention-deficit hyperactivity disorder (ADHD). The disease has its onset in childhood and is characterized by lack of attention, impulsiveness, and hyperactivity. ADHD often continues into adolescence and adulthood. The disease has long-term adverse affects on success at school, work, and in social relationships. Stimulants are used to treat the symptoms of ADHD. Children with the disorder seldom outgrow it, and long-term therapy is not advised.
Pain Pain arises in response to a noxious stimulus or tissue injury. In some instances, pain may continue after the tissue damage has healed or in the absence of evident tissue damage. This is chronic pain. Millions of Americans have some form of persisting or recurring pain. They usually suffer from tension or migraine headaches, low back pain, or arthritis. Chronic pain is also a byproduct of heart diseases and cancer. Chronic pain is often unresponsive to conventional therapies. People with chronic pain are treated with a wide variety of medications, usually with limited success.
Substance Abuse/Addiction
Substance abuse and addiction are considered to be one of the serious social issues in modern times. Despite growing efforts to address them, there are no effective medications available to treat most people with substance abuse and addiction problems. People who abuse substances, but are not yet addicted to them, are usually treated with behavioral therapies. Treatment of addicted people often involves a combination of behavior therapy and medication. In either case, the results are poor. Only a minority is helped by these treatments. Nuclear Receptor Expression in Non-Neural Tissues
Adrenal gland. Nuclear receptors expressed in the adrenal gland are listed in Table 15. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of a nuclear receptor in the adrenal gland. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the adrenal gland, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 15. Nuclear Receptors Expressed in the Adrenal Gland
Figure imgf000159_0001
Exemplary diseases and disorders of the adrenal gland include 11-hydroxylase deficiency, 17-hydroxylase deficiency, 3β-dehydrogenase deficiency, acquired immune deficiency syndrome, ACTH-dependent adrenal hyperfunction (Gushing disease), ACTH-independent adrenal hyperfunction, acute adrenal insufficiency, adrenal abscess, adrenal adenoma, adrenal calcification, adrenal cysts, adrenal cytomegaly, adrenal dysfunction in glycerol kinase deficiency, adrenal hematoma, adrenal hemonhage, adrenal histoplasmosis, adrenal hyperfunction, adrenal hypeφlasia, adrenal medullary hypeφlasia, adrenal myelolipoma, adrenal tuberculosis, adrenocortical adenoma, adrenocortical adenoma with primary hyperaldosteronism (Conn's syndrome), adrenocortical carcinoma, adrenocortical carcinoma with Cushing's syndrome, adrenocortical hyperfunction, adrenocortical insufficiency, adrenocortical neoplasms, adrenoleukodysfrophy, amyloidosis, anencephaly, autoimmune Addison's disease, Beckwith-Wiedemann syndrome, bilateral adrenal hypeφlasia, chronic insufficiency of adrenocortical hormone synthesis, complete 21-hydroxylase deficiency, congenital adrenal hypeφlasia, congenital adrenal hypoplasia, cortical hypeφlasia, desmolase deficiency, ectopic ACTH syndrome, excess aldosterone secretion, excess cortisol secretion (Cushing's syndrome), excess secretion of adrenocortical hormones, excess sex hormone secretion, familial glucocorticoid deficiency, functional "black" adenomas, ganglioneuroblastoma, ganglioneuroma, glucocorticoid remediable hyperaldosteronism, heφetic adrenalitis, hyperaldosteronism, idiopathic Addison's disease, idiopathic hyperaldosteronism with bilateral hypeφlasia of zona glomeralosa, latrogenic hypercortisolism, lysosomal storage diseases, macronodular hypeφlasia, macronodular hypeφlasia with marked adrenal enlargement, malignant lymphoma, malignant melanoma, metastatic carcinoma, metastatic tumors, micronocular hypeφlasia, multiple endocrine neoplasia syndromes, multiple endocrine neoplasia type 1 (Wermer syndrome), multiple endocrine neoplasia type 2a (Sipple syndrome), multiple endocrine neoplasia type 2b, neuroblastoma, Niemann-Pick disease, ovarian thecal metaplasia, paraganglioma, partial 21-hydroxylase deficiency, pheochromocytoma, primary aldosteronism (Conn's syndrome), primary chronic adrenal insufficiency (Addison's disease), primary hyperaldosteronism, primary mesenchymal tumors, primary pigmented nodular adrenocortical disease, salt- wasting congenital adrenal hypeφlasia, secondary Addison's disease, secondary hyperaldosteronsim, selective hypoaldosteronism, simple virilizing congenital adrenal hypeφlasia, Waterhouse-Friderichsen syndrome, and Wolman's disease.
Colon. Nuclear receptors expressed in the colon are listed in Table 16. These receptors are thus potential targets for therapeutic compounds that may modulate the . activity, expression, or stability of these nuclear receptors in the colon. These polypeptides, or polymoφhs of these polypeptides, may form the basis of therapeutic regimen or a diagnostic test to determine, e.g., the presence of disease or disorder involving the colon, the risk of developing a particular disease or disorder, or an appropriate therapeutic course. Table 16. Nuclear Receptors Expressed in the Colon
Figure imgf000161_0001
Exemplary diseases and disorders involving the colon include acute self-limited infectious colitis, adenocarcinoma, adenoma, adenoma-carcinoma sequence, adenomatous polyposis coli, adenosquamous carcinomas, allergic (eosinophilic) proctitis and colitis, amebiasis, amyloidosis, angiodysplasia, anorectal malformations, blue rubber bleb nevus syndrome, brown bowel syndrome, Campylobacter fetus infection, carcinoid tumors, carcinoma of the anal canal, carcinoma of the colon and rectum, chlamidial proctitis, Crohn's disease, clear cell carcinomas, Clostridium difficile pseudomembranous enterocolitis, collagenous colitis, colonic adenoma, colonic diverticulosis, colonic inertia, colonic ischemia, congenital atresia, congenital megacolon (Hirschsprung's disease), congenital stenosis, constipation, Cowden's syndrome, cystic fibrosis, cytomegalovirus colitis, dianhea, dieulafor lesion, diversion colitis, diverticulitis, diverticulosis, drug-induced diseases, dysplasia and malignancy in inflammatory bowel disease, Ehlers-Danlos syndromes, enterobiasis, familial adenomatous polyposis, familial polyposis syndromes, Gardner's syndrome, gastrointestinal stromal neoplasms, hemangiomas and vascular anomalies, hemonhoids, hereditary hemonhagic telangiectasia, heφes colitis, hypeφlastic polyps, idiopathic inflammatory bowel disease, incontinence, inflammatory bowel syndrome, inflammatory polyps, inherited adenomatous polyposis syndromes, intestinal hamartomas, intestinal pseudo-obstruction, initable bowel syndrome, ischemic colitis, juvenile polyposis, juvenile polyps, Klippel-Trenaunay- Weber syndrome, leiomyomas, lipomas, lymphocytic (microscopic) colitis, lymphoid hypeφlasia and lymphoma, malakoplakia, malignant lymphoma, malignant neoplasms, malrotation, metastatic neoplasms, mixed hypeφlastic and adenomatous polyps, mucosal prolapse syndrome, neonatal necrotizing enterocolitis, neuroendocrine cell tumors, neurogenic tumors, neutropenic enterocolitis, non-neoplastic polyps, Peutz-Jeghers syndrome, pneumatosis cystoides intestinalis, polyposis coli, pseudomembranous colitis, pseudoxanthoma elasticum, pure squamous carcinomas, radiation colitis, schistosomiasis, Shigella colitis (bacilliary dysentery), spindle cell carcinomas, spirochetosis, stercolar ulcers, stromal tumors, systemic sclerosis and CREST syndrome, trichuriasis, tubular adenoma (adenomatous polyp, polypoid adenoma), Turcot's syndrome, Turner's syndrome, ulcerative colitis, villous adenoma, and volvulus.
Heart. Nuclear receptors expressed in the heart are listed in Table 17. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of any of these nuclear receptors in the heart. These polypeptides, or polymoφhs of these polypeptides, may also form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular cardiovascular disease or disorder, or an appropriate therapeutic course.
Table 17. Nuclear Receptors Expressed in the Heart
Figure imgf000162_0001
Cardiovascular diseases and disorders include, for example, acute coronary syndrome, acute idiopathic pericarditis, acute rheumatic fever, American trypanosomiasis (Chagas' disease), angina pectoris, ankylosing spondyhtis, anomalous pulmonary venous connection, anomalous pulmonary venous drainage, aortic atresia, aortic regurgitation, aortic stenosis, aortic valve insufficiency, aortopulmonary septal defect, asymmetric septal hypertrophy, asystole, atrial fibrillation, atrial flutter, atrial septal defect, atrioventricular septal defect, autoimmune myocarditis, bacterial endocarditis, calcific aortic stenosis, calcification of the cental valve, calcification of the valve ring, carcinoid heart disease, cardiac amyloidosis, cardiac anhythmia, cardiac failure, cardiac myxoma, cardiac rejection, cardiac tamponade, cardiogenic shock, cardiomyopathy of pregnancy, chronic adhesive pericarditis, chronic constrictive pericarditis, chronic left ventricular failure, coarctation of the aorta, complete heart block, complete transposition of the great vessels, congenital bicuspid aortic valves, congenital nano wing of the left ventricular outflow tract, congenital pulmonary valve stenosis, congenitally conected transposition of the great arteries, congestive heart failure, constrictive pericarditis, cor pulmonale, coronary artery origin from pulmonary artery, coronary atherosclerosis, dilated (congestive) cardiomyopathy, diphtheria, double inlet left ventricle, double outlet right ventricle, Ebstein's malformation, endocardial fibroelastosis, endocarditis, endomyocardial fibrosis, eosinophilic endomyocardial disease (Loffler endocarditis), fibroma, glycogen storage diseases, hemochromatosis, hypertensive heart disease, hyperthyroid heart disease, hypertrophic cardiomyopathy, hypothyroid heart disease, idiopathic dilated cardiomyopathy, idiopathic myocarditis, infectious myocarditis, infective endocarditis, ischemic heart disease, left ventricular failure, Libman-Sachs endocarditis, lupus erythematosus, lyme disease, marantic endocarditis, metastatic tumors, mitral insufficiency, mitral regurgitation, mitral stenosis, mitral valve prolapse, mucopolysaccharidoses, multifocal atrial tachycardia, myocardial infarction, myocardial ischemia, myocardial rupture, myocarditis, myxomatuos degeneration, nonatheromatous coronary artery disease, nonbacterial thrombotic endocarditis, noninfectious acute pericarditis, nonviral infectious pericarditis, oblitaerative cardiomyopathy, patent ductus arteriosus, pericardial effusion, pericardial tumors, pericarditis, persistent truncus arteriosis, premature ventricular contraction, progressive infarction, pulmonary atresia with intact ventricular septum, pulmonary atresia with vertricular septal defect, pulmonary insufficiency, pulmonary regurgitation, pulmonary stenosis, pulmonary valve lesions, pulmonary valve stenosis, pyogenic pericarditis, Q fever, radiations myocarditis, restrictive cardiomyopathy, rhabdomyoma, rheumatic aortic stenosis, rheumatic heart disease, rocky mountain spotted fever, rupture of the aortic valve, sarcoid myocarditis, scleroderma, shingolipidoses, sinus brachycardia, sudden death, syphilis, systemic embolism from mural thrombi, systemic lupus erythematosus, tetralogy of fallot, thiamine deficiency (Beriberi) heart disease, thoracic outlet syndrome, Torsade de Pointes, toxic cardiomyopathy, toxic myocarditis, toxoplasmosis, trichinosis, tricuspid atresia, tricuspid insufficiency, tricuspid regurgitation, tricuspid stenosis, tricuspid valve lesions, tuberculuos pericarditis, typhus, ventricular aneurysm, ventricular fibrillation, ventricular septal defect, ventricular tachycardia, venfriculoarterial septal defect, viral pericarditis, and Wolff-Parkinson- White syndrome.
Intestine. Nuclear receptors expressed in the intestine are listed in Table 18. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the intestine. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease or disorder involving the intestine, the risk of developing a particular disease or disorder involving the intestine, or an appropriate therapeutic course.
Table 18. Nuclear Receptors Expressed in the Intestine
Figure imgf000164_0001
Diseases and disorders involving the intestine include abdominal hernia, abetalipoproteinemia, abnormal rotation, acute hypotensive hypoperfusion, acute intestinal ischemia, acute small intestinal infarction, adenocarcinoma, adenoma, adhesions, amebiasis, anemia, arterial occlusion, atypical mycobacteriosis, bacterial dianhea, bacterial overgrowild typeh syndromes, botulism, Campylobacter fetus infection, Campylobacter jejuni infection, carbohydrate absoφtion defects, carcinoid tumors, celiac disease (nontropical sprue, gluten-induced enteropathy), cholera,
Chrohn's disease, chronic intestinal ischemia, Clostridium difficile pseudomembranous enterocolitis, Clostridium perfringens infection, congenital umbilical hernia, Cronkite- Canada syndrome, cytomegalovirus enterocolitis, dianhea, dianhea caused by invasive bacteria, diverticulitits, diverticulosis, dysentery, enteroinvasive and enterohemoπhagic Escherichia coli infection, eosinophilic gastroenteritis, failure of peristalsis, familial polyposis syndromes, food poisoning, fungal enteritis, gangliocytic paragangliomas, Gardner's syndrome, gastrointestinal stromal neoplasms, giardiasis, hemonoids, hernia, hypeφlastic polyps, idiopathic inflammatory bowel disease, ileus, imperforate anus, intestinal (abdominal ischemia), intestinal atresia, intestinal cryptosporidiosis, microsporidiosis & isosporiasis in AIDS, intestinal hamartomas, intestinal helminthiasis, intestinal hemonhage, intestinal infiltrative disorders, intestinal lymphangiectasia, intestinal obstruction, intestinal perforation, intestinal reduplication, intestinal stenosis, intestinal tuberculosis, intussusception, jejunal diverticulosis, juvenile polyposis, juvenile retention polyps, lactase deficiency, lymphomas, malabsoφtion syndrome, malignant lymphoma, malignant neoplasms, malrotations, mechanical obstraction, Meckel's diverticulum, meconium ileus, meditenanean lymphoma, mesenchymal tumors, mesenteric vasculitis, mesenteric vein thrombosis, metastatic neoplasms, microvillus inclusion disease, mixed hypeφlastic and adenomatous polyps, neonatal necrotizing enterocolitis, nodular duodenum, nonocclusive intestinal ischemia, nonspecific duodenitis, nontyphoidal salmonellosis, omphalocele, parasitic infections, peptic ulcer disease, Peutz-Jeghers syndrome, pneumatosis cystoides intestinalis, poorly differentiated neuroendocrine carcinomas, primary lymphoma, protein-losing enteropathy, Salmonella gastroenteritis, sarcoidosis, sarcomas, shigellosis, staphlococcal food poisoning, steatonhea, sugar intolerance, thrombosis of the mesenteric veins, toxigenic dianhea, toxigenic Escherichia coli infection, tropical sprue, tubular adenoma (adenomatous polyp, polypoid adenoma), typhoid fever, ulcers, vascular malformations, villous adenoma, viral enteritis, viral gastroenteritis, visceral myopathy, visceral neuropathy, vitelline duct remnants, volvulus, Western-type intestinal lymphoma, Whipple's disease (intestinal lipopystrophy), Yersinia enterocolitica & Yersinia pseudotuberculosis infection, and Zollinger-EUison syndrome.
Kidney. Nuclear receptors expressed in the kidney are listed in Table 19. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the kidney. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular kidney disease or disorder, or an appropriate therapeutic course.
Figure imgf000166_0001
Exemplary diseases and disorders of the kidney include acquired cystic disease, acute (postinfectious) glomerulonephritis, acute infectious interstitial nephritis, acute interstitial nephritis, acute pyelonephritis, acute renal failure, acute transplant failure, acute tubular necrosis, adult polycystic kidney disease, AL amyloid, analgesic nephropathy, anti-glomerular basement membrane disease (Goodpasture's Syndrome), asymptomatic hematuria, asymptomatic proteinuria, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bence Jones cast nephropathy, benign familial hematuria, benign nephrosclerosis and atheromatous embolization, bilateral cortical necrosis, chronic glomeralonephritis, chronic interstitial nephritis, chronic pyelonephritis, chronic renal failure, chronic transplant failure, circulating immune complex nephritis, crescentic glomerulonephritis, cryoglobulinemia, cystic renal dysplasia, diabetic glomerulosclerosis, diabetic nephropathy, dialysis cystic disease, drug induced (allergic) acute interstitial nephritis, ectopic kidney, Fabry's disease, familial juvenile nephronophthisis-medullary cystic disease complex, focal glomerulosclerosis (segmental hyalinosis), glomeralocystic disease, glomerulonephritis, glomerulonephritis associated with bacterial endocarditis, glomerulosclerosis, hemolytic-uremic syndrome, Henoch-Schδnlein puφura, hepatitis-associated glomeralonephritis, hereditary nephritis (Alport syndrome), horseshoe kidney, hydronephrosis, IgA nephropathy, infantile polycystic kidney disease, ischemic acute tubular necrosis, light-chain deposit disease, malignant nephrosclerosis, medullary cystic disease, membranoproliferative (mesangiocapiUary) glomeralonephritis, membranous glomerulonephritis, membranous nephropathy, mesangial proliferative glomerulonephritis (includes Berger's Disease), minimal change glomeralar disease, minimal change nephrotic syndrome, nephritic syndrome, nephroblastoma (Wilms tumor), nephronophthisis (medullary cystic disease complex), nephrotic syndrome, plasma cell dyscrasias (monoclonal immunoglobulin-induced renal damage), polyarteritis nodosa, proteinuria, pyelonephritis, rapidly progressive (crescentic) glomeralonephritis, renal agenesis, renal amyloidosis, renal cell carcinoma, renal dysgenesis, renal dysplasia, renal hypoplasia, renal infection, renal osteodystrophy, renal stones (urolithiasis), renal tubular acidosis, renal vasculitis, renovascular hypertension, scleroderma (progressive systemic sclerosis), secondary acquired glomeralonephritis, simple renal cysts, systemic lupus erythematosus, thin basement membrane nephropathy, thrombotic microangiopathy, thrombotic thrombocytopenic puφura, toxic acute tubular necrosis, tubular defects, tubulointerstitial disease in multiple myeloma, urate nephropathy, urinary obstruction, and vasculitis.
Liver. Nuclear receptors expressed in the liver are listed in Table 20. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the liver. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular liver disease or disorder, or an appropriate therapeutic course.
Figure imgf000167_0001
Exemplary liver diseases and disorders include acute alcoholic hepatitis (acute sclerosing hyaline necrosis of the liver), acute graft-versus-host disease, acute hepatitis, acute hepatocellular injury associated with infectious diseases other than viral hepatitis., acute liver failure, acute viral hepatitis, adenovirus hepatitis, Alagille syndrome, alcoholic cinhosis, alcoholic hepatitis, alcoholic liver disease, alphal-antitrypsin deficiency, amebic abscess, angiolmyolipoma, angiosarcoma, ascending cholangitis, autoimmune chronic active hepatitis (lupoid hepatitis), bile duct adenoma, bile duct cystadenocarcinoma, bile duct cystadenoma, biliary atresia, biliary cinhosis, biliary papillomatosis, bridging necrosis, Budd-Chiari syndrome, Byler disease, cardiac fibrosis of the liver, Caroli disease, cavernous hemangioma, cholangiocarcinoma, cholangitic abcess, choleostasis, cholestatic viral hepatitis, chronic active hepatitis, chronic alcoholic liver disease, chronic graft-versus-host disease, chronic hepatic venous congestion, chronic hepatitis, chronic liver failure, chronic passive congestion, chronic viral hepatitis, cinhosis, combined hepatocellular and cholangiocarcinoma, confluent hepatic necrosis, congenital hepatic fibrosis, Crigler-Najjar syndrome, cryptogenic cinhosis, cystic fibrosis, defects of coagulation, delta hepatitis, Dubin- Johnson syndrome, epithelioid hemangioendothelioma, erythrohepatic protopoφhyria, extrahepatic biliary obstraction (primary biliary cinhosis), fatty change, fatty liver, focal necrosis, focal nodular hypeφlasia, fulminant viral hepatitis, galactosemia, Gilbert's syndrome, glycogen storage diseases, graft-versus-host disease, granulomatous hepatitis, hemangioma, hemangiosarcoma, hemochromatosis, hepatic adenoma, hepatic amebiasis, hepatic encephalopathy, hepatic failure, hepatic schistosomiasis, hepatic veno-occlusive disease, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, hepatoblastoma, hepatocellular adenoma, hepatocellular carcinoma, hepatocellular necrosis, hepatorenal syndrome, hereditary fructose intolerance, hereditary hemochromatosis, heφesvirus hepatitis, hydatid cust, hypeφlastic lesions, hypoalbuminenia, infantile hemangioendothelioma, infarction of the liver, infectious mononucleosis hepatitis, inflammatory pseudotumor of the liver, intrahepatic cholangiocarcinoma, intrahepatic cholestasis, intrahepatic protal hypertension, ischemic necrosis (ischemic hepatitis), isoniazid-induced necrosis, jaundice, leptospirosis, liver cell adenoma, liver manifestations of Rocky Mountain spotted fever, macronodular cinhosis, macrovesicular steatosis, malignant vascular neoplasts, mass lesions, massive hepatocellular necrosis, massive necrosis, mesenchymal hamartoma, metastatic tumors, micronodular cinhosis, microvesicular steatosis, neonatal (physiologic) jaundice, neonatal hepatitis, neoplastic lesions, nodular transformation (nodular regenerative hypeφlasia, nonsuppurative infections, nutritional cinhosis, nutritional liver disease, oriental cholangiohepatitis, parasitic infestation of the liver, peliosis hepatis, poφhyria cutaneo tarda, portal hypertension, portal vein thrombosis, posthepatic portal hypertension, predictable (dose-related) toxicity, prehepatic portal hypertension, primary biliary cinhosis, primary sclerosing cholangitis, pyogenic liver abcess, Q-fever hepatitis, Rotor's syndrome, sclerosing bile duct adenoma, sclerosing cholangitis, secondary hemochromatosis, submassive necrosis, syphilis, toxic liver injury, tyrosinemia, undifferentiated sarcoma, unpredictable (idiosyncratic) toxicity, vascular lesions, virus- induced cinhosis, Wilson's disease, and zonal necrosis.
Lung. Nuclear receptors expressed in the lung are listed in Table 21. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptorin the lung. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a lung disease or disorder, the risk of developing such a disease or disorder, or an appropriate therapeutic course.
Table 21. Nuclear Receptors Expressed in the Lung
Figure imgf000169_0001
Exemplary lung diseases and disorders (including those of the trachea) include abnormal diffusion, abnormal perfusion, abnormal ventilation, accelerated silicosis, actinomycosis, acute air space pneumonia (acute bacterial pneumonia), acute bronchiolitis, acute congestion, acute infections of the lung, acute interstitial pneumonia, acute necrotizing viral pneumonia, acute organic dust toxic syndrome, acute pneumonia, acute radiation pneumonitis, acute rheumatic fever, acute silicosis, acute tracheobronchitis, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adenovirus, adult respiratory distress syndrome (shock lung), agenesis, AIDS, air embolism, allergic bronchopulmonary mycosis, allergic granulomatosis and angiitis (Churg-Strauss), allograft rejection, aluminum pneumoconiosis, alveolar microlithiasis, alveolar proteinosis, amebic lung abscess, amniotic fluid embolism, amyloidosis of the lung, anomalies of pulmonary vasculature, anomalous pulmonary venous return, aspiration pneumonia, aplasia, asbestosis, asbestos-related diseases, aspergillosis, asthma, atelectasis, atriovenous fistulas, atypical mycobacterial infection, bacteremia, bacterial pneumonia, benign clear cell tumor, benign epithelial tumors, benign fibrous mesothelioma, berylliosis, blastomycosis, bromchial atresia, bronchial asthma, bronchial carcinoid tumor, bronchial isomerism, bronchial obstraction, bronchial stenosis, bronchiectasis, bronchiolalveolar carcinoma, bronchiolitis, bronchiolitis obliterans-organizing pneumonia, bronchocentric granulomatosis, bronchogenic cyst, bronchopneumonia, bronchopulmonary dysplasia, bronchopulmonary sequestration, bullae, bullous emphysema, cancer, carcinoid tumors, carcinoma of the lung (bronchogenic carcinoma), central (bronchogenic) carcinoma, central cyanosis, centriacinar emphysema, cetrilobular emphysema, chest pain, Chlamydial pneumonia, chondroid hamartoma, chronic airflow obstraction, chronic bronchitis, chronic diffuse interstitial lung disease, chronic idiopathic pulmonary fibrosis, chronic lung abscess, chronic obstructive pulmonary diseases, chronic radiation pneumonitis, chronic silicosis, chylothorax, ciliary dyskinesia, coal worker's pneumoconiosis (anthracosis), coccidioidomycosis, collagen-vascular diseases, common cold, compensatory emphysema, congenital acinar dysplasia, congenital alveolar capillary dysplasia, congenital bronchobiliary fistula, congenital bronchoesophageal fistula, congenital cystic adenomatoid malformation, congenital pulmonary lymphangiectasis, congenital pulmonary overinflation (congenital emphysema), congestion, cough, cryptococcosis, cyanosis, cystic fibrosis, cysticercosis, cytomegalovirus, desquamative interstitial pneumonitis, destructive lung disease, diatomaceous earth pneumoconiosis, diffuse alveolar damage, diffuse pulmonary hemonhage, diffuse septal amyloidosis, diffuse panbronchiolitis, Dirofilaria immitis, diseases of the pleura, distal acinar (paraceptal) emphysema, drag-induced asthma, drag- induced diffuse alveolar damage, dyspnea, ectopic hormone syndromes, emphysema, empyemma, eosinophilic pneumonias, exercise-induced asthma, extralobar sequestration, extrinsic allergic asthma, fat emboli, focal dust emphysema, follicular bronchiolitis, follicular bronchitis, foreign-body embolism, Fuller's earth pneumoconiosis, functional resistance to arterial flow (vasoconstriction), fungal granulomas of the lung, fungal infections, Goodpasture's syndrome, graphite pneumoconiosis, gray hepatization, hamartomas, hard metal disease, hemoptysis, hemothorax, herniation of lung tissue, heφes simplex, heterotopic tissues, high-altitude pulmonary edema, histoplasmosis, horseshoe lung, humidifier fever, hyaline membrane disease, hydatid cysts, hydrothorax, hypersensitivity pneumonitis (extrinsic allergic alveolitis), hypoxic vascular remodeling, iatrogenic drug-, chemical-, or radiation- induced interstitial fibrosis, idiopathic interstitial pneumonia, idiopathic organizing pneumonia, idiopathic pulmonary fibrosis (fibrosing alveolitis, Hamman-Rich syndrome, acute interstitial pneumonia), idiopathic pulmonary hemosiderosis, immunologic interstitial fibrosis, immunologic interstitial pneumonitis, immunologic lung disease, infections causing chronic granulomatous inflammation, infections causing chronic suppurative inflammation, infections of the air passages, infiltrative lung disease, inflammatory lesions, inflammatory pseudotumors, influenza, interstitial diseases of uncertain etiology, interstitial lung disease, interstitial pneumonitis in connective tissue diseases, intralobar sequestration of the lung (congenital), intrinsic (nonallergic) asthma, invasive pulmonary aspergillosis, kaolin pneumoconiosis, Kartagner's syndrome, Klebsiella pneumonia, Langerhans' cell histiocytosis (histiocytosis X), large cell undifferentiated carcinoma, larval migration of Ascaris lumbricoides, larval migration of Strongyloides stercoralis, left pulmonary artery "sling", Legionella pneumonia, lipid pneumonia, lobar pneumonia, localized emphysema, long-standing bronchial obstruction, lung abscess, lung collapse, lung fluke, lung transplantation implantation response, lymphangiomyomatosis, lymphocytic interstitial pneumonitis (pseudolymphoma, lymphoma, lymphomatoid granulomatosis, malignant mesothelioma, massive pulmonary hemonhage in the newborn, measles, meconium aspiration syndrome, mesenchymal cystic hamartomas, mesenchymal tumors, mesothelioma, metal-induced lung diseases, metastatic calcification, metastatic neoplasms, metastatic ossification, mica pneumoconiosis, mixed dust fibrosis, mixed epithelial-mesenchymal tumors, mixed type neoplasms, mucoepidermoid tumor, mucoviscidosis (fibrocystic disease of the pancreas, mycoplasma pneumoniae, necrotizing bacterial pneumonia, necrotizing sarcoid granulomatosis, neonatal respiratory distress syndrome, neoplasms of the pleura, neuromuscular syndromes, nocardiosis, nondestructive lung disease, North American blastomycosis, occupational asthma, organic dust disease, panacinar emphysema, Pancoast's syndrome, paracoccidioidomycosis, parainfluenza, paraneoplastic syndromes, paraseptal emphysema (paracicatricial), parasilicosis syndromes, parasitic infections of the lung, peripheral cyanosis, peripheral lung carcinoma, persistent pulmonary hypertension of the newborn, pleural diseases, pleural effusion, pleural plaques, pheumococcal pneumonia, pneumoconioses (inorganic dust diseases), Pneumocystis carinii pneumonia, pneumocystosis, pneumonitis, pneumothorax, precapillary pulmonary hypertension, primary (childhood) tuberculosis, primary (idiopathic) pulmonary hypertension, primary mesothelial neoplasms, primary pulmonary hypertensions, progressive massive fibrosis, psittacosis, pulmonary actinomycosis, pulmonary air-leak syndromes, pulmonary alveolar proteinosis, pulmonary arteriovenous malformation, pulmonary blastoma, pulmonary capillary hemangiomatosis, pulmonary carcinosarcoma, pulmonary edema, pulmonary embolism, pulmonary eosinophilia, pulmonary fibrosis, pulmonary hypertension, pulmonary hypoplasia, pulmonary infarction, pulmonary infiltration and eosinophilia, pulmonary interstitial air (pulmonary interstitial emphysema), pulmonary lesions, pulmonary nocardiosis, pulmonary parenchymal anomalies, pulmonary thromboembolism, pulmonary tuberculosis, pulmonary vascular disorders, pulmonary vasculitides, pulmonary veno-occlusive disease, pyothorax, radiation pneumonitis, recunent pulmonary emboli, red hepatization, respiration failure, respiratory syncytial virus, Reye's syndrome, rheumatoid lung disease, Rickettsial pneumonia, rapture of pulmonary arteries, sarcoidosis, scar cancer, scimitar syndrome, scleroderma, sclerosing hemangioma, secondary (adult) tuberculosis, secondary bacterial pneumonia, secondary pleural neoplasms, secondary pulmonary hypertension, senile emphysema, siderosis, silicate pneumoconiosis asbestosis, silicatosis, silicosis, simple nodular silicosis, Sjδgren's syndrome, small airway lesions, small cell carcinoma, small cell undifferentiated (oat cell) carcinoma, spontaneous pneumothorax, sporotrichosis, sputum production, squamous (epidermoid) carcinoma, stannosis, staphlococcal pneumonia, suppuration (abscess formation), systemic lupus erythematosus, talcosis, tension pneumothorax, tracheal agenesis, tracheal stenosis, tracheobronchial amyloidosis, tracheobronchomegaly, tracheoesophageal fistula, transient tachypnea of the newborn (neonatal wet lung), tungsten carbide pneumoconiosis, usual interstitial pneumonia, usual interstitial pneumonitis, varicella, viral pneumonia, visceral pleural thickening, Wegener's granulomatosis, and whooping cough (pertussis).
Muscle. Nuclear receptors expressed in the muscle are listed in Table 22. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the muscle. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a muscular disease or disorder, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 22. Nuclear Receptors Expressed in the Muscle
Figure imgf000173_0001
Exemplary diseases and disorders involving the muscles include abnormalities of ion channel closure, acetylcholine receptor deficiency, acetylcholinesterase deficiency, acid maltase deficiencies (type 2 glycogenosis), acquired myopathies, acquired myotonia, adult myotonic dystrophy, alveolar rhabdomyosarcoma, aminoglycoside drugs, amyloidosis, amyotrophic lateral sclerosis, antimyelin antibodies, bacteremic myositis, Batten's disease (neuronal ceroid lipofuscinoses), Becker's muscular dystrophy, benign neoplasms, Bomholm disease, botulism, branching enzyme deficiency (type 4 glycogenosis), carbohydrate storage diseases, carnitine deficiencies, carnitine palmitoyltransferase deficiency, central core disease, centronuclear (myotubular) myopathy, Chagas' disease, chondrodystrophic myotonia, chronic renal disease, congenital fiber type disproportion, congenital muscular dystrophy, congenital myopathies, congenital myotonic dystrophy, congenital paucity of synaptic clefts, cysticercosis, cytoplasmic body myopathy, debranching enzyme deficiency (type 3 glycogenosis), defect in acetylcholine synthesis, denervation, dermatomyositis, diabetes mellitus, diphtheria, disorders of glycolysis, disorders of neuromuscular junction, distal muscular dystrophy, drug induced inflammatory myopathy, Duchenne muscular dystrophy, embryonal rhabdomyosarcoma, Emery-Dreifuss muscular dystrophy, exotoxic bacterial infections, facioscapulohumeral muscular dystrophy, failure of neuromuscular transmission, fiber necrosis, fibromyalgia, fmgeφrint body myopathy, Forbe's disease, gas gangrene, Guillain-Bane syndrome, inclusion body myositis, infantile spinal muscular atrophies, infectious myositis, inflammatory myopathies, influenza, Isaac's syndrome, ischemia, Kearns-Sayre syndrome, lactase dehydrogenase deficiency, Lambert-Eaton syndrome, Leigh's disease, leukodysfrophies, limb girdle muscular dystrophy, lipid storage myopathies, Luft's disease, lysosomal glycogen storage disease with normal acid maltase activity, malignant neoplasms, malignant hyperthermia, McArdle's disease, MELAS syndrome (mitochondrial myopathy, encephalopathy, lacticacidosis, and strokes), MERRF syndrome (myoclonus epilepsy with ragged-red fibers), metabolic myopathies, microfiber myopathy, mitochondrial myopathies, multicore disease (minicore disease), multisystem triglyceride storage disease, muscle wasting from diabetes, muscular dystrophies, myasthenia gravis, myasthenic syndrome (Eaton-Lambert syndrome), myoadenylate deaminase deficiency, myoglobinuria, myopathies, myophosphorylase deficiency (type 5 glycogenosis), myositis, myositis ossificans, myotonia congenita, myotonic muscular dystrophy, nemaline myopathy, ocular muscular dystrophy, oculopharyngeal muscular dystrophy, paramyotonia, parasytic myopathies, periodic paralysis, peripheral neuropathies, phosphofructokinase deficiency (type 7 glycogenosis), phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, pleomoφhic rhabdomyosarcoma, polymyositis, Pompe's disease, progressive muscular atrophy, progressive systemic sclerosis, reducing body myopathy, Refsum's disease, rhabdomyolysis, rhabdomyoma, rhabdomyosarcoma, sarcoidosis, sarcoma botryoides, sarcotubular myopathy, secondary congenital myopathies, slow channel syndrome, spasmodic torticollis, spheroid body myopathy, spinal muscular atrophy, steroid myopathy, stiff-person syndrome, systemic lupus erythematosus, Tauri's disease, tick paralysis, toxic myopathies, toxoplasmosis, trichinosis, trilaminar fiber myopathy, type 2 myofiber atrophy, typhoid fever, vasculitis, viral myositis, and zebra body myopathy.
Ovary. Nuclear receptors expressed in the ovary are listed in Table 23. These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability of the nuclear receptor in the ovary. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of disease, the risk of developing a particular ovarian disease or disorder, or an appropriate therapeutic course. Table 23. Nuclear Receptors Expressed in the Ovary
Figure imgf000175_0001
Exemplary ovarian diseases and disorders include autoimmune oophoritis, brenner tumors, choriocarcinoma, clear cell adenocarcinoma, clear cell carcinoma, coφus luteal cysts, decidual reaction, dysgerminoma, embryonal carcinoma, endometrioid tumors, endometriosis, endometriotic cysts, epithelial inclusion cysts, fibrothecoma, follicular cysts, gonadoblastoma, granulosa-stroma cell tumors, granulosa-theca cell tumor, gynandroblastoma, hilum cell hypeφlasia, luteal cysts, luteal hematomas, luteoma of pregnancy, massive ovarian edema, metastatic neoplasm, mixed germ cell tumors, monodermal tumors, mucinous tumors, neoplastic cysts, ovarian changes secondary to cytotoxic drugs and radiation, ovarian fibroma, polycystic ovary syndrome, pregnancy luteoma, premature follicle depletion, pseudomyxoma peritonei, resistant ovary, serous tumors, Sertoli-Leydig cell tumor, sex-cord tumor with annular tubules, steroid (lipid) cell tumor, stromal hypeφlasia, stromal hyperthecosis, teratoma, theca lutein cysts, thecomas, transitional cell carcinoma, undifferentiated carcinoma, and yolk sac carcinoma (endodermal sinus tumor).
Peripheral Blood Lymphocytes. Nuclear receptors expressed in the lymphocytes are listed in Table 24. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in lymphocytes. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder, the risk of developing a particular disease or disorder, or an appropriate therapeutic course. Table 24. Nuclear Receptors Expressed in Peripheral Blood Lymphocytes
Figure imgf000176_0001
Exemplary blood diseases and disorders include abnormal hemoglobins, abnormalities in granulocyte count, abnormalities in lymphocyte count, abnormalities in monocyte count, abnormalities of blood platelets, abnormalitites of platelet function, acanthocytosis, acquired neutropenia, acute granulocytic leukemia, acute idiopathic thrombocytopenic puφura, acute infections, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloblastic leukemia, acute myelocytic leukemia, acute myeloid leukemia, acute pyogenic bacterial infections, acute red cell aplasia, acute response to endotoxin, adult T-cell leukemial/lymphoma, afibrinogenemia, alpha thalassemia, altered affinity of hemoglobin for oxygen, amyloidosis, anemia, anemia due to acute blood loss, anemia due to chronic blood loss, anemia of chronic disease, anemia of chronic renal failure, anemias associated with enzyme deficiencies, anemias associated with erythrocyte cytoskeletal defects, anemias caused by inherited disorders of hemoglobin synthesis, angiogenic myeloid metaplasia, aplastic anemia, ataxia- telangiectasia, Auer rods, autoimmune hemolytic anemias, B-cell chronic lymphocytic leukemia, B-cell chronic lymphoproliferative disorders, Bemard-Soulier disease, beta thalassemia, Blackfan-Diamond disease, brucellosis, Burkitt's lymphoma, Chediak- Higashi syndrome, cholera, chronic acquired pure red cell aplasia, chronic granulocytic leukemia, chronic granulomatous disease, chronic idiopathic myelofibrosis, chronic idiopathic thrombocytopenic puφura, chronic lymphocytic leukemia, chronic lymphoproliferative disorders, chronic myelocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, congenital dyserythropoietic anemias, congenital dysfibrinogenemia, congenital neutropenia, corticosteriods, cyclic neutropenia, cytoplasmic maturation defect, deficiency of coagulation factors, delta-beta thalassemia, diphtheria, disorders of blood coagulation, disseminated intravascular coagulation & fibrinolysis, Dδhle bodies, drag & chemical- induced hemolysis, drug-induced thrombocytopenia, drags that suppress granulopoiesis, E. coli, early preleukemic myeloid leukemia, eosinophilia, eosinophilic granuloma, erythrocute enzyme deficiency, erythrocyte membrane defects, essential thrombocythemia, factor 7 deficiency, familial cyclic neutropenia, Felty's syndrome, fibrinolytic activity, folate antagonists, folic acid deficiency, Gaucher disease, Glanzmann's thrombasthenia, glucose-6-phosphate dehydrogenase deficiency, granulated T-cell lymphocyte leukemia, granulocytic sarcoma, granulocytosis, Hageman trait, hairy cell leukemia (leukemic reticuloendotheliosis), Hand-Schύller-Christian disease, heavy-chain disease, hemoglobin C disease, hemoglobin constant spring, hemoglobin S, hemoglobinopathies, hemolysis caused by infectious agents, hemolytic anemia, hemolytic anemia secondary to mechanical erythrocyte destruction, hemolytic blood transfusion reactions, hemolytic disease of the newborn, hemophagocytic disorders, hemophilia A, hemophilia B (Christmas disease, factor 9 deficiency, hepatitis, hereditary elliptocytosis, hereditary spherocytosis, heterozygous beta thalassemia (Cooley's trait), homozygous beta thalassemia (Cooley's anemia), hypereosinophilic syndrome, hypoxia, idiopathic cold hemagglutinin disease, idiopathic thrombocytopenic puφura, idiopathic warm autoimmune hemolytic anemia, immune drug induced hemolysis, immune-mediated hemolytic anemias, immunodeficiency disease, infantile neutropenia (Kostmann), instability of the hemoglobin molecule, iron deficiency anemia, isoimmune hemolytic anemia, juvenile chronic myeloid leukemia, Langerhans cell histiocytosis, large granular lymphocyte leukemia, lazy leukocyte syndrome, Letterer-Siwe disease, leukemias, leukemoid reaction, leukoerythroblastic anemia, lipid storage diseases, lymphoblastosis, lymphocytopenia, lymphocytosis, lymphoma, lymphopenia, macroangiopathic hemolytic anemia, malaria, manow aplasia, May- Hegglin anomaly, measles, megaloblastic anemia, metabolic diseases, microangiopathic hemolytic anemia, microcytic anemia, miliary tuberculosis, mixed phenotupe acute leukemia, monoclonal gammopathy of undetermined significance, monocytic leukemia, monocytosis, mucopolysaccharidosis, multiple myeloma, myeloblastic luekemia, myelodysplastic syndromes, myelofibrosis (agnogenic myeloid metaplasia), myeloproliferative diseases, myelosclerosis, neonatal thrombocytopenic puφura, neoplasms of hematopoietic cells, neutropenia, neutrophil dysfunction syndromes, neutrophil leukocytosis, neutrophilia, Niemann-Pick disease, nonimmune drag-induced hemolysis, normocytic anemia, nuclear maturation defects, parahemophilia, paroxysmal cold hemoglominuria, paroxysmal nocturnal hemoglobinuria, Pelger-Hύet anomaly, pernicious (Addisonian) anemia, plasma cell leukemia, plasma cell neoplasia, polycythemia, polycythemia rabra vera, presence of circulating anticoagulants, primary (idiopathic) thrombocythemia, primary neoplasms, prolymphocytic leukemia, Proteus, Pseudomonas, pure red cell aplasia, pyogenic bacterial infection, pyruvate kinase deficiency, radiation, red cell aplasia, refractory anemias, ricketsial infections, Rosenthal's syndrome, secondary absolute polycythemia, septicemia, severe combined immunodeficiency disease, Sezary syndrome, sickle cell disease, sickle cell-beta thalassemia, sideroblastic anemia, solitary plasmacytoma, storage pool disease, stress, structural hemoglobin variants, systemic lupus erythematosus, systemic mastocytosis, tart cell, T-cell chronic lymphoproliferative disorders, T-cell prolymphocytic leukemia, thalassemias, thrombocytopenia, thrombotic thrombocytopenic puφura, toxic granulation, toxic granules in severe infection, typhus, vitamin B12 deficiency, vitamin K deficiency, Von Willebrand's disease, Waldenstrom macroglobulinemia, and Wiskott- aldrich syndrome.
Prostate. Nuclear receptors expressed in the prostate are listed in Table 25. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the prostate. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder involving the prostate, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Figure imgf000178_0001
Exemplary diseases and disorders involving the prostate include acute bacterial prostatitis, acute prostatitis, adenoid basal cell tumor (adenoid cystic-like tumor), allergic (eosinophilic) granulomatous prostatitis, atrophy, atypical adenomatous hypeφlasia, atypical basal cell hypeφlasia, basal cell adenoma, basal cell hypeφlasia, BCG-induced granulomatous prostatitis, benign prostatic hypeφlasia, benign prostatic hypertrophy, blue nevus, carcinosarcoma, chronic abacterial prostatitis, chronic bacterial prostatitis, cribriform hypeφlasia, ductal (endometrioid) adenocarcinoma, granulomatous prostatitis, hematuria, iatrogenic granulomatous prostatitis, idiopathic (nonspecific) granulous prostatitis, impotence, infectious granulomatous prostatitis, inflammatory pseudotumor, leiomyosarcoma, leukemia, lymphoepithelioma-like carcinoma, malakoplakia, malignant lymphoma, mucinous (colloid) carcinoma, nodular hypeφlasia (benign prostatic hypeφlasia), nonbacterial prostatitis, obstruction of urinary outflow, phyllodes tumor, postatrophic hypeφlasia, postinadiation granulomatous prostatitis, postoperative spindle cell nodules, postsurgical granulomatous prostatitis, prostatic adenocarcinoma, prostatic carcinoma, prostatic intraepithelial neoplasia, prostatic melanosis, prostatic neoplasm, prostatitis, rhabdomyosarcoma, sarcomatoid carcinoma of the prostate, sclerosing adenosis, signet ring cell carcinoma, small-cell, undifferentiated carcinoma (high-grade neuroendocrine carcinoma), squamous cell carcinoma of the prostate, stromal hypeφlasia with atypia, transitional cell carcinoma of the prostate, xanthogranulomatous prostatitis, and xanthoma.
Skin. Nuclear receptors expressed in the skin are listed in Table 26. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the skin. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of skin disease or disorder, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Figure imgf000179_0001
Exemplary skin diseases and disorders include acanthosis nigricans, acne vulgaris, acquired epidermolysis bullosa, acrochordons, acrodermatitis enteropathica, acropustulosis, actinic keratosis, acute cutaneous lupus erythematosus, age spots, allergic dermatitis, alopecia areata, angioedema, angiokeratoma, angioma, anthrax, apocrine tumors, arthropid-bite reactions, atopic dermatitis, atypical fibroxanthoma, Bart's syndrome, basal cell carcinoma (basal cell epithelioma), Bateman's puφura, benign familial pemphigus (Hailey-Hailey disease), benign keratoses, Berloque dermatitis, blue nevus, borderline leprosy, Bonelia infection (lyme disease), Bowen's disease (carcinoma in situ), bullous pemphigoid, Cafe-au-lait spot, calcification, cellular blue nevus, cellulitis, Chagas' disease, chickenpox (varicella), chloasma, chondrodermatitis nodularis helicis, chondroid syringoma, chronic actinic dermatitis, chronic cutaneous lupus erythematosus, chronic discoid lesions, cicatricial pemphigoid, collagen abnormalities, compount melanocytic nevus, congenital melanocytic nevus, connective tissue nevus, contact dermatitis, cutaneous leishmaniasis, cutis laxa, cysts of the skin, dandruff, Darier's disease (keratosis follicularis), deep fungal infections, delayed-hypersensitivity reaction, dermal Spitz's nevus, dermatitis, dermatitis heφetiformis, dermatofibroma (cutaneous fibrous histiocytoma), dermatofibrosarcoma protuberans, dermatomyositis, dermatophyte infections, dermatophytid reactions, dermoid cyst, dermotropic ricketsial infections, dermotropic viral infections, desmoplastic melanoma, discoid lupus erythematosus, dominant dystrophic epidermolysis bullosa, Dowling-Meara epidermolysis bullosa, dyshidrotic dermatitis, dysplastic nevi, eccrine tumors, ecthyma, eczema, elastic tissue abnormalities, elastosis perforans seφiginosa, eosinophilic fasciitis, eosinophilic folliculitis, ephelides (freckles), epidermal cysts, epidermolysis bullosa, epidermolysis bullosa simplex, epidermotropic T-cell lymphoma, epidermotropic viruses, erysipelas, erythema multiforme, erythema nodosum, erythema nodosum leprosum, fibrotic disorders, fibrous tumors, follicular mucinosis, Fordyce's condition, fungal infections, genodermatoses, graft-versus-host disease, granuloma annulare, granulomatous vasculitis, Graver's disease, hair follicle infections, hair follicle tumors, hair loss, halo nevus, heφes simplex, heφes zoster (shingles), hidradenitis suppurativa, histiocytic lesions, HIV infections, hives, human papilloma virus, hyperhydrosis, ichthyosis, idiopathic skin diseases, impetigo, incontinentia pigmenti, intraepidermal spongiotic vesicles and bullae, invasive malignant melanoma, invasive squamous cell carcinoma, junctional epidermolysis bullosa, junctional melanocytic nevus, juvenile xanthogranuloma, , Kaposi's sarcoma, keloids, keratinocytic lesions, keratinocytic tumors, keratoacanthoma, keratoderma blennonhagicum, keratosis pilaris, leiomyoma, lentigo, lentigo maligna (Hutchinson's freckle), lepromatous leprosy, leprosy (Hansen's disease), leukocytoclastic vasculitis, lichen planus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen striatus, lichenoid disorders, lichenoid drug reactions, light eruptions, linear bullous IgA dermatitis, lipoma, Lucio's phenomenon, lupus erythematosus, lymphatic filariasis, lymphocytic vasculitis, lymphocytoma cutis, lymphoid lesions, lymphomatoid papulosis, malignant blue nevus, malignant lymphomas, malignant melanoma, malignant melanoma in situ (noninvasive malignant melanoma), mast cell neoplasms, mastocytosis, measles, melanocyte disorders, melanocytic lesions, melanocytic neoplasms, melanocytic nevus, melanocytic nevus with dysplasia, melanotic macule, reactive type, melasma, merkel cell (neuroendocrine) carcinoma, metastatic melanoma, miliara, mixed connective tissue disease, molluscum contagiosum, moφhea, mucin deposition, mucocutaneous leishmaniasis, mycetoma, mycobacterial infection, Mycobacterium marinum, Mycobacterium ulcerans, mycosis fungoides (cutaneous T cell lymphoma), myxoid cyst, necrobiosis lipoidica, necrobiosis lipoidica diabeticoram, necrolytic migratory erythema, necrotizing fasciitis, neoplasms of dermal mesenchymal cells, neoplasms of keratinocytes, neoplasms of skin appendages, neoplasms of the epidermis, neural tumors, neuroendocrine carcinoma of the skin, neurothekeoma, nevocellular nevus (melanocytic nevus), nummular dermatitis, obliterative vasculitis, onchocerciasis, Paget's disease, pale cell acanthoma of Degos, palisaded encapsulated neuroma, papillomaviras infections, paraneoplastic pemphigus, parasitic infections, pemphigoid gestationis, pemphigus, pemphigus foliaceus, pemphigus vulgaris, perivascular infiltrates, pilar cysts, pinta, pityriasis alba, pityriasis lichenoides chronica (of Juliusberg), pityriasis lichenoides et varioliformis acuta, pityriasis rosea, pityriasis rubra pilaris, plantar warts, porokeratosis, pressure necrosis, progressive systemic sclerosis, protozoal infections, pruritic urticarial papules and plasques of pregnancy, pruritis ani, pseudofolliculitis barbae, pseudoxanthoma elasticum, psoriasis vulgaris, pyogenic granuloma, radial growild typeh phase melanoma, recessive dystrophic epidermolysis bullosa, Reiter's syndrome, ringworm, Rochalimaea henselae infection, rosacea, rubella, sarcoidosis, scabies, Schamberg's disease, scleroderma, sebaceous hypeφlasia, sebaceous tumors, sebonheic dermatitis, sebonheic keratosis, Sezary syndrome, skin manifestations of systemic diseases, small plaque parapsoriasis, smallpox (variola), solitary mastocytoma, spirochetal infections, Spitz's nevus, Spitz's nevus junctional type, squamous cell carcinoma, stasis dermatitis, Stevens- Johnson syndrome, subacute cutaneous lupus erythematosus, subcorneal pustular dermatosis, superficial fungal infections, superficial spreading melanoma in situ, syphilis, syringoma, systemic lupus erythematosus, systemic mastocytosis, tinea (dermatophytosis, tinea versicolor, toxic epidermal necrolysis, transient acantholytic dermatosis, tuberculoid leprosy, tuberculosis, urticaria, urticaria pigmentosa, urticarial vasculitis, vascular tumors, verruca vulgaris (common wart), vertical growild typeh phase melanoma, visceral leishmaniasis, vitiligo, warty dyskeratoma, Weber-Cockayne epidermolysis bullosa, Woringer-Kolopp disease, xanthomas, xeroderma pigmentosum, xerosis, and yaws.
Spleen. Nuclear receptors expressed in the spleen are listed in Table 27. These receptors are thus potential targets for- therapeutic compounds that may modulate their activity, expression, or stability in the spleen. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the spleen, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 27. Nuclear Receptors Expressed in the Spleen
Figure imgf000182_0001
Exemplary diseases and disorders of the spleen include abnormal immunoblastic proliferations of unknown origin, acute infections, acute parasitemias, agnogenic myeloid metaplasia, amyloidosis, angioimmunoblastic lymphadenopathy, antibody- coated cells, asplenia, autoimmune diseases, autoimmune hemolytic anemias, B-cell chronic lymphocytic leukemia and prolymphocytic leukemia, babesiosis, bone manow involvement by carcinoma, brucellosis, carcinoma, ceroid histiocytosis, chronic alcoholism, chronic granulomatous disease, chronic hemolytic anemias, chronic hemolytic disorders, chronic immunologic inflammatory disorders, chronic infections, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic parasitemias, chronic uremia, cinhosis, cold agglutinin disease, congestive splenomegaly, cryoglobulinemia, disseminated tuberculosis, dysproteinemias, endocrine disorders, erythroblastic leukemia, erythropoiesis, essential thrombocythemia, extramedullary hematopoiesis, Felty syndrome, fibrocongestive splenomegaly, fungal infections, gamma heavy-chain disease, Gaucher's disease, graft rejection, granulomatous infiltration, hairy cell leukemia, hamartomas, Hand-Schuller-Christian disease, hemangiomas, hemangiosarcomas, hematologic disorders, hemoglobinopathies, hemolytic anemias, hereditary elliptocytosis, hereditary spherocytosis, histiocytic medullary reticulosis, histiocytosis X, Hodgkin's disease, hypersensitivity reactions, hypersplenism, hyposplenism, idiopathic thrombocytopenic puφura, IgA deficiency, immune granulomas, immune thrombocytopenia, immune thrombocytopenic pmpura, immunodeficiency disorders, infection associated hemophagocytic syndrome, infectious granulomas, infectious mononucleosis, infective endocarditis, infiltrative splenomegaly, inflammatory pseudotumors, leishmaniasis, Leterer-Siwe disease, leukemia, lipogranulomas, lymphocytic leukemias, lymphoma, malabsoφtion syndromes, malaria, malignant lymphoma, megakaryoblastic leukemia, metastatic tumor, monocytic leukemias, mucopolysaccharidoses, multicentric Castleman's disease, multiple myeloma, myelocytic leukemias, myelofibrosis, myeloproliferative syndromes, neoplasms, Niemann-Pick disease, non-Hodgkin's lymphoma, parasitic disorders, parasitized red blood cells, peliosis, polycythemia rabra vera, portal vein congestion, portal vein stenosis, portal vein thrombosis, portal venous hypertension, rheumatoid arthritis, right-sided cardiac failure, sarcoidosis, sarcoma, secondary amyloidosis, secondary myeloid metaplasia, serum sickness, sickle-cell disease, splenic cysts, splenic infarction, splenic vein hypertension, splenic vein stenosis, splenic vein thrombosis, splenomegaly, storage diseases, systemic lupus erythematosus, systemic vascuhtides, T- cell chronic lymphocytic leukemia, thalasemia, thrombocytopenic puφura, thyrotoxicosis, trapping of immature hematologic cells, tuberculosis, tumorlike conditions, typhoid fever, vascular tumors, vasculitis, and viral infections.
Stomach. Nuclear receptors expressed in the stomach are listed in Table 28.
These receptors are thus potential targets for therapeutic compounds that may modulate the activity, expression, or stability in the stomach. These polypeptides, or polymoφhs of these polypeptides, may form the basis' of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the stomach, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 28. Nuclear Receptors Expressed in the Stomach
Figure imgf000184_0001
Exemplary diseases and disorders of the stomach include acute erosive gastropathy, acute gastric ulcers, adenocarcinomas, adenomas, adenomatous polyps, advanced gastric cancer, ampullary carcinoma, atrophic gastritis, bacterial gastritis, carcinoid tumors, carcinoma of the stomach, chemical gastritis, chronic (nonerosive) gastritis, chronic idiopathic gastritis, chronic nonatrophic gastritis, Cronkite-Canada syndrome, congenital cysts, congenital diaphragmatic hernias, congenital diverticula, congenital duplications, congenital pyloric stenosis, congestive gastropathy, cyclic vomiting syndrome, decreased mucosal resistance to acid, diffuse or infiltrating adenocarcinoma, early gastric cancer, emphysematous gastritis, endocrine cell hypeφlasia, environmental gastritis, eosinophilic gastritis, eosinophilic gastroenteritis, epithelial polyps, erosive (acute) gastritis, fundic gland polyps, fungal gastritis, gangliocytic paragangliomas, gastral antral vascular ectasia, gastric adenocarcinoma, gastric outlet obstruction (pyloric stenosis), gastric ulcers, gastritis, gastroesophageal reflux, gastroparesis, granulomatous gastritis, H. pylori infection, hamartomatous polyps, heterotopias, heterotopic pancreatic tissue, heterotopic polyps, hypeφlastic gastropathy, hypeφlastic polyps, hypersecretion of acid, infectious gastritis, inflammatory lesions of the stomach, inflammatory polyps, intestinal metaplasia, invasive carcinoma, ischemia, leiomyoma, linitis plastica, luminally acting toxic chemicals, lymphocytic gastritis, lymphomas, malignant gastric stromal neoplasms, malignant lymphoma, malignant transformation of a benign gastric ulcer, Menentrier's disease (hypertrophic gastritis, ragal hypertrophy), mesenchymal neoplasms, metastatic tumors, mucosal polyps, myoepithelial adenomas, myoepithelial hamartomas, neoplasms, neuroendocrine hypeφlasias, neuroendocrine tumors, nonerosive gastritis and stomach cancer, nonneoplastic polyps, parasitic gastritis, peptic ulcer disease, phlegmonous gastritis, plasma cell gastritis, polypoid (fungating) adenocarcinoma, poorly differentiated neuroendocrine carcinomas, precancerous lesions, Puetz-Jeghers syndrome, pyloric atresia, rapid gastric emptying, reflux of bile, stress ulcers, stromal tumors, superficial gastritis, type A chronic gastritis (autoimmune gastritis and pernicious anemia), type B chronic gastritis (chronic antral gastritis, H. pylori gastritis), ulcerating adenocarcinoma, vasculitis, viral gastritis, xanthomatous gastritis, and Zollinger-EUison syndrome.
Testes. Nuclear receptors expressed in the testes are listed in Table 29. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability of the nuclear receptor in the testes. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder involving the testes, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Figure imgf000185_0001
Exemplary diseases and disorders involving the testes include abenant ducts of Haller, abnormal productions of hormones, abnormalities of testicular descent, acute epididymoorhcitis, adenomatoid tumor, adenomatous hypeφlasia of the rete testis, adenovirus, administration of estrogens, adrenal rests, alcoholic cinhosis, amyloidosis, anorchism, appendix testes, bacterial infections, Bracella, cachexia, carcinoma in situ, carcinoma of the rete testis, chlamydia, choriocarcinoma, choristomas, chronic fibrosing epididymoorchitis, coxsackie virus B, cryptorchidism, cystic dysplasia of the rete testis, cytomegalovirus, dystopia, E. coli infection, Echinococcus granulosus, ectopic testes, embryonal carcinoma, epididymoorchitis, Foumier's scrotal gangrene, fungal infection, germ cell aplasia, germ cell neoplasms, gonadal dysgenesis, gonadal stromal neoplasms, granulomatous orchitis, granulosa cell tumors, Haemophilus influenzae, HIV, hypergonadism, hypσgonadotropic hypogonadism, hypopituitarism, hypospermatogenesis, hyrocele, idiopathic granulomatous orchitis, incomplete maturation anest, infarction, infertility, inflammatory diseases, inflammatory lesions, interstitial (Leydig) cell tumors, Klinefelter's syndrome, latrogenic lesions, Leydig cell tumors, malakoplakia, malignant lymphoma, malnutrition, maturation anest of spermatogenesis, metastatic tumors, mixed germ cell tumors, monorchism, mumps orchitis, mycobacteria, Neisseria gonorrhoeae infection, neoplasms, obstruction to outflow of semen, orchitis, parasitic infection, polyorchidism, radiation, Salmonella, sarcoidosis, Schistosoma haematobium infection, seminoma, Sertoli cell tumors, sex cord stromal tumors, sperm granuloma, spermatocytic seminoma, syphilis, teratocarcinoma, teratoma, testicular atrophy, testicular neoplasms, testicular torsion, Treponema pallidum infection, tuberculous epididymoorchitis, tumors of nonspecific stroma, undescended testes, uropathogens, varicocele, vascular disturbances, vasculitis, viral infection, Wuchereria bancrofti infection, and yolk sac carcinoma.
Thymus. Nuclear receptors expressed in the thymus are listed in Table 30. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the thymus. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the thymus, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Figure imgf000187_0001
Exemplary diseases and disorders of the thymus include accidental involution, acute accidental involution, acute lymphoblastic leukemia of T cell type, agenesis, age- related involution, anaplastic carcinoma, ataxia telangiectasia, atrophy, bacterial infections, bacterial mediastinitis, basaloid carcinoma, bone manow transplantation, Braton's agammaglobulinemia, carcinosarcoma, chronic accidental involution, clear cell carcinoma, cortical thymoma, cytomegalovirus, DiGeorge syndrome, dysgenesis, dysplasia with pattern similar to severe atrophy, dysplasia with pseudoglandular appearance, dysplasia with stromal conticomedullary differentiation, ectopia, germ cell tumors, Grave's disease, histiocytosis X, HIV, Hodgkin's disease, hypeφlasia, infectious mononucleosis, involution, lymphoblastic lymphoma of T-cell type, lymphoepithelioma-like carcinoma, lymphofollicular thymitis, maldescent, malignant lymphomas, malignant thymoma, measles giant cell pneumonia, medullary thymoma, mixed (composite) thymoma, mucoepidermoid carcinoma, myasthenia gravis, neonatal syphilis, neoplasms, Omenn's syndrome, predominantly cortical (organoid) thymoma, primary mediastinal B-cell lymphoma of high-grade malignancy, sarcomatoid carcinoma, seminoma, severe combined immunodeficiency, short limb dwarfism, simple dysplasia, small cell carcinoma, small-cell B-cell lymphoma of MALT type, squamous cell carcinoma, systemic lupus erythematosus, teratoma, thymic carcinoid, thymic carcinoma, thymic cysts, thymic epithelial cysts, thymic epithelial tumors, thymic neoplasms, thymitis with diffuse B-cell infiltrations, thymolipoma, thymoma, true thymic hypeφlasia, varicella-zoster, viral infections, well differentiated thymic carcinoma, and Wiscott-Aldrich syndrome.
Thyroid. Nuclear receptors expressed in the thyroid are listed in Table 31. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the thyroid. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeμtic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the thyroid, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Figure imgf000188_0001
Exemplary diseases and disorders of the thyroid include abenant thyroid glands, accessory thyroid glands, adenoma with bizane nuclei, agenesis, amphicrine variant of medullary carcinoma, anaplastic (undifferentiated) carcinoma, aplasia, atrophic thyroiditis, atypical adenoma, autoimmune thyroiditis, carcinoma, C-cell hypeφlasia, clear cell tumors, clear cell, variant of medullary carcinoma, colloid adenoma, columnar variant of papillary carcinoma, congenital hypothyroidism (cretinism), diffuse nontoxic goiter, diffuse sclerosing variant of papillary carcinoma, dyshormonogenic goiter, embryonal adenoma, encapsulated variant of papillary carcinoma, endemic cretinism, endemic goiter, enzyme deficiency, fetal adenoma, follicular adenoma, follicular carcinoma, follicular variant of medullary carcinoma, follicular variant of papillary carcinoma, fungal infection, giant cell variant of medullary carcinoma, goiter induced by antithyroid agents, goitrous hypothyroidism, Graves' disease, Hashimoto's autoimmune thyroiditis', Hϋrthle cell (oncocytic) adenoma, hyalinized trabecular adenoma, hyperthyroidism, hypothyroid cretinism, hypothyroidism, iodine deficiency, juvenile thyroiditis, latrogenic hypothyroidism, lingual thyroid glands, malignant lymphoma, medullary carcinoma, melanocytic variant of medullary carcinoma, mesenchymal tumors, metastatic tumors, minimally invasive follicular carcinoma, mixed medullary and follicular carcinoma, mixed medullary and papillary carcinoma, mucinous carcinoma, mucoepidermoid carcinoma, multinodular goiter, myxedema, neoplasms, neurologic cretinism, nonspecific lymphocytic (simple chronic) thyroiditis, oncocytic variant of medullary carcinoma, palpation thyroiditis, papillary carcinoma, papillary microcarcinoma, papillary variant of medullary carcinoma, partial agenesis, pituitary thyrotropic adenoma, poorly differentiated carcinoma, primary hypothyroidism, pseudopapillary variant of medullary carcinoma, Riedel's thyroiditis, sclerosing mucoepidermoid carcinoma with eosinophilia, silent thyroiditis, simple adenoma, small cell variant of medullary carcinoma, solitary thyroid nodule, sporadic goiter, squamous cell carcinoma, squamous variant of medullary carcinoma, subacute throiditis (DeQuervain, granulomatous, giant cell thyroiditis), tall cell variant of papillary carcinoma, tertiary sypliilis, thyroglossal duct cyst, thyroid agenesis, thyroid nodules, thyroiditis, thyrotoxicosis, toxic adenoma, toxic multinodular goiter, toxic nodular goiter (Plummer's disease), tuberculosis, tubular variant of medullary carcinoma, and widely invasive follicular carcinoma.
Uterus. Nuclear receptors expressed in the uteras are listed in Table 32. These receptors are thus potential targets for therapeutic compounds that may modulate their activity, expression, or stability in the uteras. These polypeptides, or polymoφhs of these polypeptides, may form the basis of a therapeutic regimen, or a diagnostic test to determine, e.g., the presence of a disease or disorder of the uteras, the risk of developing a particular disease or disorder, or an appropriate therapeutic course.
Table 32. Nuclear Receptors Expressed in the Uterus
Figure imgf000189_0001
Exemplary diseases and disorders of the uteras include acute cervicitis, acute endometritis, adenocanthoma, adenocarcinoma, adenocarcinoma in situ, adenoid cystic carcinoma, adenomatoid tumor, adenomyoma, adenomyosis (endometriosis intema), adenosquamous carcinoma, amebiasis, arias-Stella phenomenon, atrophy of the endometrium, atypical hypeφlasia, benign polypoid lesions, benign stromal nodule, carcinoid tumors, carcinoma in situ, cervical intraepithelial neoplasia, chlamydia, chronic cervicitis, chronic nonspecific endometritis, ciliated (tubal) metaplasia, clear cell adenocarcinoma, clear cell carcinoma, clear cell metaplasia, complex hypeφlasia with atypia, complex hypeφlasia without atypia, condyloma aduminatum, congenital abnormalities, coφus cancer syndrome, cystic hypeφlasia, dysfunctional uterine bleeding, dysmenonhea, dysplasia of the cervix (cervical intraepithelial neoplasia, squamous intraepithelial lesion), endocervical adenocarcinoma, endocervical polyp, endolymphatic stromal myosis, endometrial adenocarcinoma, endometrial carcinoma, endometrial hypeφlasia, endometrial polyps, endometrial stromal neoplasms, endometriosis, endometritis, endometroid (pure) adenocarcinoma of the endometrium, endometroid adenocarcinoma with squamous differentiation, eosinophilic metaplasia, epimenonhea, exogenous progestational hormone effect, extrauterine endometriosis (endometriosis extemia), gestational trophoplastic disease, gononhea, hemangioma, heφes simplex virus type 2, high-grade squamous intraepithelial lesion, human papillomaviras, hypeφlasia, inadequate luteal phase, infertility, inflammatory cervical lesions, inflammatory lesions of the endometrium, intravenous leiomyomatosis, invasive carcinoma of cervix, invasive squamous cell carcinoma, leiomyoma, leiomyosarcoma, lipoma, low-grade squamous intraepithelial lesion, malignant mixed mesodermal (Mϋllerian) tumor, menonhagia, metaplasia, metastasizing leiomyoma, metastatic carcinoma, microglandular hypeφlasia, microinvasive carcinoma, microinvasive squamous cell carcinoma, mucinous adenocarcinoma, mucinous metaplasia, neoplasms of the cervix, neoplasms of the endometrium, neoplasms of the myometrium, nonneoplastic cervical proliferations, papillary synctial metaplasia, papilloma, pelvic inflammatory disease, peritoneal leiomyomatosis, persistent luteal phase, postmenopausal bleeding, serous papillary adenocarcinoma, simple hypeφlasia with atypia, simple hypeφlasia without atypia, spontaneous abortion, squamous carcinoma, squamous cell neoplasia, squamous intraepithelial lesions, squamous metaplasia, squamous metaplasia (acanthosis), stromal sarcoma, tuberculous endometritis, unopposed estrogen effect, uterine leiomyomata, verracou carcinoma, vestigial and heterotopic structures, villoglandular papillary adenocarcinoma, and viral endometritis. Other Tissues
Nuclear receptors listed in Table 1 may also be expressed in the pancreas, bone and joints, breasts, immune system, or systemically. These nuclear receptors may thus be involved in metabolic diseases or disorders and diseases or disorders of the pancreas, bone and joints, breast, or immune system. Any nuclear receptors involved in these diseases are targets for diagnostic tests, drag design, and therapy.
Exemplary diseases and disorders of the pancreas include ACTHoma, acute pancreatitis, adult onset diabetes, annulare pancreas, carcinoid syndrome, carcinoid tumors, carcinoma of the pancreas, chronic pancreatitis, congenital cysts, Cushing's syndrome, cystadenocarcinoma, cystic fibrosis (mucoviscidosis, fibrocystic disease), diabetes mellitus, ectopic pancreatic tissue, gastinoma, gastrin excess, glucagon excess, glucagonomas, GRFomas, hereditary pancreatitis, hyperinsulinism, impaired insulin release, infected pancreatic necrosis, insulin resistance, insulinomas, islet cell hypeφlasia, islet cell neoplasms, juvenile onset diabetes, macroamylasemia, maldevelopment of the pancreas, maturity-onset diabetes of the young, metastatic neoplasms, mucinous cystadenoma, neoplastic cysts, nonfunctional pancreatic endocrine tumors, pancreas divisum, pancreatic abcess, pancreatic cancer, pancreatic cholera, pancreatic cysts, pancreatic endocrine tumor causing carcinoid syndrome, pancreatic endocrine tumor causing hypercalcemia, pancreatic endocrine tumors, pancreatic exocrine insufficiency, pancreatic pleural effusion, pancreatic polypeptide excess, pancreatic pseudocyst, pancreatic trauma, pancreatogenous ascites, serous cystadenoma, Shwachman's syndrome, somatostatin excess, somatostatinoma syndrome, traumatic pancreatitis, type 1 (insulin-dependent) diabetes, type 2 (non-insulin-dependent) diabetes, vasoactive intestinal polypeptide excess, VIPomas, and Zollinger-Ellison syndrome.
Exemplary diseases and disorders of the bone and joints include achondroplasia, acute bacterial arthritis, acute pyogenic osteomyelitis, Albright's syndrome, alkaptonuria (ochronosis), aneurysmal bone cyst, ankylosing spondyhtis, arthritic, arthropathies associated with hemoglobinopathies, arthropathy of acromegaly, arthropathy of hemochromatosis, bone cysts, calcium hydroxyapatite deposition disease, calcium pyrophosphate deposition disease, chondrocalcinosis, chondroma, chondrosarcoma, chostochondritis, chrondromblastoma, congenital dislocation of the hip, congenital disorders of joints, echondromatosis (dyschondroplasia, Ollier's disease), erosive osteoarthritis, Ewing's sarcoma, Felty's syndrome, fibromyalgia, fibrous cortical defect, fibrous dysplasia (McCune- Albright syndrome, fungal arthritis, ganglion, giant cell tumor, gout, hematogenous osteomyelitis, hemophilic arthropathy, hereditary hypeφhosphatasia, hyperostosis, hyperostosis frontalis intema, hypeφarathyroidism (osteitis fibrosa cystica), hypertrophic osteoarthropathy, infections diseases of joints, juvenile rheumatoid arthritis (Still's disease), lyme disease, lymphoid neoplasms, melorheostosis, metabolic diseases of joints, metastatic carcinoma, metastatic neoplasms, monostatic fibrous dysplasia, multiple exostoses (diaphyseal aclasis, osteochondromatosis), neoplasms, neuropathic joint (Charcot's joint), osteoarthritis, osteoarthrosis, osteoblastoma, osteochondroma (exostosis), osteogenesis imperfecta (brittle bone disease), osteoid osteoma, osteoma, osteomalacia, osteomyelitis, osteomyelosclerosis, osteopetrosis (marbel bone disease, Albers-Schόnberg disease), osteopoikilosis, osteoporosis (osteopenia), osteosarcoma, osteosclerosis, Paget's disease of bone (osteitis deformans), parasitic arthritis, parosteal osteosarcome, pigmented villonodular synovitis, polyostotic fibrous dysplasia, postmfectious or reactive arthritis, progressive diaphyseal dysplasia (Camurati-Engelmann disease), pseudogout, psoriatic arthritis, pyknodysostosis, pyogenic arthritis, reflex sympathetic dystrophy syndrome, relapsing polychondritis, rheumatoid arthritis, rickets, senile osteoporosis, sickle cell disease, spondyloepiphyseal dysplasia, synovial chondromatosis, synovial sarcoma, syphilitic arthritis, talipes calcaneovalgus, talipes equinovaras, thalassemia, Tietze's syndrome, tuberculosis of bone, tuberculous arthritis, unicameral bone cyst (solitary bone cyst), and viral arthritis.
Exemplary diseases and disorders of the immune system include abnormal neutrophil function, acquired immunodeficiency, acute rejection, Addison's disease, ' advanced cancer, aging, allergic rhinitis, angioedema, arthras-type hypersensitivity reaction, ataxia-telangiectasia, autoimmune disorders, autoimmune gastritis, autosomal recessive agammaglobulinemia, blood transfusion reactions, Bloom's syndrome, Braton's congenital agammaglobulinemia, bullous pemphigoid, Chediak-Higashi syndrome, chronic active hepatitis, chronic granulomatous disease of childhood, chronic rejection, chronic renal failure, common variable immunodeficiency, complement deficiency, congenital (primary) immunodeficiency, contact dermatitis, deficiencies of immune response, deficiency of the vascular response, dermatomyositis, diabetes mellitus, disorders of microbial killing, disorders of phagocytosis, Goodpasture's syndrome, graft rejection, graft-versus-host disease, granulocyt deficiency, granulocytic leukemia, Graves' disease, Hashimoto's thyroiditis, hemolytic anemia, hemolytic disease of the newborn, HIV infection (AIDS), Hodgkin's disease, hyperacute rejection, hyper-IgE syndrome, hypersensitivity pneumonitis, hypoparathyroidism, IgA deficiency, IgG subclass deficiencies, immunodeficiency with thymoma, immunoglobulin deficiency syndromes, immunologic hypersensitivity, immunosupressive drag therapy, infertility, insulin-resistant diabetes mellitus, interferon γ receptor deficiency, interleukin 12 receptor deficiency, iron deficiency, juvenile insulin-dependent diabetes mellitus, Kaposi's sarcoma, lazy leukocyte syndrom, localized type 1 hypersensitivity, lymphocytic leukemia, lymphoma, malignant B cell lymphoma, major histocompatibility complex class 2 deficiency, mixed connective tissue disease, multiple myeloma, myasthenia gravis, myeloperoxidase deficiency, neutropenia, nude syndrome, pemphigus vulgaris, pernicious anemia, postmfectious immunodeficiency, primary biliary cinhosis, primary immunodeficiency, primary T cell immunodeficiency, progressive systemic sclerosis, protein-calorie malnutrition, purine nucleoside phosphorylation deficiency, rheumatic fever, rheumatoid arthritis, secondary immunodeficiency, selective (isolated) IgA deficiency, serum sickness type hypersensitivity reaction, severe combined immunodeficiency, Sjόgren's syndrome, sympathetic ophthalmitis, systemic lupus erythematosus, systemic mastocytosis, systemic type 1 hypersensitivity, T cell receptor deficiency, T lymphopenia (Nezelof s syndrome), thrombocytopenia, thymic hypoplasia (DiGeorge syndrome), thymic neoplasms, thymoma (Goode's syndrome), transient hypogammaglobulinemia of infancy, type 1 (immediate) hypersensitivity (atopy, anaphylaxis), type 2 hypersensitivity, type 3 hypersensitivity (immune complex injury), type 4 (delayed) hypersensitivity, urticaria, variable immunodeficiency, vitiligo, Wiskott-Aldrich syndrom, x-linked agammaglobulinemia, x-linked immunodeficiency with hyper IgM, x-linked lymphoproliferative syndrome, and zap70 tyrosine kinase deficiency.
Exemplary diseases and disorders of the breasts include acute mastitis, breast abcess, carcinoma, chronic mastitis, congenital breast anomalies, cystic mastopathy, ductal carcinoma, ductal carcinoma in situ, ductal papiUoma, fat necrosis, fibroadenoma, fibrocystic changes, fibrocystic disease, galactonhea, granular cell tumor, gynecomastia, infiltrating ductal carcinoma, inflammatory breast carcinoma, inflammatory breast lesions, invasive lobular carcinoma, juvenile hypertrophy of the breast, lactating adenoma, lobular carcinoma in situ, neoplasms, Paget's disease of the nipple, phyllodes tumor (cystosarcome phyllodes), polymastia, polymazia, polythelia, silicone granuloma, supernumerary breast, and supernumerary nipples.
Exemplary metabolic or nutritive diseases or disorders include 5,10- methylenetetrahydrofolate reductase deficiency, achondrogenesis type IB, acid α-1,4 glucosidase deficiency, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Banaquer-Simons syndrome), acute intermittent poφhyria, acute panniculitis, adenine phosphoribosyltransferase deficiency, adenosine deaminase deficiency, adenylosuccinate lyase deficiency, adiposis dolorosa (Dercum disease), ALA dehydratase-deficient poφhyria, albinism, alkaptonuria, amulopectinosis, Andersen disease, argininemia, argininosuccinic aciduria, astelosteogenesis type 2, Bartter's syndrome, benign familial neonatal epilepsy, benign fructosuria, benign recunent and progressive familial intrahepatic cholestasis, biotin deficiency, branching enzyme deficiency, calcium deficiency, carnitine transport defect, choline deficiency, choline toxicity, chromium deficiency, clironic fat malabsoφtion, citrallinemia, classic branched-chain ketoaciduria, classic cystinuria, congenital chloridonhea, congenital erythropoietic poφhyria, congenital generalized lipodystrophy, congenital myotonia, copper deficiency, copper toxicity, cystathionine β-synthase deficiency, cystathioninuria, cystic fibrosis, cystinosis, cystinuria, Darier disease, defect in transport of long-chain fatty acids, deficiency of cobalamin coenzyme deficiency, Dent's syndrome, diatrophic dysplasia, dibasic aminoaciduria, dicarboxylic aminoaciduria, dihydropyrimidine dehydrogenase deficiency, distal renal tubular acidosis, dry beriberi, Dubin- Johnson syndrome, dysbetalipoproteinemia, end-organ insensitivity to vitamin D, erythropoietic protopoφhyria, Fabry disease, failure of intestinal absoφtion, familial apoprotein C2 deficiency, familial combined hyperlipidemia, familial defective Apo B100, familial goiter, familial hypercholesterolemia, familial hypertriglyceridemia, familial hypophosphatemic rickets, familial lipoprotein lipase deficiency, familial partial lipodystrophy, Fanconi-Bickel syndrome, fluoride deficiency, folate malabsoφtion, folic adic deficiency, formiminoglutamic aciduria, fructose 1,6 diphosphatase deficiency, galactokinase deficiency, galactose 1 -phosphate uridyl transferase deficiency galactosemia, Gaucher disease, Gitelman's syndrome, globoid cell leukodystrophy, glucose-6-phosphatease deficiency, glucose-6-translocase deficiency, glucose-galactose malabsoφtion, glucose-transporter protein syndrome, glutaric aciduria, glycogen storage disease type 2, glycogen storage disease type lb, glycogen storage disease type ID, glycogen synthase deficiency, gout, Hartnup disease, hawkinsinuria, hemochromatosis, hepatic glycogenosis with renal fanconi syndrome, hepatic lipase deficiency, hepatic poφhyria, hereditary copropoφhyria, hereditary fructose intolerance, hereditary xanthinuria, Hers disease, histidinemia, histidmuria, HIV-1 protease inhibitor-induced lipodystrophy, homocitruUinuria, homocystinuria, homocystinuria, homocystinuria and methylmalonic acidemia, homocystinurias, Hunter syndrome, Hurler disease, Hurler- Scheie disease, hyophosphatemic rickets, hyperammonemia, hyperammonemia, hypercholesterolemia, hypercystinuria, hyperglycinemia, hyperhydroxyprolinemia, hyperkalemic periodic paralysis, hyperleucmeisoleucinemia, hyperlipoprotememias, hyperlysinemia, hypermagnesemia, hypermetabolism, hypermethioninemia, hyperomithinemia, hyperoxaluria, hypeφhenylalaninemia with primapterinuria, hypeφhenylalaninemias, hypeφhosphatemia, hypeφrolinemia, hypertriglyceridemia, hyperuricemia, hypervalinemia, hypervitaminosis A, hypervitaminosis D, hypocholesterolemia, hypometabolism, hypophosphatemia, hypouricemia, hypovitaminosis A, hypoxanthine phosphoribosyltransferase deficiency, iminoglycinuria, iminopeptiduria, intermittent branched-chain ketoaciduria, intestinal malabsoφtion, iodine deficiency, iron deficiency, iso valeric acidemia, Jervell and Lange-Nielsen syndrome, juvenile pernicious anemia, keshan disease, Korsakoff s syndrome, kwashiorkor, leukodystrophies, Liddle's syndrome, lipodystrophies, lipomatosis, liver glycogenoses, liver phosphorylase kinase deficiency, long QT syndrome, lysinuria, lysosomal storage diseases, magnesium deficiency, malabsoφtive diseases, malignant hypeφhenylalaninemia, manganese deficiency, marasmus, Maroteaux-Lamy disease, McArdle disease, Menkes' disease, metachromatic leukodystrophy, methionine malabsoφtion, methylmalonic acidemia, molybdenum deficiency, monosodiumurate gout, Morquio syndrome, mucolipidoses, mucopolysaccharidoses, multiple carboxylase deficiency syndrome, multiple symmetric lipomatosis, Madelung disease, muscle glycogenoses, muscle phosphofructokinase deficiency, muscle phosphorylase deficiency, myoadenylate deaminase deficiency, nephrogenic diabetes insipidus, nesidioblastosis of pancreas, niacin deficiency, niacin toxicity, Niemann-Pick disease, obesity, orotic aciduria, osteomalacia, paramyotonia congenita, pellagra, Pendred syndrome, phenylketonuria, phenylketonuria type 1 , phenylketonuria type 2, phenylketonuria type 3, phosphate deficiency, phosphoribosylpyrophosphate synthetase overactivity, polygenic hypercholesterolemia, Pompe disease, poφhyria cutanea tarda, poφhyrias, primary bile acid malabsoφtion, primary hyperoxaluria, primary hypoalphalipoproteinemia, propionic acidemia, protein- energy malnutrition, proximal renal tubular acidosis, purine nucleoside phosphorylase deficiency, pyridoxine deficiency, pyrimidine 5'-nucleotidase deficiency, renal glycosuria, riboflavin deficiency, rickets, Rogers' syndrome, saccharopinuria, Sandhoff disease, Sanfilippo syndromes, sarcosinemia, Scheie disease, scurvy (vitamin C deficiency), selenium deficiency, selenosis, sialic acid storage disease, S-sulfo-L- cysteine, sulfite, thiosulfaturia, Tarai disease, Tay-Sachs disease, thiamine deficiency, tryptophan malabsoφtion, tryptophanuria, type 1 pseudohypoaldosteromsm, type 3 glycogen storage disease (debrancher deficiency, limit dextrinosis), tyrosinemia, tyrosinemia type 1, tyrosinemia type 2, tyrosinemia type 3, uridine diphosphate galactose 4-epimerase deficiency, urocanic aciduria, variegate poφhyria, vitamin B 12 deficiency, vitamin C toxicity, vitamin D deficiency, vitamin D-resistant rickets, vitamin d-sensitive rickets, vitamin E deficiency, vitamin E toxicity, vitamin K deficiency, vitamin K toxicity, von Gierke disease, Wernicke's encephalopathy, wet beriberi, Wilson's disease, xanthurenic aciduria, X-linked sideroblastic anemia, zinc deficiency, zinc toxicity, α-ketoadipic aciduria, α-methylacetoacetic aciduria, β-hydroxy-β- methylglutaric aciduria, and β-methylcrotonyl glycinuria. . *
Therapeutic Compounds
A large number of nuclear receptors are found in the nervous system. Over 89% of known nuclear receptors are active in the nervous system. Of particular importance is that up to 79% of the known nuclear receptors in the nervous system are active in the HAP (Hypothalamus, Amygdala and Pituitary). We hypothesize that the majority of these receptors serve as modulators of behavior, memory, cognition, pain and instinctive functions.
Nuclear receptors are ideal targets for drug development. They are located in the cytoplasm of cells, where they can be accessed by pharmaceutical compounds. There are significant numbers and varieties of nuclear receptors to provide for a high degree of specificity, a key requirement, in the discovery of medicines with few or limited side effects. Given these properties, nuclear receptors, as a group, have emerged among the most coveted targets for drug development. The preference for nuclear receptors as specific drug targets derives, not only from their central role in biological processes, but also from the discriminating ability that these molecules have in recognizing and responding to their signals. Many nuclear receptors exist in several similar, but subtly distinct subtypes, which are found in different cells in the body. Such variety of sequence and location provides a high degree of selectivity, allowing the discovery of drags which specifically affect one subtype of receptor, but not another. This selectivity substantially reduces the risk of unwanted side effects.
Nuclear receptor polypeptides of the present invention have one or more biological functions that may be of relevance in one or more behavioral disorders, in particular the disorders of the invention hereinbefore mentioned. As the nuclear receptor polypeptides maybe expressed in other organs and tissues of the body, they may be of relevance to diseases and disorders that involve those organs and tissues. It is therefore useful to identify compounds that modulate nuclear receptor biological activity, expression level, or stability. Accordingly, in a further aspect, the present invention provides methods of screening candidate compounds to identify those that modulate nuclear receptor biological activity, expression level, or stability. Such methods identify potential modulators, e.g., agonists or antagonists that may be employed for therapeutic and prophylactic puφoses for treating various disorders, e.g., behavioral disorders. Compounds may be identified from a variety of sources, for example, cells, cell-free preparations, chemical libraries, collections of chemical compounds, and natural product mixtures. Modulators so identified may be natural or modified ligands, or small molecules. Such small molecules preferably have a molecular weight below 2,000 daltons, more preferably between 300 and 1,000 daltons, and most preferably between 400 and 700 daltons. It is prefened that these small molecules be organic molecules. The screening method may simply measure the interaction of a candidate compound to the polypeptide, or to cells or membranes bearing the polypeptide, or a fusion protein thereof, by means of a label directly or indirectly associated with the candidate compound, or, alternatively, the polypeptide. Alternatively, the screening method may involve measuring or detecting (qualitatively or quantitatively) the competitive interaction of a candidate compound to the polypeptide against a labeled competitor (e.g., agonist or antagonist). Further, these screening methods may test whether the candidate compound results in a signal generated by activation or inhibition of nuclear receptor polypeptide, using detection systems appropriate to the cells bearing the polypeptide. Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist by the presence of the candidate compound is observed. Further, the screening methods may include the steps of mixing a candidate compound with a solution containing a nuclear receptor polypeptide of the present invention, to form a mixture, measuring nuclear receptor biological activity in the mixture, and comparing the nuclear receptor activity of the mixture to a control mixture that contains no candidate compound.
Polypeptides of the present invention may be employed in conventional low capacity screening methods and also in high-tliroughput screening (HTS) formats. Such HTS formats include not only the well-established use of 96- and, more recently, 384- well and 1536-well micotiter plates, but also emerging methods such as the nanowell method described by Schullek et al, Anal Biochem., 246, 20-29, (1997).
Fusion proteins and tagged recombinant proteins, such as those made from the Fc portion of an antibody and a nuclear receptor polypeptide or epitope tagged nuclear receptor, can also be used for high-throughput screening (HTS) assays to identify modulators of the nuclear receptor polypeptides of the present invention (see, e.g., Bennett et al., J Mol Recognition, 8:52-58 (1995); and Johanson et al., J Biol Chem, 270:9459-9471 (1995)).
Drug Screening
A nuclear receptor of the invention and its gene or cDNA can be used in screening assays for identification of compounds that modulate its activity and which may therefore be potential drugs. Useful proteins include wild-type and polymoφhic nuclear receptors or fragments thereof (e.g., ligand binding domain, dimerization domain or DNA binding domain), in a recombinant form or endogenously expressed. Drug screens to identify compounds acting on a normally occurring or an exogenously expressed nuclear receptor may employ any functional feature of the protein. In one example, transcriptional activation or repression is monitored as a measure of nuclear receptor biological activity. .
Drag screening assays can also be based upon the ability of a nuclear receptor to interact with other proteins or to dimerize. Such interacting proteins can be identified by a variety of methods known in the art, including, for example, radioimmunoprecipitation, co-immunoprecipitation, co-purification, and yeast two- hybrid screening. Such interactions can be further assayed by means including but not limited to fluorescence polarization or scintillation proximity methods. Drug screens can also be based upon putative functions of a nuclear receptor polypeptide deduced from structure determination (e.g., by x-ray crystallography) of the protein and comparison of its 3-D structure to that of proteins with known functions. Molecular modeling of compounds that bind to the protein using a 3-D structure may also be used to determine drug candidates. Drag screens can be based upon a function or feature apparent upon creation of a transgenic or knock-out mouse, or upon overexpression of the protein or protein fragment in mammalian cells in vitro. Moreover, expression of a mammalian (e.g., human) nuclear receptor in yeast or C. elegans allows for screening of candidate compounds in wild-type and polymoφhic backgrounds, as well as screens for polymoφbisms that enhance or suppress a nuclear receptor-dependent phenotype. Modifier screens can also be performed in a nuclear receptor transgenic or knock-out mouse.
Additionally, drug screening assays can be based upon nuclear receptor functions deduced upon antisense nucleic acid inl ibition or RNA interference (RNAi) with the nuclear receptor's gene function. Intracellular localization of a nuclear receptor, or effects which occur upon a change in intracellular localization of the protein, can also be used as an assay for drug screening. Immunocytochemical methods can be used to determine the exact location of a nuclear receptor protein.
Human and rodent nuclear receptors or peptides derived from nuclear receptors can be used as antigens to raise antibodies, including monoclonal antibodies. Such antibodies will be useful for a wide variety of puφoses, including but not limited to functional studies and the development of drag screening assays and diagnostics. Monitoring the influence of agents (e.g., drags, compounds) on the expression or biological activity of a nuclear receptor can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase gene expression, protein levels, or biological activity of a nuclear receptor can be monitored in clinical trials of subjects exhibiting altered gene expression, protein levels, or biological activity of that nuclear receptor. Alternatively, the effectiveness of an agent determined by a screening assay to modulate the gene expression, protein levels, or biological activity of a nuclear receptor can be monitored in clinical trials of subjects exhibiting decreased altered gene expression, protein levels, or biological activity. In such clinical trials, the expression or activity of a nuclear receptor and, preferably, other genes that have been implicated in one or more diseases or disorders can be used to ascertain the effectiveness of a particular drug.
For example, and not by way of limitation, genes that are modulated in cells by treatment with an agent (e.g., compound, drag, or small molecule) that modulates the biological activity of a nuclear receptor polypeptide (e.g., identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on one or more diseases or disorders in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of a nuclear receptor and other genes implicated in the disorder. The levels of gene expression can be quantified by northern blot analysis or RT-PCR, followed by real time PCR, or, alternatively, by measuring the amount of protein produced, by one of a number of methods known in the art, or by measuring the levels of biological activity of a nuclear receptor or other genes. In this way, the expression of a nuclear receptor polypeptide can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent. For in vivo studies MRI, pet scans etc may be better assays. In one embodiment, the present invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drag candidate identified by the screening assays described herein) including the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a nuclear receptor polypeptide, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of a nuclear receptor polypeptide, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of a nuclear receptor polypeptide, mRNA, or genomic DNA in the pre-administration sample with the polypeptide, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of a nuclear receptor polypeptide to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of a nuclear receptor polypeptide to lower levels than detected. A nuclear receptor polynucleotide can be used as a tool to express the nuclear receptor polypeptide in an appropriate cell in vitro or in vivo (gene therapy), or can be cloned into expression vectors that can be used to produce large enough amounts of a nuclear receptor polypeptide for use in in vitro assays for drag screening. Expression systems that may be employed include baculovirus, heφes viras, adenovirus, adeno- associated viras, bacterial systems, and eukaryotic systems such as CHO cells. Naked DNA and DNA-liposome complexes can also be used.
Assays of nuclear receptor activity include binding to intracellular interacting proteins. Furthermore, assays may be based upon the molecular dynamics of macromolecules, metabolites, and ions by means of fluorescent-protein biosensors. Alternatively, the effect of candidate modulators on expression or activity- may be measured at the level of nuclear receptor production using the same general approach in combination with standard immunological detection techniques, such as western blotting or immunoprecipitation with a nuclear receptor polypeptide-specific antibody. Again, useful modulators are identified as those that produce a change in nuclear receptor polypeptide production. Modulators may also affect nuclear receptor activity without any effect on expression level.
Candidate modulators may be purified (or substantially purified) molecules or maybe one component of a mixture of compounds (e.g., an extract or supernatant obtained from cells). In a mixed compound assay, nuclear receptor expression is tested against progressively smaller subsets of the candidate compound pool (e.g., produced by standard purification techniques, e.g., HPLC or FPLC) until a single compound or minimal compound mixture is demonstrated to modulate nuclear receptor expression. Alternatively, diverse mixtures (i.e., libraries) of test compounds maybe assayed in such a way that the pattern of response indicates which compounds in the various mixtures are responsible for the effect (deconvolution).
Agonists, antagonists, or mimetics found to be effective at modulating the level of cellular nuclear receptor expression or activity may be confirmed as useful in animal models (for example, mice, pigs, dogs, or chickens). For example, the compound may increase survival or mitigate distress in animal models of one or more diseases or disorders.
A gene encoding a nuclear receptor polypeptide may have a polymoφhism that may be, for example, a causative or risk factor of the diseases and disorders discussed below. Screening methods that identify polymoφhisms may be of diagnostic and therapeutic benefit. For example, early detection of a particular polymoφhism may enable preventative treatment or prediction of a patient's response (e.g., increased or decreased efficacy or undesirable side effects of treatment). Methods of identifying polymoφhisms include PCR, RT-PCR, northern blot (e.g., using clones encompassing discrete regions of cDNA), Southern blot, polymoφhic specific probes, sequencing analysis, hybridization assays, restriction endonuclease analysis, and exon-specific amplification.
One method for altering the biological activity of a nuclear receptor polypeptide is to increase or decrease the stabilization of the protein or to prevent its degradation. Thus, it would be useful to identify polymoφhisms in a nuclear receptor polypeptide that lead to altered protein stability. These polymoφhisms can be incoφorated into any protein therapy or gene therapy undertaken for the treatment of any condition resulting from loss of nuclear receptor biological activity. Similarly, compounds that increase the stability of a wild-type nuclear receptor polypeptide or decrease its catabolism may also be useful for the treatment of any condition resulting from loss of nuclear receptor biological activity. Such polymoφhisms and compounds can be identified using the methods described herein. In an analogous manner, decreasing stability may be used to, ' decrease the activity of a nuclear receptor.
In one example, cells expressing a nuclear receptor polypeptide having a polymoφhism are transiently metabohcally labeled during translation and the half-life of the nuclear receptor polypeptide is determined using standard techniques. Polymoφhisms that increase the half-life of a nuclear receptor polypeptide are ones that increase nuclear receptor protein stability. These polymoφhisms can then be assessed for biological activity. They can also be used to identify proteins that affect the stability of nuclear receptor mRNA or protein. One can then assay for compounds that act on these factors or on the ability of these factors to bind a nuclear receptor.
In another example, cells expressing a wild-type nuclear receptor polypeptide are transiently metabohcally labeled during translation, contacted with a candidate compound, and the half-life of the nuclear receptor polypeptide is determined using standard techniques. Compounds that modulate the half-life of a nuclear receptor polypeptide are useful compounds in the present invention.
If desired, treatment with a modulator of a nuclear receptor of the invention may be combined with any other therapy.
A nuclear receptor polypeptide (purified or unpurified) can be used in an assay to determine its ability to bind another protein (including, but not limited to, proteins found to specifically interact with a nuclear receptor). The effect of a compound on that binding is then determined. Methods of identifying compounds having the foregoing properties can be identified by standard methods known in the art. Exemplary methods for identifying compounds are described herein.
Identification of Molecules that Modulate Nuclear Receptor Biological Activity The effect of candidate compounds on nuclear receptor biological activity or cell survival may be measured at the level of translation by using the general approach described above with standard protein detection techniques, such as western blotting, sandwich or competitive immunoassays (both enzyme and radioactive tracer based) or immunoprecipitation with a nuclear receptor-specific antibody. Compounds that modulate the level of a nuclear receptor may be purified, or substantially purified, or may be one component of a mixture of compounds such as an extract or supernatant obtained from cells (Ausubel et al, supra). In an assay of a mixture of compounds, nuclear receptor expression is measured in cells administered progressively smaller subsets of the compound pool (e.g., produced by standard purification teclmiques such as HPLC or FPLC) until a single compound or minimal number of effective compounds is demonstrated to affect nuclear receptor expression. Alternatively, diverse mixtures (i.e., libraries) of test compounds maybe assayed in such a way that the pattern of response indicates which compounds in the various mixtures are responsible for the effect (deconvolution). Compounds may also be screened for their ability to modulate nuclear receptor biological activity. In this approach, the degree of nuclear receptor biological activity in the presence of a candidate compound is compared to the degree of activity in its absence, under equivalent conditions. Again, the screen may begin with a pool of candidate compounds, from which one or more useful modulator compounds are isolated in a step-wise fashion. Nuclear receptor biological activity may be measured by any standard assay, for example, those described herein.
Another method for detecting compounds that modulate nuclear receptor biological activity is to screen for compounds that interact physically with a nuclear receptor polypeptide. These compounds may be detected, for example, by adapting interaction trap expression systems known in the art. These systems detect protein interactions using a transcriptional activation assay and are generally described by Gyuris et al. (Cell 75:791-803, 1993) and Field et al., (Nature 340:245-246, 1989), and are commercially available. Alternatively, a nuclear receptor polypeptide, or a fragment thereof, can be labeled with a detectable label (e.g., direct 125I labeling of tyrosines or 125I Bolton-Hunter reagent; Bolton et al. Biochem. J. 133: 529, 1973). Candidate compounds previously anayed in the wells of a multi-well plate are incubated with the labeled nuclear receptor polypeptide. Following washing, the wells with bound, labeled nuclear receptor polypeptide are identified. Data obtained using different concentrations of nuclear receptor polypeptides are used to calculate values for the number, affinity, and association of the nuclear receptor polypeptide with the candidate compounds. If desirable, the candidate compounds can be labeled instead of the nuclear receptor polypeptide. Similarly, the nuclear receptor polypeptide may be immobilized, e.g., in wells of a multi-well plate or on a solid support, and soluble compounds are then contacted with the nuclear receptor polypeptide. Upon removal of unbound compound, the identity of bound candidate compounds is ascertained. Compounds that bind are considered to be candidate modulators of nuclear receptor biological activity. Alternatively, interaction of unlabeled nuclear receptor may be detected using direct or indirect antibody labeling.
Another such method comprises the steps of (a) contacting a composition comprising a nuclear receptor polypeptide with a compound suspected of binding a nuclear receptor; and (b) measuring binding between the compound and nuclear receptor polypeptide. The binding may be measured directly, e.g., by using a labeled compound, or may be measured indirectly by several techniques, including measuring transcriptional modulation by the nuclear receptor polypeptide induced by the compound. Following steps (a) and (b), compounds identified as binding a nuclear receptor polypeptide can be further tested in other assays including, but not limited to, in vivo models, in order to confirm or quantify binding to a nuclear receptor polypeptide.
The test compounds of the present invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the One-bead one-compound' library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, K.S. (1997) Anticancer Drug Des. 12:145).
Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad Sci. USA. 90:6909; Erb et al. (1994) Proc. Natl. Acad Sci. USA 91:11422; Zuckermann et al. (1994) J. Med. Chem. 37:2678; Cho et al. (1993) Science 261:1303; Canell et al. (1994) Angew. Chem. Int. Ed. Engl. 33 :2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33 :2061 ; and in
Gallop et al. (1994) J Med. Chem. 37:1233. Libraries of compounds maybe presented in solution (e.g., Houghten (1992) Biotechniques 13:412-421), or on beads (Lam (1991) Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria (Ladner USP 5,223,409), spores (Ladner USP 409), plasmids (Cull et al. (1992) Proc Natl Acad Sci USA 89:1865-1869) or on phage (Scott and Smith (1990) Science 249:386-390); (Devlin (1990) Science 249:404-406); (Cwirla et al. (1990) Proc. Natl. Acad. Sci. 87:6378-6382); (Felici (1991) J. Mol. Biol. 222:301-310).
Specific binding molecules, including natural ligands and synthetic compounds, can be identified or developed using isolated or recombinant nuclear receptor products, nuclear receptor variants, or preferably, cells expressing such products. Binding partners are useful for purifying nuclear receptor products and detection or quantification of nuclear receptor products in fluid and tissue samples using known immunological procedures. Binding molecules are also manifestly useful in modulating (i.e., blocking, inhibiting or stimulating) biological activities of a nuclear receptor polypeptide, especially those activities involved in transcriptional activation. The DNA and amino acid sequence information provided by the present invention also makes possible identification of binding partner compounds with which a nuclear receptor polypeptide or polynucleotide will interact. Methods to identify binding partner compounds include solution assays, in vitro assays wherein nuclear receptor polypeptides are immobilized, and cell-based assays. Identification of binding partner compounds of nuclear receptor polypeptides provides candidates for therapeutic or prophylactic intervention in pathologies associated with nuclear receptor normal and abenant biological activity.
The invention includes several assay systems for identifying nuclear receptor polypeptide binding partners. In solution assays, methods of the invention comprise the steps of (a) contacting a nuclear receptor polypeptide with one or more candidate binding partner compounds and (b) identifying the compounds that bind to the nuclear receptor polypeptide. Identification of the compounds that bind the nuclear receptor polypeptide can be achieved by isolating the nuclear receptor polypeptide/binding partner complex, and separating the binding partner compound from the nuclear receptor polypeptide.
An additional step of characterizing the physical, biological, and/or biochemical properties of the binding partner compound is also comprehended in another embodiment of the invention, wherein compounds identified as binding nuclear receptor can be further tested in other assays including, but not limited to, in vivo models, in order to confirm or quantify binding to nuclear receptor. In one aspect, the nuclear receptor polypeptide/binding partner complex is isolated using an antibody immunospecific for either the nuclear receptor polypeptide or the candidate binding partner compound.
In still other embodiments, either the nuclear receptor polypeptide or the candidate binding partner compound comprises a label or tag that facilitates its isolation, and methods of the invention to identify binding partner compounds include a step of isolating the nuclear receptor polypeptide/binding partner complex through interaction with the label or tag. An exemplary tag of this type is a poly-histidine sequence, generally around six histidine residues, that permits isolation of a compound so labeled using nickel chelation. Other labels and tags, such as the FLAG tag, well known and routinely used in the art, are embraced by the invention.
In one variation of an in vitro assay, the invention provides a method comprising the steps of (a) contacting an immobilized nuclear receptor polypeptide with a candidate binding partner compound and (b) detecting binding of the candidate compound to the nuclear receptor polypeptide. In an alternative embodiment, the candidate binding partner compound is immobilized and binding of nuclear receptor is detected. Immobilization is accomplished using any of the methods well known in the art, including covalent bonding to a support, a bead, or a chromatographic resin, as well as non-covalent, high affinity interactions such as antibody binding, or use of streptavidin/biotin binding wherein the immobilized compound includes a biotin moiety. Detection of binding can be accomplished (i) using a radioactive label on the compound that is not immobilized, (ii) using of a fluorescent label on the non-immobilized compound, (iii) using an antibody immunospecific, for the non-immobilized compound, (iv) using a label on the non-immobilized compound that excites a fluorescent support to which the immobilized compound is attached, as well as other techniques well known and routinely practiced in the art.
The invention also provides cell-based assays to identify binding partner compounds of a nuclear receptor polypeptide. In one embodiment, the invention provides a method comprising the steps of contacting a nuclear receptor polypeptide expressed in a cell with a candidate binding partner compound and detecting binding of the candidate binding partner compound to the nuclear receptor polypeptide. In a prefened embodiment, the detection comprises detecting a reporter response or other physiological event in the cell caused by the binding of the molecule.
Another aspect of the present invention is directed to methods of identifying compounds that bind to either a nuclear receptor polypeptide or nucleic acid molecules encoding a nuclear receptor polypeptide, comprising contacting nuclear receptor polypeptide, or a nucleic acid molecule encoding the same, with a compound, and determining whether the compound binds the nuclear receptor polypeptide or a nucleic acid molecule encoding the same. Binding can be determined by binding assays which are well known to the skilled artisan, including, but not limited to, gel-shift assays, Western blots, radiolabeled competition assay, phage-based expression cloning, co- fractionation by chromatography, co-precipitation, cross linking, interaction trap/two- hybrid analysis, southwestern analysis, ELISA, and the like, which are described in, for example, Cunent Protocols in Molecular Biology, 1999, John Wiley & Sons, NY, which is incoφorated herein by reference in its entirety. The compounds to be screened include (which may include compounds which are suspected to bind nuclear receptor polypeptides, or a nucleic acid molecule encoding the same), but are not limited to, . extracellular, intracellular, biologic or chemical origin. The methods of the invention also embrace ligands, especially neuropeptides, that are attached to a label, such as a radiolabel (e.g., 1251, 35S, 32P, 33P, 3H), a fluorescence label, a chemiluminescent label, an enzymatic label and an immunogenic label.
Modulators falling within the scope of the invention include, but are not limited to, non-peptide molecules such as non-peptide mimetics, non-peptide allosteric effectors, and peptides. The nuclear receptor polypeptide or polynucleotide employed in such a test may either be free in solution, attached to a solid support, bome on a cell surface or located intracellularly or associated with a portion of a cell. One skilled in the art can, for example, measure the formation of complexes between the nuclear receptor polypeptide and the compound being tested. Alternatively, one skilled in the art can examine the diminution in complex formation between a nuclear receptor polypeptide and its substrate caused by the compound being tested.
In another embodiment of the invention, high throughput screening for compounds having suitable binding affinity to a nuclear receptor polypeptide is employed. Briefly, large numbers of different test compounds are synthesized on a solid substrate. The peptide test compounds are contacted with a nuclear receptor polypeptide and washed. Bound nuclear receptor is then detected by methods well known in the art. Purified polypeptides of the invention can also be coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies can be used to capture the protein and immobilize it on the solid support.
Generally, an expressed nuclear receptor polypeptide can be used for HTS binding assays in conjunction with its defined ligand, in this case the conesponding neuropeptide that activates it. The identified peptide is labeled with a suitable radioisotope, including, but not limited to, 1251, 3H, 35S or 32P, by methods that are well known to those skilled in the art. Alternatively, the peptides may be labeled by well-known methods with a suitable fluorescent derivative (Baindur et al., Drug Dev. Res., 1994, 33, 373-398; Rogers, Drug Discovery Today, 1997, 2, 156-160). Radioactive ligand specifically bound to the recombinant nuclear receptor can be detected in HTS assays in one of several standard ways, including filtration of the receptor-ligand complex to separate bound ligand from unbound ligand (Williams, Med. Res. Rev., 1991, 11, 147-184; Sweetnam. et al., J Natural Products, 1993, 56, 441-455). Alternative methods include a scintillation proximity assay (SPA) or a FlashPlate format in which such separation is unnecessary (Nakayama, Cur. Opinion Drag Disc. Dev., 1998, 1, 85-91; Boss et al., J Biomolecular Screening, 1998, 3, 285-292). Binding of fluorescent ligands can be detected in various ways, including fluorescence energy transfer (FRET), direct specfrophotofluorometric analysis of bound ligand, or fluorescence polarization (Rogers, Drag Discovery Today, 1997, 2, 156-160; Hill, Cur. Opinion Drag Disc. Dev., 1998, 1, 92-97).
Other assays may be used to identify specific ligands of a nuclear receptor, including assays that identify ligands of the target protein through measuring direct binding of test ligands to the target protein, as well as assays that identify ligands of target proteins through affinity ultrafiltration with ion spray mass spectroscopy/HPLC methods or other physical and analytical methods. Alternatively, such binding interactions are evaluated indirectly using the yeast two hybrid system described in Fields et al., Nature, 340:245-246 (1989), and Fields et al, Trends in Genetics, 10:286- 292 (1994), both of which are incoφorated herein by reference in its entirety.
The two-hybrid system is a genetic assay for detecting interactions between two proteins or polypeptides. It can be used to identify proteins that bind to a known protein of interest, or to delineate domains or residues critical for an interaction. Variations on this methodology have been developed to clone genes that encode DNA binding proteins, to identify peptides that bind to a protein, and to screen for drags. The two- hybrid system exploits the ability of a pair of interacting proteins to bring a transcription activation domain into close proximity with a DNA binding domain that binds to an upstream activation sequence (UAS) of a reporter gene, and is generally performed in yeast. The assay requires the construction of two hybrid genes encoding (1) a DNA- binding domain that is fused to a first protein and (2) an activation domain fused to a second protein. The DNA-binding domain targets the first hybrid protein to the UAS of the reporter gene; however, because most proteins lack an activation domain, this DNA- binding hybrid protein does not activate transcription of the reporter gene. The second hybrid protein, which contains the activation domain, cannot by itself activate expression of the reporter gene because it does not bind the UAS. However, when both hybrid proteins are present, the noncovalent interaction of the first and second proteins tethers the activation domain to the UAS, activating transcription of the reporter gene. For example, when the first protein is a nuclear receptor gene product, or fragment thereof, that is known to interact with another protein or nucleic acid, this assay can be used to detect agents that interfere with the binding interaction. Expression of the reporter gene is monitored as different test agents are added to the system. The presence of an inhibitory agent results in lack of a reporter signal.
The yeast two-hybrid assay can also be used to identify proteins that bind to the gene product. In an assay to identify proteins that bind to a nuclear receptor, or fragment thereof (such as the ligand binding domain), a fusion polynucleotide encoding both a nuclear receptor (or fragment) and a UAS binding domain (i.e., a first protein) may be used. In addition, a large number of hybrid genes each encoding a different second protein fused to an activation domain are produced and screened in the assay. Typically, the second protein is encoded by one or more members of a total cDNA or genomic DNA fusion library, with each second protein-coding region being fused to the activation domain. This system is applicable to a wide variety of proteins, and it is not even necessary to know the identity or function of the second binding protein. The system is highly sensitive and can detect interactions not revealed by other methods; even transient interactions may trigger transcription to produce a stable mRNA that can be repeatedly translated to yield the reporter protein.
Other assays may be used to search for agents that bind to the target protein. One such screening method to identify direct binding of test ligands to a target protein relies on the principle that proteins generally exist as a mixture of folded and unfolded states, and continually alternate between the two states. When a test ligand binds to the folded form of a target protein (i.e., when the test ligand is a ligand of the target protein), the target protein molecule bound by the ligand remains in its folded state. Thus, the folded target protein is present to a greater extent in the presence of a test ligand which binds the target protein, than in the absence of a ligand. Binding of the ligand to the target protein can be determined by any method that distinguishes between the folded and unfolded states of the target protein. The function of the target protein need not be known in order for this assay to be performed. Virtually any agent can be assessed by this method as a test ligand, including, but not limited to, metals, polypeptides, proteins, lipids, polysaccharides, polynucleotides and small organic molecules.
Another method for identifying ligands of a target protein is described in Wieboldt et al., Anal. Chem., 69:1683-1691 (1997), incoφorated herein by reference in its entirety. This technique screens combinatorial libraries of 20-30 agents at a time in solution phase for binding to the target protein. Agents that bind to the target protein are separated from other library components by simple membrane washing. The specifically selected molecules that are retained on the filter are subsequently liberated from the target protein and analyzed by HPLC and pneumatically assisted elecfrospray (ion spray) ionization mass spectroscopy. This procedure selects library components with the greatest affinity for the target protein, and is particularly useful for small molecule libraries.
Determining whether a test compound binds to a nuclear receptor polypeptide can also be accomplished by measuring the intrinsic fluorescence of the nuclear receptor polypeptide and determining whether the intrinsic fluorescence is modulated in the presence of the test compound. Preferably, the intrinsic fluorescence of nuclear receptor polypeptide is measured as a function of the tryptophan residue(s) of the nuclear receptor. Preferably, fluorescence of the nuclear receptor polypeptide is measured and compared to the fluorescence intensity of the nuclear receptor polypeptide in the presence of the test compound, wherein a decrease in fluorescence intensity indicates binding of the test compound to a nuclear receptor. Prefened methodology is set forth in "Principles of Fluorescence Spectroscopy" by Joseph R. Lakowicz, New York, Plenum Press, 1983 (ISBN 0306412853) and "Spectrophotometry And Spectrofluoromefry" by CL. Bashford and D.A. Hanis Oxford, Washington DC, IRL Press, 1987, each of which is incoφorated herein by reference in its entirety.
Other embodiments of the invention comprise using competitive screening assays in which neutralizing antibodies capable of binding a polypeptide of the invention specifically compete with a test compound for binding to the polypeptide. In this manner, the antibodies can be used to detect the presence of any peptide that shares one or more antigenic determinants with a nuclear receptor polypeptide. Radiolabeled competitive binding studies are described in A. H. Lin et al. Antimicrobial Agents and Chemotherapy, 1997, vol. 41, no. 10. pp. 2127-2131, the disclosure of which is incoφorated herein by reference in its entirety.
Another aspect of the present invention relates to methods of identifying a compound that binds to or modulates a nuclear receptor polypeptide. The methods comprise contacting a composition comprising a nuclear receptor and Peptide A with a test compound, or a plurality of test compounds, and determining whether the test compound competes with Peptide A for binding to the nuclear receptor polypeptide.
A decrease in the amount of the complex between Peptide A, or a protein homologous thereto, and the nuclear receptor polypeptide in the presence of a test compound or compounds confirms that the compound or compounds binds to the nuclear receptor polypeptide. In some embodiments, the affinity or displacement of Peptide A is measured, wherein a low affinity indicates that the test compound interacts with the nuclear receptor polypeptide. In these methods, the composition that comprises a nuclear receptor polypeptide and Peptide A can be cells. Compounds identified as binding to a nuclear receptor polypeptide are also expected to modulate nuclear receptor activity. Binding of a test compound to a nuclear receptor polypeptide can be determined by any of the binding assays described above.
The invention also provides methods for identifying a modulator of binding between a nuclear receptor polypeptide and a nuclear receptor binding partner, comprising the steps of (a) contacting a nuclear receptor binding partner and a composition comprising a nuclear receptor polypeptide in the presence and in the absence of a putative modulator compound; (b) detecting binding between the binding partner and the nuclear receptor polypeptide; and (c) identifying a putative modulator compound or a modulator compound in view of decreased or increased binding between the binding partner and the nuclear receptor polypeptide in the presence of the putative modulator, as compared to binding in the absence of the putative modulator.
Following steps (a) and (b), compounds identified as modulating binding between nuclear receptor and a nuclear receptor binding partner can be further tested in other assays including, but not limited to, in vivo models, in order to confirm or quantify modulation of binding to a nuclear receptor polypeptide. Nuclear receptor binding partners that stimulate nuclear receptor activity are useful as agonists in disease states or conditions characterized by insufficient nuclear receptor function (e.g., as a result of insufficient activity of a nuclear receptor ligand). Nuclear receptor binding partners that block ligand-mediated nuclear receptor signaling are useful as nuclear receptor antagonists to treat disease states or conditions characterized by excessive nuclear receptor signaling. In addition, nuclear receptor modulators in general, as well as nuclear receptor polynucleotides and polypeptides, are useful in diagnostic assays for such diseases or conditions.
In another aspect, the invention provides methods for treating a disease or abnormal condition by administering to a patient in need of such treatment a substance that modulates the activity or expression of a polypeptide having sequences selected from the group consisting of sequences listed in Table 1.
Agents that modulate (i.e., increase, decrease, or block) nuclear receptor activity or expression may be identified by incubating a putative modulator with a cell containing a nuclear receptor polypeptide or polynucleotide and determining the effect of the putative modulator on nuclear receptor activity or expression. The selectivity of a compound that modulates the activity of a nuclear receptor can be evaluated by comparing its effects on nuclear receptor to its effect on other nuclear receptor compounds.
Methods of the invention to identify modulators include variations on any of the methods described above to identify binding partner compounds, the variations including teclmiques wherein a binding partner compound has been identified and the binding assay is canied out in the presence and absence of a candidate modulator. A modulator is identified in those instances where binding between the nuclear receptor polypeptide and the binding partner compound changes in the presence of the candidate modulator compared to binding in the absence of the candidate modulator compound. A modulator that increases binding between the nuclear receptor polypeptide and the binding partner compound is described as an enhancer or activator, and a modulator that decreases binding between the nuclear receptor polypeptide and the binding partner compound is described as an inhibitor. Following identification of modulators, such compounds can be further tested in other assays including, but not limited to, in vivo models, in order to confirm or quantify their activity as modulators. The invention also comprehends high-throughput screening (HTS) assays to identify compounds that interact with or inhibit biological activity (i.e., affect enzymatic activity, binding activity, etc.) of a nuclear receptor polypeptide. HTS assays permit screening of large numbers of compounds in an efficient manner. Cell-based HTS systems are contemplated to investigate nuclear receptor receptor-ligand interaction. HTS assays are designed to identify "hits" or "lead compounds" having the desired property, from which modifications can be designed to improve the desired property. Chemical modification of the "hit" or "lead compound" is often based on an identifiable structure/activity relationship between the "hit" and the nuclear receptor polypeptide.
Another aspect of the present invention is directed to methods of identifying compounds which modulate (i.e., increase or decrease) activity of nuclear receptor comprising contacting a nuclear receptor polypeptide with a compound, and determining whether the compound modifies activity of the nuclear receptor. The activity in the presence of the test compared is measured to the activity in the absence of the test compound. Where the activity of the sample containing the test compound is higher than the activity in the sample lacking the test compound, the compound will have increased activity. Similarly, where the activity of the sample containing the test compound is lower than the activity in the sample lacking the test compound, the compound will have inhibited activity.
The present invention is particularly useful for screening compounds by using nuclear receptor in any of a variety of drug screening techniques. The compounds to be screened include (which may include compounds which are suspected to modulate nuclear receptor activity), but are not limited to, extracellular, intracellular, biologic or chemical origin. The nuclear receptor polypeptide employed in such a test may be in any form, preferably, free in solution, attached to a solid support, on a cell surface or located intracellularly. One skilled in the art can, for example, measure the formation of complexes between nuclear receptor and the compound being tested. Alternatively, one skilled in the art can examine the diminution in complex formation between nuclear receptor and its substrate caused by the compound being tested.
The activity of nuclear receptor polypeptides of the invention can be determined by, for example, examining the ability to bind or be activated by chemically synthesized peptide ligands. Alternatively, the activity of nuclear receptor polypeptides can be assayed by examining their ability to bind hormones, neuropeptides, neurotransmitters, nucleotides and lipids. Alternatively, the activity of the nuclear receptor polypeptides can be determined by examining the activation or repression of gene expression. Thus, modulators of nuclear receptor polypeptide activity may alter nuclear receptor function, such as a binding property of a receptor or an activity such as nuclear receptor-mediated transcriptional activation or repression. In various embodiments of the method, the assay may take the form of a reporter assay for transcriptional activation or repression, a yeast growth assay, an Aequorin assay, a Luciferase assay, a FLIPR assay for intracellular Ca2+ concentration, a mitogenesis assay, a MAP Kinase activity assay, an assay for extracellular acidification rates, as well as other binding or function-based assays of nuclear receptor activity that are generally known in the art.
The modulators of the invention exhibit a variety of chemical structures, which can be generally grouped into non-peptide mimetics of natural nuclear receptor ligands, peptide and non-peptide allosteric effectors of nuclear receptor, and peptides that may function as activators or inhibitors (competitive, uncompetitive and non-competitive) (e.g., antibody products) of nuclear receptors. The invention does not restrict the sources for suitable modulators, which may be obtained from natural sources such as plant, animal or mineral extracts, or non-natural sources such as small molecule libraries, including the products of combinatorial chemical approaches to library construction, and peptide libraries.
Other assays can be used to examine enzymatic activity including, but not limited to, photometric, radiometric, BPLC, electrochemical, and the like, which are described in, for example, Enzyme Assays: A Practical Approach, eds. R. Eisenthal and M. J. Danson, 1992, Oxford University Press, which is incoφorated herein by reference in its entirety.
The use of cDNAs encoding nuclear receptors in drag discovery programs is well- known; assays capable of testing thousands of unknown compounds per day in high- throughput screens (HTSs) are thoroughly documented. The literature is replete with examples of the use of radiolabelled ligands in HTS binding assays for drag discovery (see Williams, Medicinal Research Reviews, 1991, 11, 147-184; Sweetnam, et al, J Natural Products, 1993, 56, 441- 455 for review). Recombinant receptors are prefened for binding assay HTS because they allow for better specificity (higher relative purity), provide the ability to generate large amounts of receptor material, and can be used in a broad variety of formats (see Hodgson, BioTechnology, 1992, 10, 973-980; each of which is incoφorated herein by reference in its entirety).
A variety of heterologous systems is available for functional expression of recombinant receptors that are well known to those skilled in the art. Such systems include bacteria (Strosberg, et al., Trends in Pharmacological Sciences, 1992, 13, 95- 98), yeast (Pausch, Trends in Biotechnology, 1997, 15, 487-494), several kinds of insect cells (Vanden Broeck, Int. Rev. Cytology, 1996, 164, 189-268), amphibian cells
(Jayawickreme et al., Cunent Opinion in Biotechnology, 1997, 8, 629-634) and several mammalian cell lines (CHO, HEK293, COS, etc.; see Gerhardt, et al, Eur. J. Pharmacology, 1997, 334, 1-23). These examples do not preclude the use of other possible cell expression systems, including cell lines obtained from nematodes.
In prefened embodiments of the invention, methods of screening for compounds that modulate nuclear receptor activity comprise contacting test compounds with nuclear receptor and assaying for the presence of a complex between the compound and nuclear receptor. In such assays, the ligand is typically labeled. After suitable incubation, free ligand is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of the particular compound to bind to nuclear receptor.
The invention contemplates a multitude of assays to screen and identify inhibitors of ligand binding to nuclear receptors. In one example, the nuclear receptor is immobilized and interaction with a binding partner is assessed in the presence and absence of a candidate modulator such as an inhibitor compound. In another example, interaction between the nuclear receptor and its binding partner is assessed in a solution assay, both in the presence and absence of a candidate inhibitor compound. In either assay, an inhibitor is identified as a compound that decreases binding between the nuclear receptor and its binding partner.
Still other candidate inhibitors contemplated by the invention can be designed and include soluble forms of binding partners, as well as such binding partners as chimeric, or fusion, proteins. A "binding partner" as used herein broadly encompasses non-peptide modulators, as well as such peptide modulators as neuropeptides other than natural ligands, antibodies, antibody fragments, and modified compounds comprising antibody domains that are immunospecific for the expression product of the identified nuclear receptor gene.
Compounds may be identified which exhibit similar properties to the ligand for the nuclear receptor of the invention, but which are smaller and exhibit a longer half time than the endogenous ligand in a human or animal body. When an organic compound is designed, a molecule according to the invention is used as a "lead" compound. The design of mimetics to known pharmaceutically active compounds is a well-known approach in the development of pharmaceuticals based on such "lead" compounds. Mimetic design, synthesis and testing are generally used to avoid randomly screening a large number of molecules for a target property.
Furthermore, structural data deriving from the analysis of the deduced amino acid sequences encoded by the DNAs of the present invention are useful to design new drugs, more specific and therefore with a higher pharmacological potency.
The present invention also encompasses a method of agonizing (stimulating) or antagonizing a nuclear receptor natural binding partner associated activity in a mammal comprising administering to said mammal an agonist or antagonist to one of the above disclosed polypeptides in an amount sufficient to effect said agonism or antagonism. One embodiment of the present invention, then, is a method of treating diseases in a mammal with an agonist or antagonist of the protein of the present invention comprises administering the agonist or antagonist to a mammal in an amount sufficient to agonize or antagonize nuclear receptor-associated functions.
Methods for Cell Based Assays for the Identification of Nuclear Receptor Modulators
Set forth below are several nonlimiting methods for identifying modulators (agonists and antagonists) of nuclear receptor activity. Among the modulators that can be identified by these assays are natural ligand compounds of the receptor; synthetic analogs and derivatives of natural ligands; antibodies, antibody fragments, and/or antibody-like compounds derived from natural antibodies or from antibody-like combinatorial libraries; and/or synthetic compounds identified by high-throughput screening of libraries; and the like. All modulators that bind nuclear receptors are useful for identifying nuclear receptors in tissue samples (e.g., for diagnostic puφoses, pathological puφoses, and the like). Agonist and antagonist modulators are useful for up-regulating and down-regulating nuclear receptor activity, respectively, to treat disease states characterized by abnormal levels of nuclear receptor activity. The assays may be performed using single putative modulators, and/or may be performed using a known agonist in combination with candidate antagonists (or visa versa).
A. Luciferase Reporter Gene Assay
The photoprotein luciferase provides another useful tool for assaying for modulators of nuclear receptor activity. Cells (e.g., CHO cells or COS 7 cells) are transiently co-transfected with both a nuclear receptor expression construct (e.g., nuclear receptor in pzeoSV2) and a reporter construct which includes a gene for the luciferase protein downstream from a nuclear receptor transcription factor binding site, such as a hormone or other nuclear receptor response element. Agonist binding to nuclear receptor causes the nuclear receptor to bind to the nuclear receptor response element and active expression of the luciferase gene. Expression levels of luciferase reflect the activation status of the signaling events (George et al., Journal of Biomolecular Screening, 2(4): 235-240 (1997); and Stratowa et al., Cunent Opinion in Biotechnology 6: 574-581
(1995)). Luciferase activity may be quantitatively measured using, e.g., luciferase assay reagents that are commercially available from Promega (Madison, WI).
In one exemplary assay, CHO cells are plated in 24-well culture dishes at a density of 100,000 cells/well one day prior to transfection and cultured at 37°C in MEM (Gibco/13RL) supplemented with 10% fetal bovine serum, 2 mM glutamine, 10 U/ml penicillin and 10 ug/ml streptomycin. Cells are transiently co-transfected with both a nuclear receptor expression construct and a reporter construct containing the luciferase gene.
Transfections are perfoπned using the FuGENE 6 transfection reagent (Boehringer- Mannheim) according to the supplier's instructions. Cells transfected with the reporter construct alone are used as a control. Twenty-four hours after transfection, cells are washed once with PBS pre-warmed to 37°C. Seram-free MEM is then added to the cells either alone (control) or with one or more candidate modulators and the cells are incubated at 37°C for five hours. Thereafter, cells are washed once with ice-cold PBS and lysed by the addition of lysis buffer from the luciferase assay kit supplied by Promega. After incubation for 15 minutes at room temperature, lysate is mixed with substrate solution (Promega) in an opaque- white, 96-well plate, and the luminescence is read immediately on a scintillation and luminescence counter (Wallace Instruments, Gaithersburg, MD). Differences in luminescence in the presence versus the absence of a candidate modulator compound are indicative of modulatory activity. Receptors that are either constitutively active or activated by agonists typically give a 3 to 20-fold stimulation of luminescence compared to cells transfected with the reporter gene alone. Modulators that act as inverse agonists will reverse this effect.
B. Mitogenesis Assay
In a mitogenesis assay, the ability of candidate modulators to induce or inhibit nuclear receptor mediated cell division is determined (See, e.g., Lajiness et al., Journal of Pharmacology and Experimental Therapeutics 267(3): 1573-1581 (1993)). For example, CHO cells stably expressing nuclear receptor are seeded into 96-well plates at a density of 5000 cells/well and grown in MEM with 10% fetal calf serum for 48 hours, at which time the cells are rinsed twice with seram-free MEM. After rinsing, fresh MEM, or MEM containing a known mitogen, is added along with MEM containing varying concentrations of one or more candidate modulators or test compounds diluted in serum-free medium. As controls, some wells on each plate receive seram-free medium alone, and some receive medium containing 10% fetal bovine serum. Untransfected cells or cells transfected with vector alone also may serve as controls. After culture for 16-18 hours, [3H]-thymidine is added to the wells and cells are incubated for an additional 2 hours at 37°C The cells are trypsinized and collected on filter mats with a cell harvester, the filters are then counted in a Betaplate counter. The incoφoration of [3H]-thymidine in seram-free test wells is compared to the results achieved in cells stimulated with serum (positive control). Use of multiple concentrations of test compounds permits creation and analysis of dose-response curves using the non-linear, least squares fit equation: A = B x [CI (D + Q + G where A is the percent of serum stimulation; B is the maximal effect minus baseline; C is the EC50; D is the concentration of the compound; and G is the maximal effect. Parameters B, C and G are determined by Simplex optimization. Agonists that bind to the receptor are expected to increase [3H]-thymidine incoφoration into cells. Antagonists that bind to the receptor will inhibit the stimulation seen with a known agonist.
Identification of natural nuclear receptor ligands
Isolated nuclear receptors can be used to isolate novel or known ligands (Saito et al., Nature, 400: 265-269, 1999). The cDNAs that encode the isolated nuclear receptor selected from the group consisting of sequences listed in Table 1 , can be cloned into mammalian expression vectors and used to stably or transiently fransfect mammalian cells including CHO, Cos or HEK293 cells. Receptor expression can be determined by Northern blot analysis of transfected cells and identification of an appropriately sized mRNA band (predicted size from the cDNA) or PCR. Tissues shown by mRNA analysis to express each of the nuclear receptor proteins could be processed for ligand extraction using any of several protocols ((Reinsheidk R.K. et al., Science 270: 243-247, 1996; Sakurai, T., et al., Cell 92; 573-585, 1998; Hinuma, S., et al., Nature 393: 272-276, 1998). Chromotographic fractions of organ extracts could be tested for ability to activate nuclear receptor proteins by measuring reporter gene activation. This assay could also be performed using baculovirases containing nuclear receptor proteins infected into SF9 insect cells.
The ligand which activates nuclear receptor proteins can be purified to homogeneity through successive rounds of purification using nuclear receptor protein activation as a measurement of activity. The composition of the ligand can be detennined by mass spectrometry and other methods. Ligands isolated in this manner will be bioactive materials which will affect physiological processes.
Protein Interaction Assays
Protein interaction assays may also be utilized to identify nuclear receptor modulator compounds. To cany out such an assay, a nuclear receptor polypeptide of the invention (or a polypeptide fragment thereof or an epitope-tagged form or fragment thereof) is harvested from a suitable source (e.g., from a prokaryotic expression system, eukaryotic cells, a cell-free system, or by immunoprecipitation from nuclear receptor polypeptide-expressing cells). The nuclear receptor polypeptide is then bound to a suitable support (e.g., nitrocellulose or an antibody or a metal agarose column in the case of, for example, a his-tagged form of a nuclear receptor polypeptide). Binding to the support is preferably done under conditions that allow polypeptides associated with a nuclear receptor polypeptide to remain associated with it. Such conditions may include use of buffers that minimize interference with protein-protein interactions. The binding step can be done in the presence and absence of compounds being tested for their ability to interfere with interactions between a nuclear receptor polypeptide of the invention and other molecules. If desired, other proteins (e.g., a cell lysate) are added, and allowed time to associate with the polypeptide. The immobilized nuclear receptor polypeptide is then washed to remove proteins or other cell constituents that may be non-specifically associated with the polypeptide or the support. The immobilized nuclear receptor polypeptide is then dissociated from its support, and so that proteins bound to it are released (for example, by heating), or alternatively, associated proteins are released from the nuclear receptor polypeptide without releasing the nuclear receptor polypeptide from the support. The released proteins and other cell constituents can be analyzed, for example, by SDS-PAGE gel electrophoresis, western blotting and detection with specific antibodies, phosphoamino acid analysis, protease digestion, protein sequencing, or isoelectric focusing. Normal and polymoφhic (or mutagenized) forms of a nuclear receptor polypeptide of the invention can be employed in these assays to gain additional information about the part of a nuclear receptor polypeptide to which a given factor binds. In addition, when incompletely purified polypeptide is employed, comparison of the normal and polymoφhic forms of the polypeptide can be used to help distinguish true binding proteins. The proceeding assay can be performed using a purified or semipurified protein or other molecule that is known to interact with a nuclear receptor polypeptide of the invention. This assay may include the following steps.
1. Harvest a nuclear receptor polypeptide of the invention and couple a suitable fluorescent label to it; 2. Label an interacting polypeptide (or other molecule) with a second, different fluorescent label. Use dyes that will produce different quenching patterns when they are in close proximity to each other vs. when they are physically separated (i.e., dyes that quench each other when they are close together but fluoresce when they are not in close proximity);
3. Expose the interacting molecule to the immobilized nuclear receptor polypeptide in the presence or absence of a compound being tested for its ability to interfere with an interaction between the two; and
4. Collect fluorescent readout data.
Another assay includes a Fluorescent Resonance Energy Transfer (FRET) assay. This assay can be performed as follows. 1. Provide a nuclear receptor polypeptide of the invention or a suitable polypeptide fragment thereof and couple a suitable FRET donor (e.g., nitro- benzoxadiazole (NBD)) to it;
2. Label an interacting polypeptide (or other molecule) with a FRET acceptor (e.g., rhodamine); 3. Expose the acceptor-labeled interacting molecule to the donor-labeled nuclear receptor polypeptide in the presence or absence of a compound being tested for its ability to interfere with an interaction between the two; and . 4. Measure fluorescence resonance energy transfer.
• Quenching and FRET assays are related. Either one can be applied in a given case, depending on which pair of fluorophores is used in the assay.
Interaction Trap/Two-Hybrid System
In order to assay for nuclear receptor-interacting proteins, the interaction trap/two-hybrid library screening method can be used. This assay was first described in Fields et al., Nature, 1989, 340, 245, which is incoφorated herein by reference in its entirety. A protocol is published in Cunent Protocols in Molecular Biology 1999, John Wiley & Sons, NY, and Ausubel, F. M. et 132 al. 1992, Short protocols in molecular biology, Fourth edition, Greene and Wiley-interscience, NY, each of which is incoφorated herein by reference in its entirety. Kits are available from Clontech, Palo Alto, CA (Matchmaker Two-Hybrid System).
A fusion of the nucleotide sequences encoding the nuclear receptor lacking the activation domain and the yeast transcription factor GAL4 DNA-binding domain (DNA- BD) is constructed in an appropriate plasmid (i.e., pGBKT7) using standard subcloning techniques. Similarly, a GAL4 active domain (AD) fusion library is constructed in a second plasmid (i.e., p GADT7) from cDNA of potential nuclear receptor-binding proteins (for protocols on forming cDNA libraries, see Sambrook et al. 1989, Molecular cloning: a laboratory manual, second edition, Cold Spring Harbor Press, Cold Spring Harbor, NY), which is incoφorated herein by reference in its entirety. The DNA- BD/nuclear receptor fusion construct is verified by sequencing, and tested for autonomous reporter gene activation and cell toxicity, both of which would prevent a successful two-hybrid analysis. Similar controls are performed with the AD/library fusion construct to ensure expression in host cells and lack of transcriptional activity. Yeast cells are transformed with both the nuclear receptor and library fusion plasmids according to standard procedures (Ausubel et al., 1992, Short protocols in molecular biology, fourth edition, Greene and Wiley-interscience, NY, which is incoφorated herein by reference in its entirety). In vivo binding of DNA-BD/nuclear receptor with AD/library proteins results in transcription of specific yeast plasmid reporter genes (i.e., lacZ, HIS3, ADE2, LEU2). Yeast cells are plated on nutrient-deficient media to screen for expression of reporter genes. Colonies are dually assayed for β-galactosidase activity upon growth in Xgal (5-bromo-4-chloro-3-indolyl-p-D-galactoside) supplemented media (filter assay for P-galactosidase activity is described in Breeden et al., Cold Spring Harb. Symp. Quant. Biol., 1985, 50, 643, which is incoφorated herein in its entirety). Positive AD library plasmids are rescued from transformants and reintroduced into the original yeast strain as well as other strains containing unrelated DNA-BD fusion proteins to confirm specific nuclear receptor /library protein interactions. Insert DNA is sequenced to verify the presence of an open reading frame fused to GAL4 AD and to determine the identity of the nuclear receptor-binding protein.
Nucleic Acid-based Assays
Nucleic acid encoding a nuclear receptor polypeptide of the invention may be used in an assay based on the interaction of factors necessary for nuclear receptor gene transcription. The association between the DNA and the binding factor may be assessed by means of any system that discriminates between protein-bound and non-protein- bound DNA (e.g., a gel retardation assay). The effect of a compound on the interaction of a factor to DNA is assessed by means of such an assay. In addition to in vitro binding assays, in vivo assays in which the regulatory regions of a nuclear receptor gene are linked to reporter systems can also be performed.
Assays Measuring the Stability of a Nuclear Receptor Polypeptide A cell-based or cell-free system can be used to screen for compounds based on their effect on the half-life of nuclear receptor mRNA or polypeptide. The assay may employ labeled mRNA or polypeptide. Alternatively, nuclear receptor mRNA may be detected by means of specifically hybridizing probes or a quantitative PCR assay. Protein can be quantified, for example, by fluorescent or radioactively labeled antibody- based methods. The following represent exemplary assays:
In vitro mRNA stability assay
1. Isolate or produce, by in vitro transcription, a suitable quantity of nuclear receptor mRNA; 2. Label the nuclear receptor mRNA;
3. Expose aliquots of the mRNA to a cell lysate in the presence or absence of a compound being tested for its ability to modulate nuclear receptor mRNA stability; and
4. Assess intactness of the remaining mRNA at suitable time points.
In vitro protein stability assay
1. Express a suitable amount of a nuclear receptor polypeptide of the invention;
2. Label the polypeptide;
3. Expose aliquots of the labeled polypeptide to a cell lysate in the presence or absence of a compound being tested for its ability to modulate nuclear receptor polypeptide stability; and
4. Assess intactness of the remaining polypeptide at suitable time points.
In vivo mRNA or polypeptide stability assay
1. Incubate cells expressing nuclear receptor mRNA or polypeptide with a tracer (radiolabeled ribonucleotide or radiolabeled amino acid, respectively) for a very brief time period (e.g., five minutes) in the presence or absence of a compound being tested for its effect on mRNA or polypeptide stability;
2. Incubate with unlabeled ribonucleotide or amino acid; and 3. Quantify the nuclear receptor mRNA or protein radioactivity at time intervals beginning with the start of step 2 and extending to the time when the radioactivity in nuclear receptor mRNA or protein has declined by approximately 80%. It is preferable to separate the intact or mostly intact mRNA or protein from its radioactive breakdown products by a means such as hybridization, antibody precipitation, and/or gel electrophoresis in order to quantify the mRNA or protein.
Assays Measuring Inhibition of Dominant Negative Activity
Polymoφhic nuclear receptor polypeptides may have dominant negative activity (i.e., activity that interferes with the function of a wild-type nuclear receptor). An assay for a compound that can interfere with such a polymoφh may be based on any method of quantifying the normal activity of a nuclear receptor in the presence of the polymoφh. For example, a normal nuclear receptor facilitates signal transduction and gene activation, and a dominant negative polymoφh would interfere with this effect. Measurement of the ability of a compound to counteract the effect of a dominant negative polymoφh may be based on signal transduction, or on any other normal activity of a wild-type nuclear receptor that was inhibited in the polymoφh.
Assays Measuring Phosphorylation The effect of a compound on phosphorylation of a nuclear receptor polypeptide of the invention can be assayed by methods that quantify phosphates on proteins or that assess the phosphorylation state of a specific residue of a nuclear receptor. Such methods include but are not limited to P and P labeling and immunoprecipitation, detection with antiphosphoamino acid antibodies (e.g., antiphosphoserine antibodies), phosphoamino acid analysis on 2-dimensional TLC plates, techniques involving mass spectroscopy of fragmented or digested nuclear receptors (e.g. MOLDI-TOF), and protease digestion fingeφrinting of proteins followed by detection of 32P- or 33P- labeled fragments.
Assays Measuring Other Post-translational Modifications
The effect of a compound on the post-translational modification of a nuclear receptor polypeptide of the invention may be based on any method capable of quantifying that particular modification. For example, effects of compounds on glycosylation may be assayed by treating a nuclear receptor polypeptide with glycosylase and quantifying the amount and nature of carbohydrate released.
Animal Model Systems Compounds identified as having activity in any of the above-described assays may be subsequently screened in any available animal model system, including, but not limited to, mice, pigs, and dogs. Test compounds are administered to these animals according to standard methods. Test compounds may also be tested in mice bearing mutations in a gene encoding a nuclear receptor polypeptide. Additionally, compounds may be screened for their ability to modulate an interaction between a nuclear receptor polypeptide of the invention and a ligand that binds the protein.
Knock-out Mice
An animal, such as a mouse, that has had one or both alleles of a nuclear receptor polypeptide of the invention inactivated (e.g., by homologous recombination or by insertional mutagenesis) is a prefened animal model for screening for compounds that alleviate abenant behavior or symptoms from a disease or disorder associated with loss of a nuclear receptor activity. The availability of inbred strains of genetically identical mice is of immense value in behavioral studies. Uniformity of mice in an inbred strain permits the assessment of subtle differences in the expression of behavioral traits. As a result, mice can be altered genetically, or bred in different combinations, to study specific behavioral characteristics.
In the mouse, it is possible to perfomi targeted changes in a gene, such that the altered gene can be passed from one generation to the next. This is accomplished by the use of mouse embryonic stem (ES) cells. These cells can be genetically modified in vitro and then implanted into a foster mother, where they develop into embryos and are brought to term. The resulting offspring are derived from the altered ES cells and cany the introduced genetic modification in their genome.
The most common laboratory procedure perfoπried in ES cells is the elimination, or knock-out (KO), of a specific gene. For this puφose, a mutation inactivating a target gene is introduced into ES cells. These cells are then used to produce mice containing the faulty gene. Since mice, like humans, contain two copies of every gene, one from each parent, the first generation of mice reared from the modified ES cells contains one copy of the mutant gene and one healthy variety. A single round of interbreeding leads to mice with two copies of the mutant gene and the full manifestation of the introduced mutation (KO mice) or mice bom by foster mothers are bred with wild type mice to produce heterozygotes, and these heterozygotes are interbred to produce KO mice.
Knock-in Mice
Instead of deleting a polynucleotide sequence from the mouse genome, it may be desirable to insert a polynucleotide sequence into the mouse genome. This technique, commonly refened to as "knocking in," can be accomplished using many of the methods described for the production of knock-out mice. In some instances, it maybe desirable to "knock in" a polynucleotide encoding a human nuclear receptor polypeptide of the invention to replace the polynucleotide encoding the orthologous mouse nuclear receptor polypeptide. The knocked-in polynucleotide may be expressed under the control of the endogenous mouse regulatory sequence, or may have exogenous regulatory sequences.
ES Library, Screening, and Isolation
The methods used to generate a library of ES cells with random gene disraptions and the screening and isolation of ES clones containing a nuclear receptor disraption may be canied out essentially as described in U.S. Patent No. 6,228,639. In brief, to generate a library of ES cells with random gene disraptions, we infected ES cells with a retroviral vector. The vector is designed to inactivate genes in which it gets inserted. The ES cell insertional library is organized in a 3-D matrix of tubes. One copy of the library is stored as viable cells and the other copy is used to isolate DNA. DNA from the library pools is screened by PCR for the insertions in the genes of interest. The same insertion found by PCR in pools conesponding to the other dimensions of the library matrix determines the 3-D address of the ES clone containing the disrupted gene.
Other methods are known in the art to generate gene disruptions in animals, including homologous recombination, chemical, radiation, and other mutational methods (Shastry, B.S., Mol Cell Biochem (1998) 181:163-79; Shasfry, B.S., Experientia (1995) 51:1028-1039; Zheng B. et al., Nucleic Acids Res (1999) 27:2354-2360; Koda T. et al., Hokkaido Igaku Zasshi (2002) 77:151-156; Babinet C. et al., An Acad Bras Cienc (2001) 73:577-80; Williams R.S., J Appl Physiol (2000) 88:1119-1126). In one embodiment, mice having mutations in a gene encoding a nuclear receptor polypeptide of the present invention are made using homologous recombination. Suitable methods and reagents are described, for example, in U.S. Patent Nos. 5,464,764, 5,487,992, 5,612,205, 5,627,059, 5,789,215, and 6,204,061.
Generation of Knock-out and Knock-in Mice
Knock-out and knock-in mice are produced according to methods well known in the art (see, e.g., Manipulating the Mouse Embryo. A Laboratory Manual, 2nd ed. B. Hogan, R. Beddington, F. Constantini, E. Lacy, Cold Spring Harbor Laboratory press, 1984). In brief, ES cells containing a disrupted nuclear receptor gene are injected into mice blastocysts. These blastocysts are then transfened into uteri of pseudopregnant female mice. Pups bom are scored for fur color, and chimeric mice (black and agouti color) with high contribution of agouti fur (50% or more) are tested for germ line transmission by breeding with C57B6/J mice. Presence of agouti progeny indicates germ line transmission, and the same chimera mice are then bred to generate knock-out mice on an inbred background. Alternatively, the chimeric mice may be bred directly to 129 mice and geπn line transmission may be determined by PCR, Southern blotting, or other methods known in the art. The resulting heterozygous mice would then be bred to generate knock-out mice on an inbred background. To generate mice heterozygous for the disrapted nuclear receptor gene
(heterozygous knock outs), the chimera mice are mated with other mice. The progeny from these matings are genotyped by PCR, Southern blotting, or other methods known in the art for the presence of the knocked out copy of nuclear receptor gene. Knock out mice homozygous for disraption of the nuclear receptor gene are generated by intercrossing heterozygous mice and genotyping progeny from these crosses.
Mice Having Altered Behavior
Behavioral tests may be used to determine the behavioral phenotype of animals (e.g., mice in which one or more nuclear receptor gene of the present invention has been deleted or otherwise modified, and mice overexpressing one or more nuclear receptor polypeptides of the present invention). Suitable tests include, but are not limited to, those that measure behaviors related to anxiety, hyperactivity, hypoactivity, appetite, eating habits, attention, drag abuse, drag addiction, learning and memory, mood, depression, schizophrenia, pain, sleep, arousal, sexuality, and social dominance.
The functional observational battery (FOB) is a series of tests applied to an animal to determine gross sensory and motor deficits. In general, short-duration, non- hannful tactile, olfactory, and visual stimuli are applied to the animal to determine its ability to detect and respond normally to the stimuli. The FOB also provides an opportunity for an investigator to closely observe each animal for skeletal and spontaneous neurological deficits (Crawley and Paylor, Hormones and Behavior 31 : 197-211 (1997)). General observational tests include, for example, swim tests, the auditory click test, measurement of body temperature or body weight, the Irwin Observational Test Battery, the olfactory acuity test, and the visual cliff test.
One means for measuring animal activity is the home cage activity test. Infrared photobeams provide information of when an animal is moving in its home cage. Animals in their home cages are placed in the photobeam boxes, and data are generated that provide insight into the animal's circadian rhythms activity, as well as general traits of activity (e.g., hypoactivity or hyperactivity) during the testing period.
Another test assays open field activity. Locomotor activity is detected by photobeam breaks as the animal crosses each beam. Measurements used to assess locomotor activity include, for example, total distance traveled, total number of rearing events (animal raises up on hindlimbs), and distance traveled in the center compared to total distance traveled (center: total distance ratio). Typically, mice are placed in the center of the field. Mice will normally explore the edges/walls first and then, over time, spend more time in the center as they become familiar with the environment. Open field activity determination provides data on the general activity level of mice (i.e. hypo- or hyper-active), as well as an indication of the animal's anxiety-related behaviors in an open-space.
Other means for measuring animal activity include measurement of circadian activity, electroencephalography, electromyography, locomotor activity, novel object exploration, sleep deprivation and sleep rebound after deprivation, susceptibility to acute administration of pharmacological agents in activity and sleep-related tests, susceptibility to chronic administration of pharmacological agents in activity and sleep- related tests, and wheel running activity. The study of sleep is canied out with the use of the electroencephalograph (EEG) and/or electromyography (EMG). Stereotaxic placement of electrodes onto the cortex for EEG recording and bilateral placement of electrodes into the trapezius muscle in the neck (EMG) allow the different stages of wake and sleep to be analyzed. Animals that display disrapted or altered sleep pattern may serve as models for screening for drugs that treat sleep disorders such as dysomnias and parasomnias.
Tests for determining whether a mouse has altered coordination or movement include the Balance Beam test, Bilateral Tactile Stimulation test, Circling Behavior test, Disengage test, Grip Strength test, Holeboard test, Paw Reaching test, Parallel Bar Walking test, Ring Catalepsy test, Rotorod test, Sterotypy Behavior test, or Vertical Pole test. Coordination and movement can also be assessed by assessment of exercise capacity, footprint pattern, forelimb asymmetry, posture, and gait.
In one example, motor coordination and skill learning is assessed using the rotarod assay, which measures the ability of an animal to maintain balance on an accelerating rotating rod. The mice must walk continuously to avoid falling off (see Crawley and Paylor, Hormones and Behavior 31 : 197-211 (1997)). Animals are generally given multiple trials spaced at least 20 minutes apart to allow for recovery from any fatigue testing may cause. In general, the time the animal spends walking on top of the rotating rod increases over the trials, thus demonstrating motor coordination and the ability to leam a rudimentary skill. This test relates to coordination and balance deficiencies.
Feeding and ingestive behaviors can be examined, for example, by monitoring 24 hour food consumption, 24 hour water consumption, body weight during development, circadian feeding patterns, conditioned taste aversion, conditioned taste preference, fasting studies (e.g., weight loss during fasting, weight gain after fasting, feeding response after fasting), liquid intake, macronutrient choice, novel food preference, rebound food consumption response after restricted daily access to food, response to specialized diets (e.g., cafeteria diet, high or low protein diet, high or low fat diet, and high or low carbohydrate diet), susceptibility to acute administration of pharmacological agents in feeding paradigms, and susceptibility to chronic administration of pharmacological agents in feeding paradigms. Food consumption over consecutive days may be determined, e.g., during the monitoring of home cage activity. The amount of consumed food and the body weight of the mouse are determined at various timepoints. If desired, the frequency and duration of eating may also be determined. This assay provides insight into the appetite and eating habits that might relate to eating conditions or disorders.
Sexual responsiveness can be tested, e.g., in a clear chamber with video recording. Male mice are tested to determine if they respond normally to a female mouse. Measurements used to assess normal male responsiveness include, but not limited to, mount latency, mount frequency, pelvic thrusts, intromissions, and ejaculation. Female mice are also tested to determine their sexual receptivity to a male. Measurements used to assess normal female receptivity involve assessing the degree and frequency of lordosis behavior. Sexual behaviors can also be measured by examining sexual motivation, ethologically relevant behaviors (e.g., anogenital investigation) as part of normal social interactions, susceptibility to acute administration of pharmacological agents in sexual responsiveness assays, and susceptibility to chronic administration of pharmacological agents in sexual responsiveness assays. These assays can be used to determine sexual activity in general and to detect any abnormal sexual behavior that might relate to sexual conditions or disorders.
Nociceptive behaviors can be assessed using a test that measures, for example, allodynia as a model for chronic pain, inflammatory pain, pain threshold, sensitivity to drag-induced analgesia, thermal pain, mechanical pain, chemical pain, hyperalgesia, or shock sensitivity. Particular tests include the allodynia/place avoidance, calibrated von Frey hairs for mechanical pain, cold plate test, cold water tail immersion test, conditioned suppression, formalin paw assay, Hargreaves test, hot plate test, hot water tail immersion test, paw pressure test, paw withdrawal, plantar test, tail flick test, tail pressure test, and the writhing test, susceptibility to acute administration of pharmacological agents in nociception tests, and susceptibility to chronic administration of pharmacological agents in nociception tests. In one example, a mouse's nociception is assessed by placing the mouse on a 55°C hot plate. The latency to a hind limb response (shake or lick) is measured. This assay provides data on the animal's general analgesic response to a thermal stimulus, and is used to detect a nociceptive condition or disorder. The formalin paw assay measures the response to a noxious chemical injected into the hindpaw. Licking and biting of the hindpaw is quantified as the amount of time engaged in these activities. Two phases of responses are demonstrated with the first phase representing an acute pain response and the second phase representing a hyperalgesic response. Alterations in this normal biphasic display may serve as a model of various forms of pain and chronic pain disorders (Abbott et al., Pain 60: 91-102 (1995)).
Tests that measure or detect anxiety-related behaviors include acoustic startle habituation, acoustic startle reactivity, active avoidance, the canopy test, conditioned emotional response, conditioned suppression of drinking, conditioned ultrasonic vocalization, dark light emergence task, defensive burying, dPAG-induced flight, elevated plus maze, elevated zero maze, exploration tests in a novel environment, fear- potentiated startle, food exploration test, four plate test, Gellar-Seifter conflict test, light- dark box, light-enhanced startle, marble burying test, minor chamber, novelty supressed feeding, pain-induced ultrasonic vocalizations, petition test, passive avoidance, probe burying test, punished locomotion test, separation-induced ultrasonic vocalizations, shock sensitization of startle response, social competition, social interaction, staircase test, susceptibility to acute administration of pharmacological agents in anxiety-related assays, and susceptibility to chronic administration of pharmacological agents in anxiety-related assays. One such test is the light-dark exploration test, which measures the conflict between the natural tendencies of mice to explore novel environments but to avoid the aversive properties of brightly lit (anxiety-provoking) open areas. In this test, the brightly lit compartment encompasses about two-thirds of the surface area, while the dark compartment encompasses the remaining one-third of the area. An opening is designed to allow the mouse access to both compartments. The mouse is placed at the one end of the brightly lit compartment. The latency to enter the dark compartment, total time spent in the dark compartment, and the number of transitions between the two compartments is measured to give a sense of an anxiety-related response that might be related to an anxiety condition or disorder.
Tests for identifying stress-related behaviors include electric footshock stress tests, handling stress test, maternal separation stress test, restraint induced stress test, sleep deprivation stress test, social isolation stress test, swim stress test, stress-induced hyperthermia, and susceptibility to acute or chronic administration of pharmacological agents in stress-related tasks. These assays provide the ability to study stress and to provide insight into behaviors that may be related to stress conditions or disorders.
Tests for identifying fear-related behaviors in rodents include conditioned fear, fear potentiated startle, fear-response behavior, mouse defense test battery, ultrasonic vocalization test, and susceptibility to acute or chronic adminisfration of pharmacological agents in fear-related tests. These assays provide the ability to study emotional based behaviors that may be related to fear-based conditions or disorders. Depression-related tests include acute restraint, chronic restraint, circadian activity, conditioned defensive burying, differential reinforcement to low rate of responding, learned helplessness, Porsolt forced swim test, tail suspension test, sucrose preference test, and susceptibility to acute or chronic administration of pharmacological agents in depression-related tests. Another is the tail suspension test, which includes suspending a mouse by its tail and measuring the duration of time it continues to straggle to escape from an inescapable situation. The time spent struggling is considered a measure of learned helplessness behavior or behavioral despair. The latency to the onset of the end of the straggling can be increased by clinically effective antidepressants. This assay therefore can be used to identify mice that may serve as models for depressive disorders. Mood related behavioral assays include latent inhibition, marble burying, prepulse inhibition of the acoustic startle response, and susceptibility to acute and chronic administration in mood-related tests. Prepulse inhibition of the acoustic startle response occurs when a loud (120 dB) startle stimulus is preceded by a softer tone that does not elicit a startle response (the prepulse). It is believed that this is a measure of a filtering mechanism in the nervous system that allows an individual to focus on important incoming information and to ignore unimportant information. Schizophrenic patients have been documented to have impaired prepulse inhibition; therefore this test can be used employing mice to identify those having a response that may be indicative of schizophrenia or another psychotic disorder. Suitable tests for assessing a mouse's learning and memory capacity include, for example, those that measure active avoidance, autoshaping, bames maze, conditioned taste aversion, conditional spatial alternation, context and auditory cued conditioned fear, contextual discrimination, delayed matching to position, delayed matching/non- matching to position, eyeblink conditioning, fear potentiated startle, figure 8 maze, holeboard test, motor learning using an accelerated rotarod, place aversion test, novel object recognition, olfactory discrimination, passive-avoidance, position/response learning, schedule-induced operant behaviors, radial arm maze, social recognition, social transmission of food preference, step down avoidance, taste learning, temporal processing using the Peak procedure, trace conditioning, T maze avoidance, transverse patterning, visual discrimination, water maze, place memory test, vigilance test, and Y maze, and Y maze avoidance.
The Morris water maze test is an assay that measures spatial learning and memory. An animal is trained in a pool of opaque water to locate a platform hidden under the water's surface using spatial cues external cues in the room. Measurements of spatial learning require analysis of spatial selectivity on a probe trial, in which the platform has been removed and the pattern in which the animal searches is examined. An animal that has learned the position of the platfonn using spatial cues will spend more time in the quadrant where the platform was located, and will also cross the precise location of the platform more often versus other possible sites. This complex learning task provides a way to determine learning and memory deficits and enhancements, and offers insight into the neural mechanisms of learning and memory (Crawley et al., Psychopharmacology 132: 107-124 (1997)). Context and auditory cue fear conditioning (i.e., conditioned fear) is determined by placing a mouse in an enclosed chamber in which the floor is equipped to deliver a mild electrical shock to the mouse's feet. The.training day consists of placing the mouse in the chamber and allowing it to explore the environment. At the end of the exploration period, a white noise is turned on (i.e., the conditioning stimulus, CS). A footshock is paired with the white noise turning off. This training trial is then repeated again. At the end of the second trial, the mouse is returned to its home cage. The mouse is tested 24 hours later by separately assaying the amount of freezing exhibited in the context in which it was shocked (Context Test) and the amount of freezing exhibited to the white noise (CS Test). As the mouse conditions to the pairing of the tone and shock, it may exhibit a freezing behavior due to the fear that the mild foot shock imparts to the mouse. Freezing behavior on the test day suggests that the mouse has learned that it received a shock in this particular context when the white noise is turned off. This test is considered to provide data about emotional-based learning and memory.
Aggression and other social behaviors can be monitored by observation or quantification of behaviors such as grooming, home cage behaviors (e.g., nesting, huddling, playing, and barbering) isolation-induced fighting, maternal behavior, parental behavior, social interaction, social investigation. Particular tests include the Partition test, the social defeat test, the Resident versus Intruder test, and the Social Place Preference test. Any of the foregoing can be used to determine a mouse's susceptibility to acute or chronic administration of pharmacological agents. The resident-intruder paradigm is an assay that demonstrates species-specific aggressive behavior. This test is conducted by individually housing an animal (the resident) and introducing a new animal of the same gender (the intrader) into the cage. The new animal is viewed by the resident animal as an intruder and displays aggressive behaviors toward the intruder (Crasio, Behavior Genetics 26: 459-533 (1996)). The normal display of aggression towards an intrader may serve as a model for examining increased or decreased aggression to a normal environmental situation. One test for social dominance can be carried out to assay social interactions and social behaviors. In the so-called "tube test," a mouse is placed into the end of a plexiglass cylinder and another mouse (called a social cohort) is placed at the other end of the tube. The animal that backs out of the tube first is considered the loser and the mouse that remains in the tube is considered the winner. In general, an animal that backs out of the tube during the first round generally backs out of the tube in subsequent rounds. A ranking can then be given to each animal, thus identifying the dominance or submissive status of an animal within a social context, as well as detecting abnormal social behaviors that can be related to antisocial personality conditions or disorders.
Behaviors relating to reward and addiction are assessed using tests that measure, for example, reward and place preference, self-administration of drags of abuse (acute and chronic), sensitization and tolerance to drags of abuse, sensitization to the motor activating properties of drags, tolerance to repeated analgesic drag adminisfration, or withdrawal symptoms after repeated self-administration of drags of abuse. The impact on self-administration of drags of abuse in stress tests can also be used to assess addiction.
Tolerance and sensitivity to. ethanol and cocaine can be tested, for example, by examining core body temperature of the mice after an infra-peritoneal (i.p.) injection of cocaine or ethanol. Initial sensitivity to cocaine and alcohol can be measured in mice after a single (acute) dose. In rodents, repeated exposure to alcohol or cocaine via repeated injections across days has been shown to produce tolerance. In both the alcohol studies and the cocaine studies, mice are administered an i.p. dose, and core body temperature is measured post injection with a digital thermometer with a rectal probe. On Day 2, mice are administered the same dose using the same route, and temperature again recorded post injection. For the cocaine studies, mice will be administered an i.p. dose and core body temperature will be measured post injection with a rectal thermometer. On Day 2 mice will be administered the same dose using the same route and temperature will be recorded post injection. Tolerance to the drug is indicated by an increase in body temperature on the second day of drag administration compared to the first day of drug administration. These assays detect sensitivity to various drug substances and, thus, are indicators of alcohol or cocaine use disorders.
The rewarding effects of various substances of abuse can be studied using the conditioned place preference paradigm and self-administration tests. The place preference paradigm is a non-invasive method that is amenable to classical Pavlovian conditioning. The rewarding drag serves as an unconditioned stimulus (US) that is paired with an environment that serves as the conditioned stimulus (CS). Given a choice between exploring a novel environment and the drug-paired CS environment, the animals prefer the drag-paired CS environment, thereby demonstrating conditioned place preference (Itzhak and Martin, Neuropsychopharmacology 26: 130-134 (2002)). This Pavlovian conditioned response to a drag of abuse has been postulated to be involved in drug-seeking behavior and relapse following exposure to cues that were previously associated with drag use. Self-administration studies, in general, allow the animal to regulate the administration of a drag to its nervous system. With these types of studies, extinction and reinstatement of drag intake behaviors can be examined and may serve as a model for drag-seeking behavior and relapse in humans (Stewart J, Vezina P., Brain Res 1988 Aug 9; 457(2):287-94).
Administration of a drag such as bicuculine can be utilized to study an animal's susceptibility to seizures or seizure-like events. Mice that enter into classical seizure symptoms earliest are considered to be more susceptible to seizures. Likewise, mice that present seizure symptoms later than normal, are considered to be more resistant to seizures. This assay may allow the identification of alterations central to the formation of seizure disorders and related conditions.
Methods for performing many of the foregoing screens are well known in the art (see, e.g., Brunner et al., J. Exp. Psychol. Anim. Behav. Process 20: 331-346 (1994), Crawley, What's Wrong With My Mouse? (John Wiley and Sons, Somerset, NJ, 2000). Crawley et al., (eds.) Cunent Protocols in Neuroscience (John Wiley and Sons, Somerset, NJ, 2001), Crawley et al., Hormones Behav. 31: 197-211 (1997), Crawley et al., Psychopharmocol. (Berl) 132: 107-124 (1997), Galey et al, Neurosci. Lett. 143: 87- 90 (1992), Hascoet et al., Pharmacol. Biochem. Behav. 65: 339-344 (2000), Martinez- Mota et al., Psychoneuroendocrinol. 25: 109-120 (2000), Mogil et al., Pain 80: 67-82 (1999), Toubas et al, Pharmacol. Biochem. and Behav. 35: 121-126 (1990), Van Der Hyden et al, Physiol. Behav. 62: 463-470 (1997), Walker et al., Molec. Med. Today 5: 319-321 (1999)).
In addition to the initial screening of test compounds, the animals having mutant nuclear receptor genes are useful for further testing of efficacy and safety of drags or agents first identified using one of the other screening methods described herein. Cells taken from the animal and placed in culture can also be exposed to test compounds.
Testing Mice with Other Diseases, Disorders, Conditions, or Syndromes
The effect of overexpression, underexpression, misexpression, or mutation of a nuclear receptor of the present invention can be assayed, for example, using any of a wide variety, of measurements or tests; Barbee et al., Am. J. Physiol. 263:R728-733,
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General physiological tests and measurements include, for example, measurement of body temperature, body length and proportions, body mass index, general health appearance, vocalization during handling, and lacrimation and salivation, visual tests (e.g., visual cliff, reaching response, visual menace), auditory tests (e.g., click test, acoustic startle, acoustic threshold), olfactory tests (e.g., sniffing and habituation to a novel odor, finding buried food), reflex tests (e.g., righting reflex, eye blink, whisker twitch), measurement of metabolic hormones (e.g., leptin, IGF-1, insulin, metabolites), whole body densitometry by dual energy x-ray absoφtiomefry DEXA or high resolution radiography (Faxitron), and necropsy examination of organ systems. Identification of a skin disease or disorder may be made by histopathology, examination of fur and skin condition, examination of pigmentation of fur and skin, and determination of wound healing by an ear punch test.
Cardiac diseases and disorders can be identified, for example, by means of histopathology or electrocardiography, or by determination of blood pressure, blood velocity, blood flow, or pulse rate.
Identifying mice having a disorder of the respiratory system, including the lungs, nose, larynx, trachea, and pleura, can be performed by histopathology, or by determination of lung capacity, respiration rate, VO2, pCO2, arterial pO2, and tidal volume. Testing mice for disorders of the immune and hematopoietic systems, including blood, bone manow, thymus, spleen and lymph nodes, can be performed, for example, by histopathology, delayed hypersensitivity test, measurement of seram immunoglobins, blood pH, or coagulation time, volumetric analysis using Evans blue dye technique, or analysis of bone manow smears, hematocrit, hemoglobin, erythrocytes, reticulocytes, leukocytes, platelets, prothrombin, electrolytes, or lymphocytes.
Knock-out or transgenic mice of the present invention may have a disease or disorder of the digestive tract (e.g., the esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, and rectum). Testing for these diseases and disorders of the digestive tract, may include fecal analysis, measurement of digestive enzymes, or histopathology. Identification of mice having a disease or disorder of the liver may be by means of histopathology or analysis of total proteins, albumin, bilirabin, creatinine, transaminase, cholesterol, aldolase, ammonia, sorbitol dehydrogenase, or seram bile acids
Testing for disorders of the pancreas in mice may be performed, for example, by histopathology, a glucose tolerance test, an insulin challenge test, or analysis of glucose, insulin, glucogon, or exocrine enzymes.
Testing for diseases or disorders of the urinary system, including the kidney, ureter, and urinary bladder, may include histolopathological examination, or analysis of sodium osmolality, potassium, urea nitrates, creatinine, chloride, bicarbonate, glucose, cystatin c, or urine electrolytes or blood pressure.
Testing mice for diseases or disorders of the female reproductive tract, including the ovary, oviducts, uteras, and vagina, may include determination of fertility (e.g., by vaginal plugging), cyclicity (e.g., by vaginal smears), parturition (e.g., by litter size), maternal behavior (e.g., by pup survival and nesting, histopathology, or analysis of levels of estrogens, follicle-stimulating hormone, or luteinizing hormone. Similarly, testing mice for diseases or disorders of the male reproductive tract, including the testis, epididymus, prostate, seminal glands, accessory glands, and penis may include histopathological examination, determination of fertility, sperm counts and motility, erectile capacity (e.g., by plethysmography), and/or analysis of levels of androgens, follicle-stimulating hormone, PSA or luteinizing hormone.
Mice having diseases or disorders of the musculature may be identified by histopathology, electromyography, testing of muscle strength and contractibility, or analysis of levels of creatinine, lactate, myoglobin, or isoenzymes.
Testing mice for diseases or disorders of the skeletal system may include, for example, bone strength determination, histopathological examination, mineral analysis, dual energy x-ray absoφtiometry (DEXA), or analysis of osteocalcin, calcitrol, urine pyridinium, or N-telopeptide. Testing mice for diseases or disorders of the endocrine system, including the pituitary, thyroid gland, adrenal gland, and mammary glands, may also be performed. Testing may include, for example, histopathological examination, determination of lactation capacity, testing of hormone release, and/or analysis of corticosterone, adrenocorticotrophic hormone, corticotrophin releasing hormone, thyroid hormone, thyrotropin releasing hormone, thyroid stimulating hormone, chorionic gonadotripin, growth hormone, growth hormone-releasing hormone, somatostatin, prolactin, alpha- melanocyte stimulating hormone, follicle-stimulating hormone, luteinizing hormone, or gonadofropin hormone-releasing hormone.
Finally, testing for mice for diseases or disorders of the nervous system, including the brain, spinal cord and peripheral ganglia, may include determination of stroke susceptibility (e.g., by focal ischemia or cerebral occlusion), histopathological examination, determination of neurotransmitter release (e.g., by microdialysis or cell culture) or synaptic transmission (e.g., by electrophysiology in brain slices), brain wave analysis by electroencephalography (EEG), whole brain imaging by magnetic resonance imaging, transmitter content determination by HPLC, protein localization and cell type analysis (e.g., by immunohistochemistry), neuron apoptosis determination (e.g., by TUNEL assay), total cell count, or examination of fiber tract localization and integrity, dendritic and axonal moφhology, and structural integrity by moφhometric analysis.
Therapy
Compounds of the invention, including but not limited to, nuclear receptor polypeptides, nuclear receptor polynucleotideis, and any therapeutic agent that modulates biological activity or expression of a nuclear receptor polypeptide identified using any of the methods disclosed herein, maybe administered with a pharmaceutically-acceptable diluent, carrier, or excipient, in unit dosage form. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer such compositions to patients. Any appropriate route of administration may be employed, for example, parenteral, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracistemal, intraperitoneal, intranasal, aerosol, or oral administration. Therapeutic formulations maybe in the form of liquid solutions or suspension; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols.
Methods well known in the art for making formulations are found in, for example, Remington: The Science and Practice' of Pharmacy, (20th ed.) ed. A.R. Gennaro AR., 2000, Lippincott: Philadelphia. Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for agonists of the invention include ethylenevinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, or example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils,. polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
In all cases, the composition must be sterile, and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absoφtion of the injectable compositions can be brought about by including in the composition an agent which delays absoφtion, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incoφorating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the prefened methods of preparation are vacuum drying and freeze- drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. ι Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the puφose of oral therapeutic administration, the active compound can be incoφorated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention 5 enemas for rectal delivery. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic
10 acid.
Methods for preparation of such formulations will be apparent to those skilled in ■ the art. The materials can also be obtained commercially from Alza Coφoration and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with- monoclonal antibodies to' viral antigens) can also be used as
15 pharmaceutically acceptable caniers. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in
20 association with the required pharmaceutical carrier. Depending on the type and severity of the disease, about 1 ug/kg to 15 mg/kg (e.g., 0.1 to 20 mg/kg) of antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. A typical daily dosage might range from about 1 ug/kg to 100 mg/kg or more, depending on the factors mentioned above.
25 For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy can be monitored by standard techniques and assays. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique
3.0 . characteristics of the active compound and the particular therapeutic effect to-be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic.index and it can be expressed as the ratio
LD50/ED50. Compounds which exhibit large therapeutic indices are prefened. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any. compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a protein, polypeptide, or antibody can include a single treatment or, preferably, can include a series of treatments.
The present invention encompasses agents that modulate expression or activity. An agent may, for example, be a small molecule. For example, such small molecules include, but are not limited to, peptides, peptidomimetics, amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e.,. including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds. It is understood that appropriate doses of small molecule agents depends upon a number of factors within the ken of the ordinarily skilled physician, veterinarian, or researcher. The dose(s) of the small molecule will vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable, and the effect which the practitioner desires the small molecule to have upon the nucleic acid or polypeptide of the invention.
It is understood that appropriate doses of a small molecule depend upon the potency of the small molecule with respect to the expression or activity to be modulated. Such appropriate doses may be determined using the assays described herein. When one or more of these small molecules is to be administered to an animal (e.g., a human) in order to modulate expression or activity of a polypeptide or nucleic acid of the invention, a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.
Diagnostics
Expression, biological activity, and mutational analysis of a nuclear receptor gene of the invention can each serve as a diagnostic tool for a disease or disorder involving the nuclear receptor; thus determination of the genetic subtyping of a nuclear receptor gene sequence can be used to subtype individuals or families to determine their predisposition for developing a particular disease or disorder.
An exemplary method for detecting the presence or absence of a nuclear receptor protein or nucleic acid in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting nuclear receptor protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes nuclear receptor protein such that the presence of nuclear receptor protein or nucleic acid is detected in the biological sample. A prefened agent for detecting nuclear receptor mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to nuclear receptor mRNA or genomic DNA.
The nucleic acid probe can be, for example, a full-length nuclear receptor nucleic acid, such as the nucleic acid of Table 1, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to nuclear receptor mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.
Another method for detecting the presence or absence of a nuclear receptor protein in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with an antibody that is capable of detecting nuclear receptor protein. Where said antibody capable of binding to the nuclear receptor protein preferably has a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')2) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect nuclear receptor mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of nuclear receptor mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of nuclear receptor protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence. In vitro techniques for detection of nuclear receptor genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of nuclear receptor protein include introducing into a subject a labeled anti-nuclear receptor antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.
In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A prefened biological sample is a seram sample isolated by conventional means from a subject.
In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting nuclear receptor protein, mRNA, or genomic DNA, such that the presence of nuclear receptor protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of nuclear receptor protein, mRNA or genomic DNA in the control sample with the presence of nuclear receptor protein, mRNA or genomic DNA in the test sample.
The invention also encompasses kits for detecting the presence of nuclear receptor in a biological sample. For example, the kit can comprise a labeled compound or agent capable of detecting nuclear receptor protein or mRNA in a biological sample; means for determining the amount of nuclear receptor in the sample; and means for comparing the amount of nuclear receptor in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect nuclear receptor protein or nucleic acid.
The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with abenant nuclear receptor expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with a misregulation in nuclear receptor protein activity or nucleic acid expression, such as a weight, cardiovascular, neurological or endocrine disorder. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disorder associated with a misregulation in nuclear receptor protein activity or nucleic acid expression, such as a weight, cardiovascular, neural or endocrine disorder. Thus, the present invention provides a method for identifying a disease or disorder associated with abenant nuclear receptor expression or activity in which a test sample is obtained from a subject and nuclear receptor protein or nucleic acid (e.g., mRNA or genomic DNA) is detected, wherein the presence of nuclear receptor protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with abenant nuclear receptor expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., seram), cell sample, or tissue.
Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic,'protein, peptide, nucleic acid, small molecule, or other drag candidate) to treat a disease or disorder associated with abenant nuclear receptor expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a weight, cardiovascular, neural or endocrine disorder. Thus, the present invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with abenant nuclear receptor expression or activity in which a test sample is obtained and nuclear receptor protein or nucleic acid expression or activity is detected.
The methods of the invention can also be used to detect genetic alterations in a nuclear receptor gene, thereby determining if a subject with the altered gene is at risk for a disorder characterized by misregulation in nuclear receptor protein activity or nucleic acid expression, such as a weight, cardiovascular, neural or endocrine disorder. In prefened embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic alteration characterized by at least one of an alteration affecting the integrity of a gene encoding a nuclear receptor -protein, or the mis- expression of the nuclear receptor gene. For example, such genetic alterations can be detected by ascertaining the existence of at least one of 1) a deletion of one or more nucleotides from a nuclear receptor gene; 2) an addition of one or more nucleotides to a nuclear receptor gene; 3) a substitution of one or more nucleotides of a nuclear receptor gene, 4) a chromosomal reanangement of a nuclear receptor gene; 5) an alteration in the level of a messenger RNA transcript of a nuclear receptor gene, 6) abenant modification of a nuclear receptor gene, such as of the methylation pattern of the genomic DNA, 7) the presence of a non- wild type splicing pattern of a messenger RNA transcript of a nuclear receptor gene, 8) a non- wild type level of a nuclear receptor-protein, 9) allelic loss of a nuclear receptor gene, and 10) inappropriate post-translational modification of an nuclear receptor- protein. As described herein, there are a large number of assays known in the art which can be used for detecting alterations in a nuclear receptor gene. A prefened biological sample is a tissue or seram sample isolated by conventional means from a subject.
In certain embodiments, detection of the alteration involves the use of a probe/primer in a polymerase chain reaction (PCR) such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al. (1988) Science 241:1077-1080; and Nakazawa et al. (1994) Proc. Natl. Acad Sci. USA 91:360- 364), the latter of which can be particularly useful for detecting point mutations in the nuclear receptor - gene (see Abravaya et al. (1995) Nucleic Acids Res.23:675-682). This method can include the steps of collecting a sample of cells from a subject, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers which specifically hybridize to a nuclear receptor gene under conditions such that hybridization and amplification of the nuclear receptor gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.
Alternative amplification methods include: self sustained sequence replication (Guatelli, J.C et al., (1990) Proc. Natl. Acad Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh, D. Y. et al., (1989) Proc. Nail. Acad Sci. USA 86:1173- 1177), Q-Beta Replicase (Lizardi, P.M. et al. (1988) Bio-Technology 6:1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.
In an alternative embodiment, mutations in a nuclear receptor gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.
In other embodiments, genetic mutations in nuclear receptor can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density anays containing hundreds or thousands of oligonucleotides probes (Cronin, M.T. et al. (1996) Human Mutation 7: 244-255; Kozal, M.J. et al. (1996) Nature Medicine 2: 753- 759). For example, genetic mutations in nuclear receptor can be identified in two dimensional anays containing light-generated DNA probes as described in Cronin, M.T. et al. (1996) Human Mutation 7: 244-255.
Briefly, a first hybridization anay of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear anays of sequential overlapping probes. This step allows the identification of point mutations. This step is followed by a second hybridization anay that allows the characterization of specific mutations by using smaller, specialized probe anays complementary to all variants or mutations detected. Each mutation anay is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.
In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the nuclear receptor gene and detect mutations by comparing the sequence of the sample nuclear receptor with the conesponding wild- type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxam and Gilbert (1977) Proc. Natl. Acad. Sci. USA 74:560 or Sanger (1977) Proc. Nati. Acad. Sci. USA 74:5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays ((1995) Biotechniques 19:448), including sequencing by mass spectrometry (Cohen et al. (1996) Adv. Chromatogr. 36:127-162; and Griffin et al. (1993) AppL. Biochem. Biotechnol. 38:147-159). Other methods for detecting mutations in the nuclear receptor gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA RNA or RNA/DNA heteroduplexes (Myers et al. (1985) Science 230:1242). In general, the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type nuclear receptor sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with SI nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. For examples see, Cotton et al. (1988) Proc. Natl Acad Sci USA 85:4397; and Saleeba et al. (1992) Methods Enzymol. 217:286-295. In a prefened embodiment, the control DNA or RNA can be labeled for detection.
In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in nuclear receptor cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches (Hsu et al. (1994) Carcinogenesis 15:1657-1662). According to an exemplary embodiment, a probe based on a nuclear receptor sequence, e.g., a wild-type nuclear receptor sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like.
In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in nuclear receptor genes. For example, single strand conformation polymoφhism (SSCP) maybe used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids (Orita et al. (1989) Proc Nati. Acad. Sci USA: 86:2766, see also Cotton (1993) Mutat. Res. 285:125-144; and Hayashi (1992) Genet. Anal. Tech. AppL. 9:73-79). Single-stranded DNA fragments of sample and control LGR6 nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change.
The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In a prefened embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet 7:5).
In yet another embodiment the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al. (1985) Nature 313:495). When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of confrol and sample DNA (Rosenbaum and Reissner (1987) Biophys Chem 265:12753).
Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions which permit hybridization only if a perfect match is found (Saiki et al. (1986) Nature 324:163); Saiki et al. (1989) Proc. Natl. Acad Sci USA 86:6230). Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA. Alternatively, allele specific amplification technology which depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may cany the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization) (Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme 3' end of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (Prossner (1993) Tibtech 11 :238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection (Gasparini et al. (1992) Mol. Cell Probes 6:1). It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification (Barany (1991) Proc. Natl. Acad Sci USA 88:189). In such cases, ligation will occur only if there is a perfect match at the 3' end of the 5' sequence making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.
The methods described herein may be performed, for example, by utilizing prepackaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a nuclear receptor gene.
This diagnostic process can also lead to the tailoring of drag treatments according to patient genotype, including prediction of side effects upon administration of drugs (refened to herein as pharmacogenomics). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual is examined to determine the ability of the individual to respond to a particular agent).
Agents, or modulators, that have a stimulatory or inliibitory effect on the biological activity or gene expression of a nuclear receptor polypeptide of the invention can be administered to individuals to treat disorders associated with abenant nuclear receptor activity. In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drag) of the individual may be considered. Differences in efficacy of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drag. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of a nuclear receptor polypeptide of the invention, expression of a nuclear receptor nucleic acid, or polymoφhic content of nuclear receptor genes in an individual can be determined to select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. Pharmacogenomics deals with clinically significant hereditary variations in the response to drags because of altered drug disposition and abnormal action in affected persons (Eichelbaum, Clin. Exp. Pharmacol. Physiol., 23:983-985, 1996; Linder, Clin. Chem., 43:254-266, 1997). In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drags act on the body (altered drag action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). Altered drug action may occur in a patient having a polymoφhism (e.g., an single nucleotide polymoφhism or SNP) in promoter, intronic, or exonic sequences of a nuclear receptor polypeptide of the invention. Thus, determining the presence and prevalence of polymoφhisms may allow for prediction of a patient's response to a particular therapeutic agent. In particular, polymoφhisms in the promoter region may be critical in determining the risk that a patient will develop a particular disease or disorder.
Gene Therapy
Gene therapy is another potential therapeutic approach in which normal copies of a gene or nucleic acid encoding sense RNA for a nuclear receptor of the invention are introduced into cells to successfully produce nuclear receptor polypeptide. The gene must be delivered to those cells in a form in which it can be taken up and encode for sufficient protein to provide effective function. Alternatively, nuclear receptor antisense RNA or other inhibitory RNA or a gene that expresses such RNA may be introduced into cells that express, perhaps excessively, a wild-type or polymoφhic nuclear receptor polypeptide. The gene or RNA must be delivered to those cells in a form in which it can be taken up and provide for sufficient RNA to provide effective function.
Retroviral vectors, adenoviral vectors, adenoviras-associated viral vectors, or other viral vectors with the appropriate tropism for a particular cell involved in disease may be used as a gene transfer delivery system for delivering such polynucleotides. Numerous vectors useful for this puφose are generally known (Miller, Human Gene Therapy 15-14,, 1990; Friedman, Science 244:1275-1281, 1989; Eglitis and Anderson, BioTechniques 6:608-614, 1988; Tolstoshev and Anderson, Cun. Opin. Biotech. 1:55- 61, 1990; Shaφ, Lancet 337: 1277-1278, 1991; Cometta et al., Nucl. Acid Res. and Mol. Biol. 36: 311-322, 1987; Anderson, Science 226: 401-409, 1984; Moen, Blood Cells 17: 407-416, 1991; Miller et al., Biotech. 7: 980-990, 1989; Le Gal La Salle et al, Science 259: 988-990, 1993; and Johnson, Chest 107: 77S-83S, 1995). Retroviral vectors are particularly well developed and have been used in clinical settings (Rosenberg et al., N. Engl. J. Med. 323: 370, 1990; Anderson et al., U.S. PatentNo. 5,399,346). Non-viral approaches may also be employed for the introduction of therapeutic DNA into diseased cells. For example, nuclear receptor may be introduced into a cell by lipofection (Feigner et al., Proc. Natl. Acad. Sci. USA 84: 7413, 1987; Ono et al., Neurosci. Lett. 117: 259, 1990; Brigham et al., Am. J. Med. Sci. 298:278, 1989; Staubinger et al., Meth. Enzymol. 101:512, 1983), asialorosonucoid-polylysine conjugation (Wu et al., J. Biol. Chem. 263:14621, 1988; Wu et al., J. Biol. Chem. 264:16985, 1989); or, less preferably, micro-injection under surgical conditions (Wolff et al., Science 247:1465, 1990).
Gene transfer can also be achieved using non- viral means requiring introduction of the nucleic acid in vitro. This method would, for example, include calcium phosphate, DEAE dextran, electroporation, and protoplast fusion. Liposomes may also be potentially beneficial for delivery of DNA into a cell.
Many methods for introducing vectors into cells or tissues are available and equally suitable for use in vivo, in vitro and ex vivo. For ex vivo therapy, vectors may be introduced into stem cells taken from the patient and clonally propagated for autologous transplant back into that same patient. Delivery by transfection and by liposome injections may be achieved using methods that are well known in the art.
Transplantation of normal genes into the affected cells of a patient can also be useful therapy. In this procedure, a normal gene encoding a nuclear receptor polypeptide is transfened into a cultivatable cell type, either exogenously or endogenously to the patient. These cells are then injected into the targeted tissue(s). In the constructs described, nuclear receptor cDNA expression can be directed from any suitable promoter (e.g., the human cytomegalovirus (CMV), simian viras 40 (SV40), or metallothionein promoters), and regulated by any appropriate mammalian regulatory element. For example, if desired, enhancers known to preferentially direct gene expression in a particular cell may be used to direct nuclear receptor expression. The enhancers used could include, without limitation, those that are characterized as tissue- or cell-specific in their expression. Alternatively, if a nuclear receptor genomic clone is used as a therapeutic construct (for example, following isolation by hybridization with the nuclear receptor cDNA described above), regulation may be mediated by the cognate regulatory sequences or, if desired, by regulatory sequences derived from a heterologous source, including any of the promoters or regulatory elements described above.
Antisense or interfering RNA based strategies may be employed to explore nuclear receptor gene function and as a basis for therapeutic drag design. The principle is based on the hypothesis that sequence-specific suppression of gene expression can be achieved by intracellular hybridization between mRNA and a complementary antisense species. The formation of a hybrid RNA duplex may then interfere with the processing/transport/translation and/or stability of the target nuclear receptor mRNA. Antisense strategies may use a variety of approaches including the use of antisense oligonucleotides and injection of antisense RNA. Antisense effects can be induced by control (sense) sequences; however, the extent of phenotypic changes are highly variable. Phenotypic effects induced by antisense effects are based on changes in criteria such as protein levels, protein activity measurement, and target mRNA levels. Such technology is well known in the art, and sense or antisense oligomers, or larger fragments, can be designed from various locations along the coding or control regions of sequences encoding a nuclear receptor of the invention. In one example, the complementary oligonucleotide is designed from the most unique 5' sequence and used either to inhibit transcription by preventing promoter binding to the upstream nontranslated sequence or translation of a nuclear receptor encoding transcript by preventing the ribosome from binding. Using an appropriate portion of the signal and 5' sequence, an effective antisense oligonucleotide includes any 15-25 nucleotides spanning the region that translates into the signal or 5' coding sequence of the polypeptide or 21-23 nucleotide spanning region for small interfering RNAs. For example, gene therapy may also be accomplished by direct administration of antisense mRNA to a cell that is expected to be involved in a disease or disorder. The antisense mRNA may be produced and isolated by any standard technique, but it is most readily produced by in vitro transcription using an antisense cDNA under the control of a high efficiency promoter (e.g., the T7 promoter). Administration of antisense mRNA to cells can be carried out by any of the methods for direct nucleic acid administration described above.
Ribozymes, enzymatic RNA molecules, may also be used to catalyze the specific cleavage of RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. Examples, which may be used, include engineered hammerhead motif ribozyme molecules that can specifically and efficiently catalyze endonucleolytic cleavage of sequences encoding a nuclear receptor of the invention. Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites which include the following sequences: GUA, GUU, and GUC. Once identified, short RNA sequences of, e.g., between 15 and 25 ribonucleotides conesponding to the region of the target gene containing the cleavage site may be evaluated for secondary structural features that render the oligonucleotide inoperable. The suitability of candidate targets may also be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays.
Other nucleic acid molecules that create triple helices within a gene have also been demonstrated to block transcription. Antisense molecules and ribozymes of the invention may be prepared by any method known in the art for the synthesis of nucleic acid molecules. These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding a nuclear receptor polypeptide of the invention. Such DNA sequences may be incoφorated into a wide variety of vectors with suitable RNA polymerase promoters such as T7 or SP6. Alternatively, these cDNA constructs that synthesize antisense RNA constitutively or inducibly can be introduced into cell lines, cells, or tissues.
RNA molecules may be modified to increase intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept can be extended in all of these molecules by the inclusion of nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine, which are not as easily recognized by endogenous endonucleases.
An alternative strategy for inhibiting nuclear receptor function using gene therapy involves intracellular expression of an anti-nuclear receptor antibody or a portion of an anti-nuclear receptor antibody. For example, the gene (or gene fragment) encoding a monoclonal antibody that specifically binds to a nuclear receptor polypeptide and inhibits its biological activity may be placed under the transcriptional control of a cell type-specific gene regulatory sequence. The nuclear receptor sequences (Table 1) taught in the present invention facilitate the design of novel transcription factors for modulating nuclear receptor expression in native cells and animals, and cells transformed or transfected with nuclear receptor polynucleotides. For example, the CYS2-HiS2 zinc fmger proteins, which bind DNA via their zinc finger domains, have been shown to be amenable to structural changes that lead to the recognition of different target sequences. These artificial zinc fmger proteins recognize specific target sites with high affinity and are able to act as gene switches to modulate gene expression. Knowledge of the particular nuclear receptor target sequence of the present invention facilitates the engineering of zinc finger proteins specific for the target sequence using known methods such as a combination of structure-based modeling and screening of phage display libraries (Segal et al, Proc. Nat. Acad. Sci. USA 96:2758-2763 (1999); Liu et al, Proc. Nat. Acad. Sci. USA 94:5525-5530 (1997); Greisman et al, Science 275:657-661 (1997); Choo et al, J Mol Biol 273:525-532 (1997)). Each zinc finger domain usually recognizes three or more base pairs. Since a recognition sequence of 18 base pairs is generally sufficient in length to render it unique in any known genome, a zinc finger protein consisting of 6 tandem repeats of zinc fingers would be expected to ensure specificity for a particular sequence (Segal et al.). The artificial zinc finger repeats, designed based on nuclear receptor sequences, are fused to activation or repression domains to promote or suppress nuclear receptor expression (Liu et al.). Alternatively, the zinc fmger domains can be fused to the TATA box-binding factor with varying lengths of linker region between the zinc fmger peptide and the TBP to create either transcriptional activators or repressors (Kim et aL, Proc. Nat. Acad. Sci. USA 94:3616-3620 (1997). Such proteins and polynucleotides that encode them, have utility for modulating nuclear receptor expression in vivo in both native cells, animals and humans; and/or cells transfected with nuclear receptor -encoding sequences. The novel transcription factor can be delivered to the target cells by transfecting constructs that express the transcription factor (gene therapy), or by introducing the protein. Engineered zinc finger proteins can also be designed to bind RNA sequences for use in therapeutics as alternatives to antisense or catalytic RNA methods (McColl et aL, Proc. Natl. Acad. Sci. USA 96:9521- 9526 (1997); Wu et aL, Proc. Natl. Acad. Sci. USA 92:344-348 (1995)). The present invention contemplates methods of designing such transcription factors based on the gene sequence of the invention, as well as customized zinc fmger proteins, that are useful to modulate nuclear receptor expression in cells (native or transformed) whose genetic complement includes these sequences.
An alternative strategy for inhibiting nuclear receptor function using gene therapy involves intracellular expression of an anti- nuclear receptor antibody or a portion of an anti- nuclear receptor antibody. For example, the gene (or gene fragment) encoding a monoclonal antibody that specifically binds to a nuclear receptor polypeptide and inhibits its biological activity may be placed under the transcriptional confrol of a cell type-specific gene regulatory sequence.
Sequences Polynucleotide and polypeptide sequences for human and mouse nuclear receptors of the invention are listed below.
ANDR Human polypeptide sequence:
MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQ QQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGY VLDEE QPSQ PQSA ECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSS CSAD KDILSEASTMQ LQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISD NAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKG SLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPST S YKS GALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRY GDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGG GGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSE MGP MDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCK VFFKRAAEGKQKYLCASR DCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLK LQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGWCAGHDNNQPDS FAAL SSLNELGERQLVHVVKWAKALPGFRNLHΛ/TDDQMAVIQYSWMGLMVFAMGWRSF TNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEF CMKA LL FSIIPVDGLKNQKFFDELRMNYIKELDRIIACKRKNPTSCSRRFYQLTKL DSVQPIA
RELHQFTFDLLIKSHMVSVDFPEMMAEIISVQVPKILSGKVKPIYFHTQ
(SEQ IDNO: 1) Human polynucleotide sequence:
ATGGAAGTGCAGTTAGGGCTGGGAAGGGTCTACCCTCGGCCGCCGTCCAAGACCTACC GAGGAGCTTTCCAGAATCTGTTCCAGAGCGTCCGCGAAGTGATCCAGAACCCGGGCCC CAGGCACCCAGAGGCCGCGAGCGCAGCACCTCCCGGCGCCAGTTTGCTGCTGCTGCAG CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAAGAGACTAGCCCCA GGCAGCAGCAGCAGCAGCAGGGTGAGGATGGTTCTCCCCAAGCCCATCGTAGAGGCCC CACAGGCTACCTGGTCCTGGATGAGGAACAGCAACCTTCACAGCCGCAGTCGGCCCTG GAGTGCCACCCCGAGAGAGGTTGCGTCCCAGAGCCTGGAGCCGCCGTGGCCGCCAGCA AGGGGCTGCCGCAGCAGCTGCCAGCACCTCCGGACGAGGATGACTCAGCTGCCCCATC CACGTTGTCCCTGCTGGCCCCCACTTTCCCCGGCTTAAGCAGCTGCTCCGCTGACCTT AAAGACATCCTGAGCGAGGCCAGCACCATGCAACTCCTTCAGCAACAGCAGCAGGAAG CAGTATCCGAAGGCAGCAGCAGCGGGAGAGCGAGGGAGGCCTCGGGGGCTCCCACTTC CTCCAAGGACAATTACTTAGGGGGCACTTCGACCATTTCTGACAACGCCAAGGAGTTG TGTAAGGCAGTGTCGGTGTCCATGGGCCTGGGTGTGGAGGCGTTGGAGCATCTGAGTC CAGGGGAACAGCTTCGGGGGGATTGCATGTACGCCCCACTTTTGGGAGTTCCACCCGC TGTGCGTCCCACTCCTTGTGCCCCATTGGCCGAATGCAAAGGTTCTCTGCTAGACGAC AGCGCAGGCAAGAGCACTGAAGATACTGCTGAGTATTCCCCTTTCAAGGGAGGTTACA CCAAAGGGCTAGAAGGCGAGAGCCTAGGCTGCTCTGGCAGCGCTGCAGCAGGGAGCTC CGGGACACTTGAACTGCCGTCTACCCTGTCTCTCTACAAGTCCGGAGCACTGGACGAG GCAGCTGCGTACCAGAGTCGCGACTACTACAACTTTCCACTGGCTCTGGCCGGACCGC CGCCCCCTCCGCCGCCTCCCCATCCCCACGCTCGCATCAAGCTGGAGAACCCGCTGGA CTACGGCAGCGCCTGGGCGGCTGCGGCGGCGCAGTGCCGCTATGGGGACCTGGCGAGC CTGCATGGCGCGGGTGCAGCGGGACCCGGTTCTGGGTCACCCTCAGCCGCCGCTTCCT CATCCTGGCACACTCTCTTCACAGCCGAAGAAGGCCAGTTGTATGGACCGTGTGGTGG TGGTGGGGGTGGTGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGAGGCGGGAGCTGTA GCCCCCTACGGCTACACTCGGCCCCCTCAGGGGCTGGCGGGCCAGGAAAGCGACTTCA CCGCACCTGATGTGTGGTACCCTGGCGGCATGGTGAGCAGAGTGCCCTATCCCAGTCC CACTTGTGTCAAAAGCGAAATGGGCCCCTGGATGGATAGCTACTCCGGACCTTACGGG GACATGCGTTTGGAGACTGCCAGGGACCATGTTTTGCCCATTGACTATTACTTTCCAC CCCAGAAGACCTGCCTGATCTGTGGAGATGAAGCTTCTGGGTGTCACTATGGAGCTCT CACATGTGGAAGCTGCAAGGTCTTCTTCAAAAGAGCCGCTGAAGGGAAACAGAAGTAC CTGTGCGCCAGCAGAAATGATTGCACTATTGATAAATTCCGAAGGAAAAATTGTCCAT CTTGTCGTCTTCGGAAATGTTATGAAGCAGGGATGACTCTGGGAGCCCGGAAGCTGAA GAAACTTGGTAATCTGAAACTACAGGAGGAAGGAGAGGCTTCCAGCACCACCAGCCCC ACTGAGGAGACAACCCAGAAGCTGACAGTGTCACACATTGAAGGCTATGAATGTCAGC CCATCTTTCTGAATGTCCTGGAAGCCATTGAGCCAGGTGTAGTGTGTGCTGGACACGA CAACAACCAGCCCGACTCCTTTGCAGCCTTGCTCTCTAGCCTCAATGAACTGGGAGAG AGACAGCTTGTACACGTGGTCAAGTGGGCCAAGGCCTTGCCTGGCCTCCGCAACTTAC ACGTGGACGACCAGATGGCTGTCATTCAGTACTCCTGGATGGGGCTCATGGTGTTTGC CATGGGCTGGCGATCCTTCACCAATGTCAACTCCAGGATGCTCTACTTCGCCCCTGAT CTGGTTTTCAATGAGTACCGCATGCACAAGTCCCGGATGTACAGCCAGTGTGTCCGAA TGAGGCACCTCTCTCAAGAGTTTGGATGGCTCCAAATCACCCCCCAGGAATTCCTGTG CATGAAAGCCATGCTACTCTTCAGCATTATTCCAGTGGATGGGCTGAAAAATCAAAAA TTCTTTGATGAACTTCGAATGAACTACATCAAGGAACTCGATCGTATCATTGCATGCA AAAGAAAAAATCCCACATCCTGCTCAAGACGCTTCTACCAGCTCACCAAGCTCCTGGA CTCCGTGCAGCCTATTGCGAGAGAGCTGCATCAGTTCACTTTTGACCTGCTAATCAAG TCACACATGGTGAGCGTGGACTTTCCGGAAATGATGGCAGAGATCATCTCTGTGCAAG TGCCCAAGATCCTTTCTGGGAAAGTCAAGCCCATCTATTTCCACACCCAGTGA (SEQ ID NO: 2) Mouse polypeptide sequence:
MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREAIQNPGPRHPEAANIAPPGACLQQRQ ETSPRRRRRQQHTEDGSPQAHIRGPTGYLALEEEQQPSQQQAASEGHPESSCLPEPGA ATAPGKGLPQQPPAPPDQDDSAAPSTLSLLGPTFPGLSSCSADIKDILNEAGTMQLLQ QQQQQQQHQQQHQQHQQQQEVISEGSSARAREATGAPSSSKDSYLGGNSTISDSAKE CKAVSVSMGLGVEALEHLSPGEQLRGDCMYASLLGGPPAVRPTPCAPLPECKGLPLDE GPGKSTEETAEYSSFKGGYAKGLEGESLGCSGSSEAGSSGTLEIPSSLSLYKSGALDE AAAYQNRDYYNFPLALSGPPHPPPPTHPHARIKLENPLDYGSAWAAAAAQCRYGDLGS LHGGSVAGPSTGSPPATTSSSWHTLFTAEEGQLYGPGGGGGSSSPSDAGPVAPYGYTR PPQGLTSQESDYSASEWYPGGWNRVPYPSPNCVKSEMGPWMENYSGPYGDMRLDST RDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRND CTIDKFRRKNCPSCRLRKCYEAG TLGARKLKKLGNLKLQEEGENSNAGSPTEDPSQK MTVSHIEGYECQPIFLNVLEAIEPGWCAGHDNNQPDSFAALLSSLNELGERQLVHW KWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYR MHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRM NYIKELDRIIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVD FPEMMAEIISVQVPKILSGKVKPIYFHTQ (SEQ ID NO: 3)
Mouse polynucleotide sequence:
ATGGAGGTGCAGTTAGGGCTGGGAAGGGTCTACCCACGGCCCCCATCCAAGACCTATC GAGGAGCGTTCCAGAATCTGTTCCAGAGCGTGCGCGAAGCGATCCAGAACCCGGGCCC CAGGCACCCTGAGGCCGCTAACATAGCACCTCCCGGCGCCTGTTTACAGCAGAGGCAG GAGACTAGCCCCCGGCGGCGGCGGCGGCAGCAGCACACTGAGGATGGTTCTCCTCAAG CCCACATCAGAGGCCCCACAGGCTACCTGGCCCTGGAGGAGGAACAGCAGCCTTCACA GCAGCAGGCAGCCTCCGAGGGCCACCCTGAGAGCAGCTGCCTCCCCGAGCCTGGGGCG GCCACCGCTCCTGGCAAGGGGCTGCCGCAGCAGCCACCAGCTCCTCCAGATCAGGATG ACTCAGCTGCCCCATCCACGTTGTCCCTGCTGGGCCCCACTTTCCCAGGCTTAAGCAG CTGCTCCGCCGACATTAAAGACATTTTGAACGAGGCCGGCACCATGCAACTTCTTCAG CAGCAGCAACAACAGCAGCAGCACCAACAGCAGCACCAACAGCACCAACAGCAGCAGG AGGTAATCTCCGAAGGCAGCAGCGCAAGAGCCAGGGAGGCCACGGGGGCTCCCTCTTC CTCCAAGGATAGTTACCTAGGGGGCAATTCAACCATATCTGACAGTGCCAAGGAGTTG TGTAAAGCAGTGTCTGTGTCCATGGGATTGGGTGTGGAAGCATTGGAACATCTGAGTC CAGGGGAACAGCTTCGGGGAGACTGCATGTACGCGTCGCTCCTGGGAGGTCCACCCGC GGTGCGTCCCACTCCTTGTGCGCCGCTGCCCGAATGCAAAGGTCTTCCCCTGGACGAA GGCCCAGGCAAAAGCACTGAAGAGACTGCTGAGTATTCCTCTTTCAAGGGAGGTTACG CCAAAGGATTGGAAGGTGAGAGCTTGGGGTGCTCTGGCAGCAGTGAAGCAGGTAGCTC TGGGACACTTGAGATCCCGTCCTCTCTGTCTCTGTATAAATCTGGAGCACTAGACGAG GCAGCAGCATACCAGAATCGCGACTACTACAACTTTCCGCTGGCTCTGTCCGGGCCGC CGCACCCCCCGCCCCCTACCCATCCACACGCCCGTATCAAGCTGGAGAACCCATTGGA CTACGGCAGCGCCTGGGCTGCGGCGGCAGCGCAATGCCGCTATGGGGACTTGGGTAGT CTACATGGAGGGAGTGTAGCCGGGCCCAGCACTGGATCGCCCCCAGCCACCACCTCTT CTTCCTGGCATACTCTCTTCACAGCTGAAGAAGGCCAATTATATGGGCCAGGAGGCGG GGGCGGCAGCAGCAGCCCAAGCGATGCCGGGCCTGTAGCCCCCTATGGCTACACTCGG CCCCCTCAGGGGCTGACAAGCCAGGAGAGTGACTACTCTGCCTCCGAAGTGTGGTATC CTGGTGGAGTTGTGAACAGAGTACCCTATCCCAGTCCCAATTGTGTCAAAAGTGAAAT GGGACCTTGGATGGAGAACTACTCCGGACCTTATGGGGACATGCGTTTGGACAGTACC AGGGACCATGTTTTACCCATCGACTATTACTTTCCACCCCAGAAGACCTGCCTGATCT GTGGAGATGAAGCTTCTGGCTGTCACTACGGAGCTCTCACTTGTGGCAGCTGCAAGGT CTTCTTCAAAAGAGCCGCTGAAGGGAAACAGAAGTATCTATGTGCCAGCAGAAACGAT TGTACCATTGATAAATTTCGGAGGAAAAATTGCCCATCTTGTCGTCTCCGGAAATGTT ATGAAGCAGGGATGACTCTGGGAGCTCGTAAGCTGAAGAAACTTGGAAATCTAAAACT ACAGGAGGAAGGAGAAAACTCCAATGCTGGCAGCCCCACTGAGGACCCATCCCAGAAG ATGACTGTATCACACATTGAAGGCTATGAATGTCAGCCTATCTTTCTTAACGTCCTGG AAGCCATTGAGCCAGGAGTGGTGTGTGCCGGACATGACAACAACCAACCAGATTCCTT TGCTGCCTTGTTATCTAGCCTCAATGAGCTTGGAGAGAGGCAGCTTGTGCATGTGGTC AAGTGGGCCAAGGCCTTGCCTGGCTTCCGCAACTTGCATGTGGATGACCAGATGGCGG TCATTCAGTATTCCTGGATGGGACTGATGGTATTTGCCATGGGTTGGCGGTCCTTCAC TAATGTCAACTCCAGGATGCTCTACTTTGCACCTGACTTGGTTTTCAATGAGTACCGC ATGCACAAGTCTCGGATGTACAGCCAGTGTGTGAGGATGAGGCACCTGTCTCAAGAGT TTGGATGGCTCCAAATAACCCCCCAGGAATTCCTGTGCATGAAAGCACTGCTGCTCTT CAGCATTATTCCAGTGGATGGGCTGAAAAATCAAAAATTCTTTGATGAACTTCGAATG AACTACATCAAGGAACTCGATCGCATCATTGCATGCAAAAGAAAGAATCCCACATCCT GCTCAAGGCGCTTCTACCAGCTCACCAAGCTCCTGGATTCTGTGCAGCCTATTGCAAG AGAGCTGCATCAGTTCACTTTTGACCTGCTAATCAAGTCCCATATGGTGAGCGTGGAC TTTCCTGAAATGATGGCAGAGATCATCTCTGTGCAAGTGCCCAAGATCCTTTCTGGGA AAGTCAAGCCCATCTATTTCCACACACAGTGA (SEQ IDNO: 4) COT1
Human polypeptide sequence:
MAMWSSWRDPQDDVAGGNPGGPNPAAQAARGGGGGAGEQQQQAGSGAPHTPQTPGQP GAPATPGTAGDKGQGPPGSGQSQQHIECWCGDKSSGKHYGQFTCEGCKSFFKRSVRR NLTYTCRANRNCPIDQHHRNQCQYCRLKKCLKVGMRREAVQRGRMPPTQPNPGQYALT NGDPLNGHCYLSGYISLLLRAEPYPTSRYGSQCMQPNNIMGIENICELAARLLFSAVE ARNIPFFPDLQITDQVSLLRLT SELFVLNAAQCSMPLHVAPLLAAAGLHASPMSAD RWAFMDHIRIFQEQVEKLKALHVDSAEYSCLKAIVLFTSDACGLSDAAHIESLQEKS QCALEEYVRSQYPNQPSRFGKLLLRLPSLRTVSSSVIEQLFFVRLVGKTPIETLIRDM LLSGSSFN PYMSIQCS (SEQ IDNO: 5)
Human polynucleotide sequence:
ATGGCAATGGTAGTTAGCAGCTGGCGAGATCCGCAGGACGACGTGGCCGGGGGCAACC CCGGCGGCCCCAACCCCGCAGCGCAGGCGGCCCGCGGCGGCGGCGGCGGCGCCGGCGA GCAGCAGCAGCAGGCGGGCTCGGGCGCGCCGCACACGCCGCAGACCCCGGGCCAGCCC GGAGCGCCCGCCACCCCCGGCACGGCGGGGGACAAGGGCCAGGGCCCGCCCGGTTCGG GCCAGAGCCAGCAGCACATCGAGTGCGTGGTGTGCGGGGACAAGTCGAGCGGCAAGCA CTACGGCCAATTCACCTGCGAGGGCTGCAAAAGTTTCTTCAAGAGGAGCGTCCGCAGG AACTTAACTTACACATGCCGTGCCAACAGGAACTGTCCCATCGACCAGCACCACCGCA ACCAGTGCCAATACTGCCGCCTCAAGAAGTGCCTCAAAGTGGGCATGAGGCGGGAAGC GGTTCAGCGAGGAAGAATGCCTCCAACCCAGCCCAATCCAGGCCAGTACGCACTCACC AACGGGGACCCCCTCAACGGCCACTGCTACCTGTCCGGCTACATCTCGCTGCTGCTGC GCGCCGAGCCCTACCCCACGTCGCGCTACGGCAGCCAGTGCATGCAGCCCAACAACAT TATGGGCATCGAGAACATCTGCGAGCTGGCCGCGCGCCTGCTCTTCAGCGCCGTCGAG TGGGCCCGCAACATCCCCTTCTTCCCGGATCTGCAGATCACCGACCAGGTGTCCCTGC TACGCCTCACCTGGAGCGAGCTGTTCGTGCTCAACGCGGCCCAGTGCTCTATGCCGCT GCACGTGGCGCCGTTGCTGGCCGCCGCCGGCCTGCATGCCTCGCCCATGTCTGCCGAC CGCGTCGTGGCCTTCATGGACCACATCCGCATCTTCCAGGAGCAGGTGGAGAAGCTCA AGGCGCTACACGTCGACTCAGCCGAGTACAGCTGCCTCAAAGCCATCGTGCTGTTCAC GTCAGACGCCTGTGGCCTGTCGGATGCGGCCCACATCGAGAGCCTGCAGGAGAAGTCG CAGTGCGCACTGGAGGAGTACGTGAGGAGCCAGTACCCCAACCAGCCCAGCCGTTTTG GCAAACTGCTGCTGCGACTGCCCTCGCTGCGCACCGTGTCCTCCTCCGTCATCGAGCA GCTCTTCTTCGTCCGTTTGGTAGGTAAAACCCCCATCGAAACTCTCATCCGCGATATG TTACTGTCTGGGAGCAGCTTCAACTGGCCTTACATGTCCATCCAGTGCTCCTAG (SEQ IDNO: 6) Mouse polypeptide sequence:
MAMWSSWRDPQDDVAGGNPGGPNPAAQAARGGGGGAGEQQQAGSGAPHTPQTPGQPG APATPGTQGDKGQGPPGSGQSQQHIECWCGDKSSGKHYGQFTCEGCKSFFKRSVRRN LTYTCRANRNCPIDQHHRNQCQYCRLKKCLKVGMRREAVQRGRMPPTQPNPGQYALTN GDPLNGHCYLSGYISLLLRAEPYPTSRYGSQCMQPNNIMGIENICELAARLLFSAVEW ARNIPFFPDLQITDQVSLLRLTWSELFVLNAAQCSMPLHVAPLLAAAGLHASPMSADR WAFMDHIRIFQEQVEKLKALHVDSAEYSCLKAIVLFTSDACGLSDAAHIESLQEKSQ CALEEYVRSQYPNQPSRFGKLLLRLPSLRTVSSSVIEQLFFVRLVGKTPIETLIRDML LSGSSFNWPYMSIQCS (SEQ ID NO: 7)
Mouse polynucleotide sequence: ATGGCAATGGTAGTTAGCAGCTGGCGAGATCCGCAGGACGACGTGGCCGGGGGCAACC CCGGCGGCCCCAACCCCGCAGCGCAGGCAGCCCGCGGCGGCGGCGGCGGCGCCGGCGA GCAGCAGCAGGCGGGCTCCGGCGCGCCGCACACGCCGCAGACCCCGGGCCAGCCCGGA GCGCCCGCCACCCCCGGCACGCAGGGGGACAAGGGCCAGGGCCCGCCCGGGTCAGGCC AGAGCCAGCAGCACATCGAGTGCGTGGTGTGCGGGGACAAGTCGAGCGGCAAGCACTA CGGCCAATTCACCTGCGAGGGCTGCAAAAGTTTCTTCAAGAGGAGCGTCCGCAGGAAC TTAACTTACACATGCCGTGCCAACAGGAACTGTCCCATCGACCAGCACCACCGCAACC AGTGCCAATACTGCCGCCTCAAGAAGTGCCTCAAAGTGGGCATGAGGCGGGAAGCGGT TCAGCGAGGAAGAATGCCTCCAACCCAGCCCAATCCAGGCCAGTATGCACTCACAAAC GGGGATCCCCTCAATGGCCACTGCTACCTGTCTGGCTACATTTCTCTGCTGCTGCGCG CAGAGCCCTACCCCACGTCGCGTTATGGCAGCCAGTGCATGCAGCCCAACAACATTAT GGGCATCGAGAACATCTGCGAGCTGGCAGCCCGCCTCCTCTTCAGCGCCGTCGAGTGG GCCCGCAACATCCCGTTCTTCCCGGATCTGCAGATCACGGACCAGGTGTCTCTGCTGC GCCTCACCTGGAGCGAGCTGTTCGTGCTCAACGCGGCCCAGTGCTCCATGCCGCTGCA CGTGGCGCCGCTGCTGGCCGCAGCCGGCCTGCACGCCTCGCCCATGTCCGCGGACCGC GTCGTGGCCTTCATGGACCACATCCGCATCTTTCAGGAACAGGTGGAGAAGCTCAAGG CGCTGCACGTCGACTCTGCCGAGTACAGCTGCCTCAAAGCCATCGTGCTATTCACGTC AGATGCTTGTGGCCTGTCGGATGCTGCCCACATCGAAAGCCTGCAGGAGAAATCACAG TGTGCCCTGGAGGAGTATGTGAGAAGCCAGTACCCCAACCAGCCCAGCCGCTTTGGCA AACTGCTGCTGCGATTGCCCTCTCTTCGCACAGTGTCCTCCTCTGTCATCGAGCAACT CTTCTTCGTACGTTTGGTAGGTAAAACTCCCATCGAAACTCTCATCCGAGATATGTTG CTGTCAGGGAGCAGTTTCAACTGGCCTTACATGTCCATCCAGTGTTCCTAG (SEQIDNO: 8)
COT2
Human polypeptide sequence:
MAMWST RDPQDEVPGSQGSQASQAPPVPGPPPGAPHTPQTPGQGGPASTPAQTAAG GQGGPGGPGSDKQQQQQHIECWCGDKSSGKHYGQFTCEGCKSFFKRSVRRNLSYTCR ANRNCPIDQHHRNQCQYCRLKKCLKVGMRREAVQRGRMPPTQPTHGQFALTNGDPLNC HSYLSGYISLLLRAEPYPTSRFGSQCMQPNNIMGIENICELAARMLFSAVE ARNIPF FPDLQITDQVALLRLTWSELFVLNAAQCSMPLHVAPLLAAAGLHASPMSADRWAFMD HIRIFQEQVEKLKALHVDSAEYSCLKAIVLFTSDACGLSDVAHVESLQEKSQCALEEY VRSQYPNQPTRFGKLLLRLPSLRTVSSSVIEQLFFVRLVGKTPIETLIRDMLLSGSSF N PYMAIQ
(SEQ ID NO: 9) Human polynucleotide sequence:
ATGGCAATGGTAGTCAGCACGTGGCGCGACCCCCAGGACGAGGTGCCCGGCTCACAGG GCAGCCAGGCCTCGCAGGCGCCGCCCGTGCCCGGCCCGCCGCCCGGCGCCCCGCACAC GCCACAGACGCCCGGCCAAGGGGGCCCAGCCAGCACGCCAGCCCAGACGGCGGCCGGT GGCCAGGGCGGCCCTGGCGGCCCGGGTAGCGACAAGCAGCAGCAGCAGCAACACATCG AGTGCGTGGTGTGCGGAGACAAGTCGAGCGGCAAGCACTACGGCCAGTTCACGTGCGA GGGCTGCAAGAGCTTCTTCAAGCGCAGCGTGCGGAGGAACCTGAGCTACACGTGCCGC GCCAACCGGAACTGTCCCATCGACCAGCACCATCGCAACCAGTGCCAGTACTGCCGCC TCAAAAAGTGCCTCAAAGTGGGCATGAGACGGGAAGCGGTGCAGAGGGGCAGGATGCC GCCGACCCAGCCGACCCACGGGCAGTTCGCGCTGACCAACGGGGATCCCCTCAACTGC CACTCGTACCTGTCCGGATATATTTCCCTGCTGTTGCGCGCGGAGCCCTATCCCACGT CGCGCTTCGGCAGCCAATGCATGCAGCCCAACAACATCATGGGTATCGAGAACATTTG CGAACTGGCCGCGAGGATGCTCTTCAGCGCCGTCGAGTGGGCCCGGAACATCCCCTTC TTCCCCGACCTGCAGATCACGGACCAGGTGGCCCTGCTTCGCCTCACCTGGAGCGAGC TGTTTGTGTTGAATGCGGCGCAGTGCTCCATGCCCCTCCACGTCGCCCCGCTCCTGGC CGCCGCCGGCCTGCATGCTTCGCCCATGTCCGCCGACCGGGTGGTCGCCTTTATGGAC CACATACGGATCTTCCAAGAGCAAGTGGAGAAGCTCAAGGCGCTGCACGTTGACTCAG CCGAGTACAGCTGCCTCAAGGCCATAGTCCTGTTCACCTCAGATGCCTGTGGTCTCTC TGATGTAGCCCATGTGGAAAGCTTGCAGGAAAAGTCTCAGTGTGCTTTGGAAGAATAC GTTAGGAGCCAGTACCCCAACCAGCCGACGAGATTCGGAAAGCTTTTGCTTCGCCTCC CTTCCCTCCGCACCGTCTCCTCCTCAGTCATAGAGCAATTGTTTTTCGTCCGTTTGGT AGGTAAAACCCCCATCGAAACCCTCATCCGGGATATGTTACTGTCCGGCAGCAGTTTT AACTGGCCGTATATGGCAATTCAATAA (SEQ ID NO: 10)
Mouse polypeptide sequence:
MAMWSTWRDPQDEVPGSQGSQASQAPPVPGPPPGPPHTPQTPGQGGPASTPAQTAAG GQGGPGGPGSDKQQQQQHIECWCGDKSSGKHYGQFTCEGCKSFFKRSVRRNLSYTCR ANRNCPIDQHHRNQCQYCRLKKCLKVGMRREAVQRGRMPPTQPTHGQFALTNGDPLNC HSYLSGYISLLLRAEPYPTSRFGSQCMQPNNIMGIENICELAARMLFSAVEWARNIPF FPDLQITDQVALLRLTWSELFVLNAAQCSMPLHVAPLLAAAGLHASPMSADRWAFMD HIRIFQEQVEKLKALHVDSAEYSCLKAIVLFTSDACGLSDVAHVESLQEKSQCALEEY VRSQYPNQPTRFGKLLLRLPSLRTVSSSVIEQLFFVRLVGKTPIETLIRDMLLSGSSF NWPYMAIQ (SEQ ID NO: 11)
Mouse polynucleotide sequence:
ATGGCAATGGTAGTCAGCACGTGGCGCGACCCCCAGGACGAGGTGCCCGGCTCTCAGG GCAGCCAGGCCTCGCAGGCGCCGCCCGTGCCGGGCCCGCCGCCTGGCCCCCCGCACAC GCCACAGACGCCCGGCCAAGGGGGCCCGGCCAGCACGCCGGCCCAGACAGCGGCTGGC GGCCAGGGCGGCCCTGGCGGCCCGGGCAGCGACAAGCAGCAGCAGCAGCAGCACATCG AGTGCGTGGTGTGCGGGGACAAGTCGAGCGGCAAGCACTACGGCCAGTTCACGTGCGA GGGCTGCAAGAGCTTCTTCAAGCGCAGCGTGCGGAGGAACCTGAGCTACACGTGCCGC GCCAACCGGAACTGTCCCATCGACCAGCACCACCGCAACCAGTGCCAGTACTGCCGCC TCAAAAAGTGCCTCAAAGTGGGCATGAGACGGGAAGCTGTACAGAGAGGCAGGATGCC TCCTACCCAGCCTACCCACGGGCAGTTTGCCCTGACCAACGGGGACCCCCTCAACTGC CACTCGTACCTGTCCGGATATATTTCCCTGCTGCTGCGCGCGGAGCCCTACCCCACGT CGCGCTTCGGCAGTCAGTGCATGCAGCCTAACAACATCATGGGCATCGAGAACATTTG CGAACTGGCCGCACGGATGCTCTTCAGCGCCGTTGAGTGGGCCCGGAACATCCCCTTC TTCCCTGACCTGCAGATCACGGACCAGGTGGCCCTCCTTCGCCTCACCTGGAGCGAGC TGTTCGTGTTGAATGCGGCCCAGTGCTCCATGCCCCTCCATGTCGCCCCGCTCCTTGC CGCTGCTGGCCTGCACGCTTCACCCATGTCAGCCGACCGGGTGGTCGCTTTTATGGAC CACATACGGATCTTCCAAGAGCAAGTGGAGAAGCTCAAGGCACTGCACGTCGACTCCG CCGAGTATAGCTGCCTCAAGGCCATAGTCCTGTTCACCTCAGATGCCTGTGGTCTGTC TGATGTAGCCCATGTGGAAAGCTTGCAGGAAAAGTCCCAGTGTGCTTTGGAAGAGTAC GTTAGGAGCCAGTACCCCAACCAGCCAACACGGTTCGGAAAGCTCTTGCTTCGTCTCC CTTCCCTCCGCACGGTCTCCTCCTCAGTCATAGAGCAATTGTTTTTCGTCCGTTTGGT AGGTAAAACCCCCATCGAAACCCTCATCCGGGATATGTTACTGTCCGGCAGCAGTTTT AACTGGCCATATATGGCAATTCAATAA (SEQ ID NO: 12)
DAX1
Human polypeptide sequence: MAGQNHQWQGSILYNMLMSAKQTRAAPEAPETRLVDQCWGCSCGDEPGVGREGLLGGR NVALLYRCCFCGKDHPRQGSILYSMLTSAKQTYAAPKAPEATLGPC GCSCGSDPGVG RAGLPGGRPVALLYRCCFCGEDHPRQGSILYSLLTSSKQTHVAPAAPEARPGGA DR SYFAQRPGGKEALPGGRATALLYRCCFCGEDHPQQGSTLYCVPTSTNQAQAAPEERPR AP WDTSSGALRPVALKSPQWCEAASAGLLKTLRFVKYLPCFQVLPLDQQLVLVRNC WASLLMLELAQDRLQFETVEVSEPSMLQKILTTRRRETGGNEPLPVPTLQHHLAPPAE ARKVPSASQVQAIKCFLSKC SLNISTKEYAYLKGTVLFNPDVPGLQCVKYIQGLQ G TQQILSEHTRMTHQGPHDRFIELNSTLFLLRFINANVIAELFFRPIIGTVSMDDMMLE MLCTKI (SEQ ID NO: 13)
Human polynucleotide sequence:
ATGGCGGGCGAGAACCACCAGTGGCAGGGCAGCATCCTCTACAACATGCTTATGAGCG CGAAGCAAACGCGCGCGGCTCCTGAGGCTCCAGAGACGCGGCTGGTGGATCAGTGTTG GGGCTGTTCGTGCGGCGATGAGCCCGGGGTGGGCAGAGAGGGGCTGCTGGGCGGGCGG AACGTGGCGCTCCTGTACCGCTGCTGCTTTTGCGGTAAAGACCACCCACGGCAGGGCA GCATCCTCTACAGCATGCTGACGAGCGCAAAGCAAACGTACGCGGCACCGAAGGCGCC CGAGGCGACGCTGGGTCCGTGCTGGGGCTGTTCGTGCGGCTCTGATCCCGGGGTGGGC AGAGCGGGGCTTCCGGGTGGGCGGCCCGTGGCACTCCTGTACCGCTGCTGCTTTTGTG GTGAAGACCACCCGCGGCAGGGCAGCATCCTCTACAGCTTGCTCACTAGCTCAAAGCA AACGCACGTGGCTCCGGCAGCGCCCGAGGCACGGCCAGGGGGCGCGTGGTGGGACCGC TCCTACTTCGCGCAGAGGCCAGGGGGTAAAGAGGCGCTACCAGGCGGGCGGGCCACGG CGCTTCTGTACCGCTGCTGCTTTTGCGGTGAAGACCACCCGCAGCAGGGCAGCACCCT CTACTGCGTGCCCACGAGCACAAATCAAGCGCAGGCGGCTCCGGAGGAGCGGCCGAGG GCCCCCTGGTGGGACACCTCCTCTGGTGCGCTGCGGCCGGTGGCGCTCAAGAGTCCAC AGGTGGTCTGCGAGGCAGCCTCAGCGGGCCTGTTGAAGACGCTGCGCTTCGTCAAGTA CTTGCCCTGCTTCCAGGTGCTGCCCCTGGACCAGCAGCTGGTGCTGGTGCGCAACTGC TGGGCGTCCCTGCTCATGCTTGAGCTGGCCCAGGACCGCTTGCAGTTCGAGACTGTGG AAGTCTCGGAGCCCAGCATGCTGCAGAAGATCCTCACCACCAGGCGGCGGGAGACCGG GGGCAACGAGCCACTGCCCGTGCCCACGCTGCAGCACCATTTGGCACCGCCGGCGGAG GCCAGGAAGGTGCCCTCCGCCTCCCAGGTCCAAGCCATCAAGTGCTTTCTTTCCAAAT GCTGGAGTCTGAACATCAGTACCAAGGAGTACGCCTACCTCAAGGGGACCGTGCTCTT TAACCCGGACGTGCCGGGCCTGCAGTGCGTGAAGTACATTCAGGGACTCCAGTGGGGA ACTCAGCAAATACTCAGTGAACACACCAGGATGACGCACCAAGGGCCCCATGACAGAT TCATCGAACTTAATAGTACCCTTTTCCTGCTGAGATTCATCAATGCCAATGTCATTGC TGAACTGTTCTTCAGGCCCATCATCGGCACAGTCAGCATGGATGATATGATGCTGGAA ATGCTCTGTACAAAGATATAA (SEQ ID NO: 14) Mouse polypeptide sequence:
MAGEDHPWQGSILYNLLMSAKQ HASQEEREVRLGAQC GCACGAQPVLGGERLSGGQ ARSLLYRCCFCGENHPRQGGILYSMLTNARQPSVATQAPRARFGAPC GCACGSAEPL VGREGLPAGQAPSLLYRCCFCGEEHPRQGSILYSLLTSAQQTHVSREAPEAHRRGEW QLSYCTQSVGGPEGLQSTQAMAFLYRSYVCGEEQPQQISVASGTPVSADQTPATPQEQ PRAP DASPGVQRLITLKDPQWCEAASAGLLKTLRFVKYLPCFQILPLDQQLVLVR SCWAPLLMLELAQDHLHFEMMEIPETNTTQEMLTTRRQETEGPEPAEPQATEQPQMVS AEAGHLLPAAAVQAIKSFFFKC SLNIDTKEYAYLKGTVLFNPDLPGLQCVKYIEGLQ WRTQQILTEHIRMMQREYQIRSAELNSALFLLRFINSDWTELFFRPIIGAVSMDDMM LEMLCAKL (SEQ IDNO: 15)
Mouse polynucleotide sequence:
ATGGCGGGTGAGGACCACCCGTGGCAGGGCAGCATCCTCTACAATCTACTGATGAGCG CGAAGCAGAAGCACGCGTCTCAGGAAGAGCGAGAGGTGCGCTTGGGGGCTCAGTGCTG GGGTTGCGCCTGCGGTGCTCAGCCCGTCCTGGGTGGGGAGAGACTGTCCGGCGGGCAA GCCAGGTCCCTCTTGTACCGCTGCTGCTTTTGTGGGGAGAATCACCCGCGCCAGGGTG GCATCCTCTACTCTATGCTCACCAACGCCAGGCAGCCAAGCGTGGCGACCCAGGCGCC GAGGGCACGATTCGGAGCACCTTGCTGGGGCTGCGCCTGCGGCAGCGCAGAGCCCCTG GTGGGCAGAGAGGGGCTGCCGGCTGGCCAGGCCCCCTCGCTCCTGTACCGCTGCTGCT TCTGCGGAGAAGAGCACCCGAGGCAGGGCAGCATCTTATACAGCTTGCTCACTAGCGC TCAGCAAACGCACGTGTCTCGGGAAGCACCCGAGGCACATCGCAGAGGCGAGTGGTGG CAGCTGTCCTACTGTACCCAGAGTGTGGGTGGCCCAGAGGGGCTGCAGAGCACACAGG CCATGGCGTTCCTGTACCGCAGCTATGTGTGCGGTGAAGAGCAGCCCCAGCAGATCAG CGTTGCCTCTGGCACGCCCGTGAGCGCAGACCAAACACCAGCGACCCCGCAAGAGCAG CCGAGGGCTCCCTGGTGGGACGCCTCACCTGGTGTGCAGCGTCTGATCACACTCAAGG ATCCACAGGTGGTGTGCGAGGCAGCGTCCGCTGGCCTGTTGAAGACCCTGCGCTTTGT CAAGTACTTGCCCTGCTTCCAGATCCTGCCCCTAGATCAGCAGCTGGTGCTGGTGCGG AGCTGTTGGGCGCCCCTACTCATGCTTGAGTTGGCCCAAGATCACCTGCACTTCGAGA TGATGGAGATCCCGGAGACCAACACGACGCAGGAAATGCTTACCACCAGGCGGCAGGA GACCGAAGGTCCAGAGCCTGCAGAGCCCCAGGCCACAGAGCAGCCACAGATGGTGTCC GCGGAGGCTGGGCACTTGCTCCCAGCTGCTGCGGTCCAGGCCATCAAGAGTTTC-TTTT TCAAGTGCTGGAGTCTGAACATTGACACCAAAGAGTATGCCTATCTGAAAGGGACCGT GCTCTTTAACCCAGACCTGCCTGGCCTGCAGTGCGTGAAATACATTGAGGGTCTTCAG TGGAGAACCCAGCAGATCCTTACTGAGCACATCCGGATGATGCAGAGAGAGTACCAGA TCAGATCCGCTGAACTGAACAGTGCCCTTTTCCTGCTGAGATTCATCAATAGCGATGT CGTCACTGAACTCTTTTTCAGGCCCATCATTGGTGCAGTCAGCATGGATGATATGATG. CTGGAGATGCTCTGTGCAAAGCTGTGA (SEQ IDNO: 16)
EAR2 Human polypeptide sequence:
MAMVTGGWGGPGGDTNGVDKAGGYPRAAEDDSASPPGAASDAEPGDEERPGLQVDCW CGDKSSGKHYGVFTCEGCKSFFKRTIRRNLSYTCRSNRDCQIDQHHRNQCQYCRLKKC FRVGMRKEAVQRGRIPHSLPGAVAASSGSPPGSALAAVASGGDLFPGQPVSELIAQLL RAEPYPAAAGRFGAGGGAAGAVLGIDNVCELAARLLFSTVEWARHGFFPELPVADQVA LLRMS SELFVLNAAQAALPLHTAPLLAAAGLHAAPMAAERAVAFMDQVRAFQEQVDK LGRLQVDSAEYGCLKAIALFTPDACGLSDPAHVESLQEKAQVALTEYVRAQYPSQPQR FGRLLLRLPALRAVPASLISQLFFMRLVGKTPIETLIRDMLLSGSTFN PYGSGQ (SEQ IDNO: 17) Human polynucleotide sequence:
ATGGCCATGGTGACCGGCGGCTGGGGCGGCCCCGGCGGCGACACGAACGGCGTGGACA AGGCGGGCGGCTACCCGCGCGCGGCCGAGGACGACTCGGCCTCGCCCCCCGGTGCCGC CAGCGACGCCGAGCCGGGCGACGAGGAGCGGCCGGGGCTGCAGGTGGACTGCGTGGTG TGCGGGGACAAGTCGAGCGGCAAGCATTACGGTGTCTTCACCTGCGAGGGCTGCAAGA GCTTTTTCAAGCGAACGATCCGCCGCAACCTCAGCTACACCTGCCGGTCCAACCGTGA CTGCCAGATCGACCAGCACCACCGGAACCAGTGCCAGTACTGCCGTCTCAAGAAGTGC TTCCGGGTGGGCATGAGGAAGGAGGCGGTGCAGCGCGGCCGCATCCCGCACTCGCTGC CTGGTGCCGTGGCCGCCTCCTCGGGCAGCCCCCCGGGCTCGGCGCTGGCGGCAGTGGC GAGCGGCGGAGACCTCTTCCCGGGGCAGCCGGTGTCCGAACTGATCGCGCAGCTGCTG CGCGCTGAGCCCTACCCTGCGGCGGCCGGACGCTTCGGCGCAGGGGGCGGCGCGGCGG GCGCGGTGCTGGGCATCGACAACGTGTGCGAGCTGGCGGCGCGGCTGCTCTTCAGCAC CGTGGAGTGGGCGCGCCACGGCTTCTTCCCCGAGCTGCCGGTGGCCGACCAGGTGGCG CTGCTGCGCATGAGCTGGAGCGAGCTCTTCGTGCTGAACGCGGCGCAGGCGGCGCTGC CCCTGCACACGGCGCCGCTACTGGCCGCCGCCGGCCTCCACGCCGCGCCTATGGCCGC CGAGCGCGCCGTGGCTTTCATGGACCAGGTGCGCGCCTTCCAGGAGCAGGTGGACAAG CTGGGCCGCCTGCAGGTCGACTCGGCCGAGTATGGCTGCCTCAAGGCCATCGCGCTCT TCACGCCCGACGCCTGTGGCCTCTCAGACCCGGCCCACGTTGAGAGCCTGCAGGAGAA' GGCGCAGGTGGCCCTCACCGAGTATGTGCGGGCGCAGTACCCGTCCCAGCCCCAGCGC TTCGGGCGCCTGCTGCTGCGGCTCCCCGCCCTGCGCGCGGTCCCTGCCTCCCTCATCT CCCAGCTGTTCTTCATGCGCCTGGTGGGGAAGACGCCCATTGAGACACTGATCAGAGA CATGCTGCTGTCGGGGAGTACCTTCAACTGGCCCTACGGCTCGGGCCAGTGA (SEQ IDNO: 18)
Mouse polypeptide sequence:
MAMVTGGWGDPGGDTNGVDKAGGSYPRATEDDSASPPGATSDAEPGDEERPGLQVDCV
VCGDKSSGKHYGVFTCEGCKSFFKRTIRRNLSYTCRSNRDCQIDQHHRNQCQYCRLKK CFRVGMRKEAVQRGRIPHALPGPAACSPPGATGVEPFTGPPVSELIAQLLRAEPYPAA
GRFGGGGAVLGIDNVCELAARLLFSTVE ARHAPFFPELPAADQVALLRLSWSELFVL NAAQAALPLHTAPLLAAAGLHAAPMAAERAVAFMDQVRAFQEQVDKLGRLQVDAAEYG
CLKAIALFTPDACGLSDPAHVESLQEKAQVALTEYVRAQYPSQPQRFGRLLLRLPALR
AVPASLISKLFFMRLVGKTPIETLIRDMLLSGSTFNWPYGSG (SEQ ID NO: 19)
Mouse polynucleotide sequence:
ATGGCCATGGTGACCGGTGGCTGGGGCGACCCCGGAGGCGACACGAACGGCGTGGACA AGGCTGGTGGGAGCTACCCACGCGCGACCGAGGACGATTCGGCGTCACCTCCCGGGGC GACCAGCGACGCGGAGCCGGGCGACGAGGAGCGTCCGGGGTTGCAGGTGGACTGCGTG GTGTGCGGGGACAAGTCCAGTGGAAAGCATTACGGCGTGTTCACCTGCGAGGGCTGCA AGAGTTTCTTCAAGCGCACGATCCGCCGCAATCTCAGCTACACCTGCCGGTCCAACCG TGACTGTCAGATTGATCAGCACCACCGGAACCAGTGTCAGTACTGTCGGCTCAAGAAG TGCTTCCGGGTGGGCATGCGCAAGGAGGCCGTGCAGCGAGGCCGCATCCCGCATGCGC TCCCCGGTCCAGCGGCCTGCAGTCCCCCGGGCGCGACGGGCGTCGAACCTTTCACGGG GCCGCCAGTGTCCGAGCTGATTGCGCAGCTGCTGCGTGCTGAGCCCTACCCCGCGGCC GGACGCTTTGGTGGCGGCGGCGCTGTACTGGGCATCGACAACGTGTGCGAGTTGGCGG CACGCCTGCTGTTCAGCACGGTCGAGTGGGCCCGGCACGCGCCCTTCTTCCCCGAGCT GCCGGCCGCCGACCAGGTGGCGCTGCTGCGGCTCAGCTGGAGTGAGCTCTTCGTGCTG AACGCGGCGCAGGCGGCGCTGCCGCTGCATACGGCACCGCTGCTGGCCGCCGCGGGGT TGCATGCCGCGCCCATGGCAGCCGAGCGGGCCGTGGCCTTCATGGACCAGGTGCGTGC CTTCCAGGAGCAGGTGGACAAGCTGGGCCGCCTGCAGGTGGATGCTGCGGAGTACGGT TGCCTCAAGGCCATCGCGCTCTTCACGCCTGATGCCTGTGGCCTTTCTGACCCAGCCC ATGTGGAGAGCCTGCAGGAGAAGGCACAGGTGGCCCTCACCGAGTATGTGCGTGCCCA GTACCCATCGCAGCCCCAGCGCTTTGGGCGTCTGCTGCTGCGGCTGCCGGCCCTGCGT GCTGTGCCCGCATCCCTCATCTCCAAGCTCTTCTTCATGCGCCTGGTGGGCAAGACAC CCATCGAGACCCTCATCCGGGACATGCTTCTGTCAGGGAGCACCTTTAACTGGCCCTA TGGCTCGGGCTAG
(SEQ IDNO: 20)
ERR1
Human polypeptide sequence: MGLEMSSKDSPGSLDGRA EDAQKPQSAWCGGRKTRVYATSSRRAPPSEGTRRGGAAR PEEAAEEGPPAAPGSLRHSGPLGPHACPTALPEPQVTSAMSSQWGIEPLYIKAEPAS PDSPKGSSETETEPPVALAPGPAPTRCLPGHKEEEDGEGAGPGEQGGGKLVLSSLPKR LCLVCGDVASGYHYGVASCEACKAFFKRTIQGSIEYSCPASNECEITKRRRKACQACR FTKCLRVGMLKEGVRLDRVRGGRQKYKRRPEVDPLPFPGPFPAGPLAVAGGPRKTAPV NALVSHLLWEPEKLYAMPDPAGPDGHLPAVATLCDLFDREIWTIS AKSIPGFSSL SLSDQMSVLQSV MEVLVLGVAQRSLPLQDELAFAEDLVLDEEGARAAGLGELGAALL QLVRRLQALRLEREEYVLLKALALANSDSVHIEDAEAVEQLREALHEALLEYEAGRAG PGGGAERRRAGRLLLTLPLLRQTAGKVLAHFYGVKLEGKVPMHKLFLEMLEAMMD (SEQ IDNO: 21)
Human polynucleotide sequence:
ATGGGATTGGAGATGAGCTCCAAGGACAGCCCTGGCAGTCTGGATGGAAGAGCTTGGG AAGATGCTCAGAAACCACAAAGTGCCTGGTGCGGTGGGAGGAAAACCAGAGTGTATGC TACAAGCAGCCGGCGGGCGCCGCCGAGTGAGGGGACGCGGCGCGGTGGGGCGGCGCGG CCCGAGGAGGCGGCGGAGGAGGGGCCGCCCGCGGCCCCCGGCTCACTCCGGCACTCCG GGCCGCTCGGCCCCCATGCCTGCCCGACCGCGCTGCCGGAGCCCCAGGTGACCAGCGC CATGTCCAGCCAGGTGGTGGGCATTGAGCCTCTCTACATCAAGGCAGAGCCGGCCAGC CCTGACAGTCCAAAGGGTTCCTCGGAGACAGAGACCGAGCCTCCTGTGGCCCTGGCCC CTGGTCCAGCTCCCACTCGCTGCCTCCCAGGCCACAAGGAAGAGGAGGATGGGGAGGG GGCTGGGCCTGGCGAGCAGGGCGGTGGGAAGCTGGTGCTCAGCTCCCTGCCCAAGCGC CTCTGCCTGGTCTGTGGGGACGTGGCCTCCGGCTACCACTATGGTGTGGCATCCTGTG AGGCCTGCAAAGCCTTCTTCAAGAGGACCATCCAGGGGAGCATCGAGTACAGCTGTCC GGCCTCCAACGAGTGTGAGATCACCAAGCGGAGACGCAAGGCCTGCCAGGCCTGCCGC TTCACCAAGTGCCTGCGGGTGGGCATGCTCAAGGAGGGAGTGCGCCTGGACCGCGTCC GGGGTGGGCGGCAGAAGTACAAGCGGCGGCCGGAGGTGGACCCACTGCCCTTCCCGGG CCCCTTCCCTGCTGGGCCCCTGGCAGTCGCTGGAGGCCCCCGGAAGACAGCAGCCCCA GTGAATGCACTGGTGTCTCATCTGCTGGTGGTTGAGCCTGAGAAGCTCTATGCCATGC CTGACCCCGCAGGCCCTGATGGGCACCTCCCAGCCGTGGCTACCCTCTGTGACCTCTT TGACCGAGAGATTGTGGTCACCATCAGCTGGGCCAAGAGCATCCCAGGCTTCTCATCG CTGTCGCTGTCTGACCAGATGTCAGTACTGCAGAGCGTGTGGATGGAGGTGCTGGTGC TGGGTGTGGCCCAGCGCTCACTGCCACTGCAGGATGAGCTGGCCTTCGCTGAGGACTT AGTCCTGGATGAAGAGGGGGCACGGGCAGCTGGCCTGGGGGAACTGGGGGCTGCCCTG CTGCAACTAGTGCGGCGGCTGCAGGCCCTGCGGCTGGAGCGAGAGGAGTATGTTCTAC TAAAGGCCTTGGCCCTTGCCAATTCAGACTCTGTGCACATCGAAGATGAGCCGAGGCT GTGGAGCAGCTGCGAGAAGCTCCTGCACGAGGCCCTGCTGGAGTATGAAGCCGGCCGG GCTGGCCCCGGAGGGGGTGCTGAGCGGCGGCGGGCGGGCAGGCTGCTGCTCACGCTAC CGCTCCTCCGCCAGACAGCGGGCAAAGTGCTGGCCCATTTCTATGGGGTGAAGCTGGA GGGCAAGGTGCCCATGCACAAGCTGTTCTTGGAGATGCTCGAGGCCATGATGGACTGA
(SEQ IDNO: 22) Mouse polypeptide sequence:
MSSQWGIEPLYI AEPASPDSPKGSSETETEPPVTLASGPAPARCLPGHKEEEDGEG AGSGEQGSGKLVLSSLPKRLCLVCGDVASGYHYGVASCEACKAFFKRTIQGSIEYSCP ASNECEITKRRRKACQACRFTKCLRVGMLKEGVRLDRVRGGRQKYKRRPEVDPLPFPG PFPAGPLAVAGGPRKTAPVNALVSHLLWEPEKLYAMPDPASPDGHLPAVATLCDLFD REIWTISWAKSIPGFSSLSLSDQMSVLQSVWMEVLVLGVAQGSLPLQDELAFAEDLV LDEEGARAAGLGDLGAALQLVRRLQALRLEREEYVLLKALALANSDSVHIEDAEAVEQ LREALHEALLEYEAGRAGPGGGAERRRAGRLLLTLPLLRQTAGKVLAHFYGVKLEGKV HAQVFLEMLEAMMD (SEQ IDNO: 23)
Mouse polynucleotide sequence: GCGGCTGCTTCCTACAAGCAGCCAGCGGCGCCGCCGAGTGAGGGGGGACGCAGCGCGG CGGGGCGGTGCGGCCGGAGGAGGCGGCCCCCGCTCACCCCGGCGCTCCGGGCCACTCG GCCCCCATGCCTGCCCGCCAGCCCTGCCGGAGCCCAAGGTGACCAGCACCATGTCCAG CCAGGTGGTGGGCATCGAGCCTCTCTACATCAAGGCAGAGCCAGCCAGCCCTGACAGT CCAAAGGGTTCCTCAGAGACTGAGACTGAACCCCCGGTGACCCTGGCCTCTGGTCCAG CTCCAGCCCGCTGCCTTCCAGGGCACAAGGAGGAGGAGGATGGGGAGGGGGCAGGGTC TGGTGAGCAGGGCAGTGGGAAGCTAGTGCTCAGCTCTCTACCCAAACGCCTCTGCCTG GTCTGTGGGGATGTGGCCTCTGGCTACCACTACGGTGTGGCATCCTGTGAGGCCTGCA AAGCCTTCTTCAAGAGGACCATCCAGGGGAGCATCGAGTACAGCTGTCCGGCCTCCAA TGAGTGTGAGATCACCAAGCGGAGACGCAAGGCCTGTCAGGCCTGCCGCTTCACCAAG TGCCTGCGGGTGGGCATGCTCAAGGAGGGAGTGCGTCTGGACCGTGTCCGCGGAGGAC GGCAGAAGTACAAACGGCGGCCAGAGGTGGACCCTTTGCCTTTCCCGGGCCCCTTCCC TGCTGGACCTCTGGCTGTAGCTGGAGGACCCAGGAAGACAGCCCCAGTGAACGCTCTG GTGTCGCATCTGCTGGTTGTTGAACCTGAGAAGCTGTACGCCATGCCTGACCCAGCAA GCCCCGATGGACACCTCCCCGCTGTGGCCACTCTCTGTGACCTTTTTGATCGAGAGAT AGTGGTCACCATCAGCTGGGCCAAGAGCATCCCAGGCTTCTCCTCACTGTCACTGTCT GACCAGATGTCAGTACTGCAGAGTGTGTGGATGGAAGTGCTGGTGCTGGGTGTGGCCC AAGGCTCACTGCCACTGCAGGATGAGCTGGCCTTTGCTGAGGACCTGGTCCTAGATGA AGAGGGGGCACGGGCAGCTGGCCTGGGGGATCTGGGGGCAGCCCTGCAGCTGGTTCGG CGACTGCAAGCTCTTCGGCTGGAGCGGGAGGAGTACGTCCTGCTGAAAGCTCTGGCCC TTGCCAATTCTGACTCTGTGCACATTGAAGATGCTGAGGCTGTGGAGCAGCTGCGCGA AGCCCTGCATGAGGCCCTGCTGGAGTATGAAGCTGGCCGGGCTGGCCCTGGAGGGGGT GCTGAGCGGAGGCGTGCAGGCAGGCTGCTGCTTACGCTGCCACTCCTCCGCCAGACAG CAGGCAAAGTCCTGGCCCATTTCTATGGGGTGAAGCTGGAGGGCAAGGTGCATGCACA AGTGTTTTTGGAAATGCTTGAGGCCATGATGGACTGAGGCAAGGGGTGGGACAGGGTG GGGTGGCTGGCAGGATCTGCCCAGCATAGGGTGTTAGCCCAAAGCGGAAAGCTGGAGT CTGGGCAGTGCCATAGCCTGCTGGCAGGGCCAGGGCAATGCCATCCGCCCCTGGGAGA ACGTTCATGCCCTTCCCTCCCCACTTTGTGTGTGTGGGGGATTGTCAGAAGCCAGGAA AGTGAATGCCCAGGTGTGGGCACAGTGCTGCCCCTTGCAGCCATAACGAGCCCCCCAA GAGTGTTGGGGGGCTCGCGGAAGCCATAGGGGGCTGCAGGGGATGTGCAGGAGGCAGA CATTGATCTCAGGGAGGGAAGGGATGGAGGCCGCCGGCTCCCACTGGGTGATGCTTTT GCTGCTGCTTAATCCGATCTCCTCTCCGGAGCAGAGGGGGGCTTGGAAAGCAAAGGCC CCGTCCCTTCGCTCCTCTCCTCATCCGCATTGGGCATTATTGCCCCCCCTTGAAGCAA TAACTCCAAGCAGGCTCCAGCCCCTGGACCCCCGGGGTGGCCAGGGCCCCCTATCAGC TCCCACCTCAAGGGGTGGGGGACAGCACTGCCTCTATGCCCTGCAGAGCAATAACACT ATATTTATTTTTGGGTTTGGCCAGGGAGGCGCAGGGCCATGGGGCAAGCCAGGGCCCA GAGCCCTTGGCTGTACAGAGACTCTATTTTAATGTATATTTGCTGCAAAGAGAAACCG CTTTTGGTTTTGAACCTTTAATGAGAAAAAAATATACTATGGAGCTCAAGTAAAAAA (SEQ ID NO: 24) ERR1L
Human polypeptide sequence: MRRQGGGRGGLQAGSGSGASLGHGRDPVEGRTGQGSGGIRRPSSGFNPALAEVPGAGK GARRGGLYVGKGALKTT GRSKGSGATLLSGSKVIAMAGKNFLFLGSPHLLPDNLVAV SRGRRGLGGGVATSGNFPKRKYKSGPAGRSRGGGVGGARFVPGIGMLGQEGSRVSGDQ NHVQPGGGQPQGRGGWEGAGPGELGGGKLVLSFLSKSLCLVCGDVASGYHYGVSSCED CKAFFKRTIQGSIKYSCPASNKCEIIKRRRKACQACRFTKCLRECAWIASGVGGRSTS GARGGPAALPGRLPC APGSRWRPPEDTPVNALVSHLLWEPEKLYAMPDPMSVLQSV WMEVLVPGVAQRSLPLQDELAFTEDRVLDEEGARAAGLGELGTALLQLVRRLQSLRLE RGEYVLLKALALANSDSVPIEDAEAVEQLPEAPHEALLEYEAGRAGTGGGAERRRPGR LLFTLPLLHQTAGKVLAHFYGVKLEGKVPMHKLFLEMLEAMMD (SEQ ID NO: 25)
Human polynucleotide sequence:
ATGCGGCGGCAGGGAGGCGGGCGGGGCGGGCTGCAGGCGGGGTCTGGCTCTGGGGCCA GTCTGGGCCACGGTCGGGACCCAGTGGAGGGCCGGACTGGTCAGGGTTCAGGCGGGAT CCGGCGTCCGAGTTCTGGGTTCAATCCCGCACTTGCCGAAGTCCCTGGGGCTGGCAAG GGTGCAAGACGCGGAGGGCTCTATGTCGGGAAAGGGGCTCTGAAGACCACGTGGGGGC GCTCTAAGGGGTCTGGGGCCACCCTGCTCTCTGGGTCAAAGGTCATCGCAATGGCCGG GAAGAACTTCCTCTTCCTTGGCTCTCCCCACTTACTTCCTGATAACCTGGTAGCGGTC TCCCGCGGGCGTCGGGGCTTGGGGGGAGGCGTAGCAACTTCAGGGAACTTCCCAAAGC GGAAGTATAAGAGTGGACCTGCAGGCCGGTCGCGAGGAGGTGGAGTGGGTGGCGCCCG CTTTGTGCCTGGGATCGGCATGCTGGGGCAGGAGGGCAGCCGCGTGTCAGGTGACCAG AACCATGTCCAGCCAGGTGGTGGGCAGCCACAAGGAAGAGGAGGATGGGAAGGGGCTG GGCCTGGCGAGCTGGGCGGTGGGAAGCTGGTGCTCAGCTTCCTGTCCAAGAGCCTCTG CCTGGTCTGTGGGGACGTGGCCTCCGGCTACCACTACGGTGTGTCATCCTGTGAGGAC TGCAAAGCCTTCTTCAAGAGGACCATCCAGGGGAGCATCAAGTACAGCTGTCCGGCCT CCAACAAGTGTGAGATCATCAAGCGGAGACGCAAGGCCTGTCAGGCCTGCCGCTTCAC CAAGTGCCTGCGGGAGTGCGCCTGGATCGCGTCCGGGGTGGGCGGAAGAAGTACAAGC GGTGCCAGAGGTGGACCCGCTGCCCTTCCCGGGCGCCTTCCCTGCTGGGCCCCTGGCA GTCGCTGGAGGCCCCCAGAAGACACCCCAGTGAATGCGCTGGTGTCTCATCTGCTGGT GGTTGAGCCTGAGAAGCTCTATGCCATGCCCGACCCCATGTCAGTACTGCAGAGCGTG TGGATGGAGGTGCTGGTGCCCGGTGTGGCCCAGCGCTCACTGCCACTGCAGGATGAGC TGGCCTTCACTGAGGACAGAGTCCTGGATGAAGAGGGGGCACGGGCAGCTGGCCTGGG GGAACTGGGGACTGCCCTGCTGCAACTGGTGCGGCGGCTGCAGTCCCTGCGGCTGGAG CGAGGGGAGTACGTTCTACTGAAGGCCCTGGCCCTTGCCAATTCAGACTCTGTGCCCA TCGAAGATGCCGAGGCTGTGGAGCAGCTGCCAGAAGCTCCGCACGAGGCCCTGCTGGA GTATGAAGCCGGCCGGGCTGGCACCGGAGGGGGTGCTGAGCGGCGGCGGCCAGGCAGG CTGCTGTTCACGCTACCGCTCCTCCACCAGACAGCGGGCAAAGTGCTGGCCCATTTCT ATGGGGTGAAGCTGGAGGGCAAGGTGCCCATGCACAAGCTGTTCTTGGAGATGCTCGA GGCCATGATGGACTGA (SEQ ID NO: 26)
ERR2
Human polypeptide sequence:
MSSDDRHLGSSCGSFIKTEPSSPSSGIDALSHHSPSGSSDASGGFGLALGTHANGLDS PPMFAGAGLGGTPCRKSYEDCASGIMEDSAIKCEYMLNAIPKRLCLVCGDIASGYHYG VASCEACKAFFKRTIQGNIEYSCPATNECEITKRRRKSCQACRFMKCLKVGMLKEGVR LDRVRGGRQKYKRRLDSESSPYLSLQISPPAKKPLTKIVSYLLVAEPDKLYAMPPPGM PEGDIKALTTLCDLADRELWIIGWAKHIPGFSSLSLGDQMSLLQSAWMEILILGIVY RSLPYDDKLVYAEDYIMDEEHSRLAGLLELYRAILQLVRRYKKLKVEKEEFVTLKALA LANSDSMYIEDLEAVQKLQDLLHEALQDYELSQRHEEPWRTGKLLLTLPLLRQTAAKA VQHFYSVKLQGKVPMHKLFLEMLEAKAWARADSLQEWRPLEQVPSPLHRATKRQHVHF LTPLPPPPSVA VGTAQAGYHLEVFLPQRAG PRAA (SEQ ID NO: 27)
Human polynucleotide sequence:
ATGTCCTCGGACGACAGGCACCTGGGCTCCAGCTGCGGCTCCTTCATCAAGACTGAGC CGTCCAGCCCGTCCTCGGGCATAGATGCCCTCAGCCACCACAGCCCCAGTGGCTCGTC CGACGCCAGCGGCGGCTTTGGCCTGGCCCTGGGCACCCACGCCAACGGTCTGGACTCG CCACCCATGTTTGCAGGCGCCGGGCTGGGAGGCACCCCATGCCGCAAGAGCTACGAGG ACTGTGCCAGCGGCATCATGGAGGACTCGGCCATCAAGTGCGAGTACATGCTCAACGC CATCCCCAAGCGCCTGTGCCTCGTGTGCGGGGACATTGCCTCTGGCTACCACTACGGC GTGGCCTCCTGCGAGGCTTGCAAGGCCTTCTTCAAGAGGACTATCCAAGGGAACATTG AGTACAGCTGCCCGGCCACCAACGAGTGCGAGATCACCAAACGGAGGCGCAAGTCCTG CCAGGCCTGCCGCTTCATGAAATGCCTCAAAGTGGGGATGCTGAAGGAAGGTGTGCGC CTTGATCGAGTGCGTGGAGGCCGTCAGAAATACAAGCGACGGCTGGACTCAGAGAGCA GCCCATACCTGAGCTTACAAATTTCTCCACCTGCTAAAAAGCCATTGACCAAGATTGT CTCATACCTACTGGTGGCTGAGCCGGACAAGCTCTATGCCATGCCTCCCCCTGGTATG CCTGAGGGGGACATCAAGGCCCTGACCACTCTCTGTGACCTGGCAGACCGAGAGCTTG TGGTCATCATTGGCTGGGCCAAGCACATCCCAGGCTTCTCAAGCCTCTCCCTGGGGGA CCAGATGAGCCTGCTGCAGAGTGCCTGGATGGAAATCCTCATCCTGGGCATCGTGTAC CGCTCGCTGCCCTACGACGACAAGCTGGTGTACGCTGAGGACTACATCATGGATGAGG AGCACTCCCGCCTCGCGGGGCTGCTGGAGCTCTACCGGGCCATCCTGCAGCTGGTACG CAGGTACAAGAAGCTCAAGGTGGAGAAGGAGGAGTTTGTGACGCTCAAGGCCCTGGCC CTCGCCAACTCCGATTCCATGTACATCGAGGATCTAGAGGCTGTCCAGAAGCTGCAGG ACCTGCTGCACGAGGCACTGCAGGACTACGAGCTGAGCCAGCGCCATGAGGAGCCCTG GAGGACGGGCAAGCTGCTGCTGACACTGCCGCTGCTGCGGCAGACGGCCGCCAAGGCC GTGCAGCACTTCTATAGCGTCAAACTGCAGGGCAAAGTGCCCATGCACAAACTCTTCC TGGAGATGCTGGAGGCCAAGGCCTGGGCCAGGGCTGACTCCCTTCAGGAGTGGAGGCC ACTGGAGCAAGTGCCCTCTCCCCTCCACCGAGCCACCAAGAGGCAGCATGTGCATTTC CTAACTCCCTTGCCCCCTCCCCCATCTGTGGCCTGGGTGGGCACTGCTCAGGCTGGAT ACCACCTGGAGGTTTTCCTTCCGCAGAGGGCAGGTTGGCCAAGAGCAGCTTAG (SEQ ID NO: 28)
Mouse polypeptide sequence:
MSSEDRHLGSSCGSFIKTEPSSPSSGIDALSHHSPSGSSDASGGFGIALSTHANGLDS PPMFAGAGLGGNPCRKSYEDCTSGIMEDSAIKCEYMLNAIPKRLCLVCGDIASGYHΫG VASCEACKAFFKRTIQGNIEYNCPATNECEITKRRRKSCQACRFMKCLKVGML.KEGVR LDRVRGGRQKYKRRLDSENSPYLNLPISPPAKKPLTKIVSNLLGVEQDKLYAMPPNDI PEGDIKALTTLCELADRELVFLINWAKHIPGFPSLTLGDQMSLLQSAWMEILILGIVY RSLPYDDKLAYAEDYIMDEEHSRLVGLLDLYRAILQLVRRYKKLKVEKEEFMILKALA LANSDSMYIENLEAVQKLQDLLHEALQDYELSQRHEEPRRAGKLL TLPLLRQTAAKA VQHFYSVKLQGKVPMHKLFLEMLEAKV (SEQ ID NO: 29)
Mouse polynucleotide sequence:
ATGTCGTCCGAAGACAGGCACCTGGGCTCTAGCTGCGGCTCCTTCATCAAGACGGAGC
CATCCAGCCCGTCCTCGGGCATTGATGCCCTCAGCCACCACAGCCCCAGCGGCTCGTC
GGACGCCAGTGGTGGCTTTGGCATTGCCCTGAGCACCCACGCCAACGGTCTGGACTCG CCGCCTATGTTCGCAGGTGCGGGGCTGGGAGGCAACCCGTGTCGCAAGAGCTACGAGG ACTGTACTAGTGGTATCATGGAGGACTCCGCCATCAAATGCGAGTACATGCTTAACGC CATCCCCAAGCGCCTGTGCCTCGTGTGCGGGGACATTGCCTCTGGCTACCACTACGGA GTGGCCTCCTGCGAGGCTTGCAAGGCGTTCTTCAAGAGAACCATTCAAGGCAACATCG AGTACAACTGCCCGGCCACCAATGAATGTGAGATCACCAAACGGAGGCGCAAGTCCTG TCAGGCCTGCCGATTCATGAAATGCCTCAAAGTGGGGATGCTGAAGGAAGGTGTGCGC CTTGACCGAGTTCGAGGAGGCCGCCAGAAGTACAAGCGACGGCTGGATTCGGAGAACA GCCCCTACCTGAACCTGCCGATTTCCCCACCTGCTAAAAAGCCATTGACTAAGATCGT CTCGAATCTACTAGGGGTTGAGCAGGACAAGCTGTATGCTATGCCTCCCAACGATATC CCCGAGGGAGATATCAAGGCCCTGACCACTCTCTGTGAATTGGCAGATCGGGAGCTTG TGTTCCTCATCAACTGGGCCAAGCACATCCCAGGCTTCCCCAGTCTGACACTTGGGGA CCAGATGAGCCTGCTGCAGAGTGCCTGGATGGAGATTCTCATCTTGGGCATCGTGTAC CGCTCGCTCCCATACGATGACAAGCTGGCATACGCCGAGGACTATATCATGGATGAGG AACACTCTCGCCTGGTAGGGCTGCTGGACCTTTACCGAGCCATCCTGCAGCTGGTGCG CAGGTACAAGAAACTCAAGGTAGAGAAGGAAGAGTTTATGATCCTCAAAGCCCTGGCC CTCGCCAACTCAGATTCGATGTACATTGAGAACCTGGAGGCGGTGCAGAAGCTTCAGG ACCTGCTGCACGAGGCGCTGCAGGACTATGAGCTGAGTCAGCGCCATGAGGAGCCGCG GAGGGCCGGCAAGCTGCTCTGGACGCTGCCCCTGCTGAGGCAGACAGCCGCCAAAGCC GTGCAACACTTCTACAGTGTGAAACTGCAGGGCAAGGTGCCCATGCACAAACTCTTCC TGGAGATGCTGGAGGCCAAGGTGTGA (SEQ ID NO: 30)
ERR3
Human polypeptide sequence:
MDSVELCLPESFSLHYEEELLCRMSNKDRHIDSSCSSFIKTEPSSPASLTDSVNHHSP GGSSDASGSYSSTMNGHQNGLDSPPLYPSAPILGGSGPVRKLYDDCSSTIVEDPQTKC EYMLNSMPKRLCLVCGDIASGYHYGVASCEACKAFFKRTIQGNIEYSCPATNECEITK RRRKSCQACRFMKCLKVGMLKEGVRLDRVRGGRQKYKRRIDAENSPYLNPQLVQPAKK PYNKIVSHLLVAEPEKIYAMPDPTVPDSDIKALTTLCDLADRELWIIGWAKHIPGFS TLSLADQMSLLQSAWMEILILGWYRSLSFEDELVYADDYIMDEDQSKLAGLLDLNNA ILQLVKKYKSMKLEKEEFVTLKAIALANSDSMHIEDVEAVQKLQDVLHEALQDYEAGQ HMEDPRRAGKMLMTLPLLRQTSTKAVQHFYNIKLEGKVPMHKLFLEMLEAKV (SEQ IDNO: 31)
Human polynucleotide sequence:
ATGTCAAACAAAGATCGACACATTGATTCCAGCTGTTCGTCCTTCATCAAGACGGAAC CTTCCAGCCCAGCCTCCCTGACGGACAGCGTCAACCACCACAGCCCTGGTGGCTCTTC AGACGCCAGTGGGAGCTACAGTTCAACCATGAATGGCCATCAGAACGGACTTGACTCG CCACCTCTCTACCCTTCTGCTCCTATCCTGGGAGGTAGTGGGCCTGTCAGGAAACTGT ATGATGACTGCTCCAGCACCATTGTTGAAGATCCCCAGACCAAGTGTGAATACATGCT CAACTCGATGCCCAAGAGACTGTGTTTAGTGTGTGGTGACATCGCTTCTGGGTACCAC TATGGGGTAGCATCATGTGAAGCCTGCAAGGCATCTTTCAAGAGGAAAATACAAGCCA ATATAGAATACAGCTGCCCTGCCACGAATGAATGTGAAATCACAAAGCGCAGACGTAA ATCCTGCCAGGCTTGCCGCTTCATGAAGTGTTTAAAAGTGGGCATGCTGAAAGAAGGG GTGCGTCTTGACAGAGTACGTGGAGGTCGGCAGAAGTACAAGCGCAGGATAGATGCGG AGAACAGCCCATACCTGAACCCTCAGCTGGTTCAGCCAGCCAAAAAGCCATATAACAA GATTGTCTCACATTTGTTGGTGGCTGAACCGGAGAAGATCTATGCCATGCCTGACCCT ACTGTCCCCGACAGTGACATCAAAGCCCTCACTACACTGTGTGACTGTGCCGACCGAG AGTTGGTGGTTATCATTGGATGGGCGAAGCATATCCCAGGCTTCTCCACGCTGTCCCT GGCGGACCAGATGAGCCTTCTGCAGAGTGCTTGGATGGAAATTTTGATCCTTGGTTTC GTATACCGGTCTCTTTCGTTTGAGGATGAACTTGTCTATGCAGACGATTATATAATGG ACGAAGACCAGTCCAAATTAGCAGGCCTTCTTGATCTAAATAATGCTATCCTGCAGCT GGTAAAGAAATACAAGAGCATGAAGCTGGAAAAAGAAGAATTTGTCACCCTCAAAGCT' ATAGCTCTTGCTAATTCAGACTCCATGCACATAGAAGATGTTGAAGCCGTTCAGAAGC TTCAGGATGTCTTACATGAAGCGCTGCAGGATTATGAAGCTGGCCAGCACATGGAAGA CCCTCGTCGAGCTGGCAAGATGCTGATGACACTGCCACTCCTGAGGCAGACCTCTACC AAGGCCGTGCAGCATTTCTACAACATCAAACTAGAAGGCAAAGTCCCAATGCACAAAC TTTTTTTGGAAATGTTGGAGGCCAAGGTCTGCTAA (SEQ ID NO: 32)
Mouse polypeptide sequence:
MDSVELCLPESFSLHYEEELLCRMSNKDRHIDS.SCSSFIKTEPSSPASLTDSVNHHSP GGSSDASGSYSSTMNGHQNGLDSPPLYPSAPILGGSGPVRKLYDDCSSTIVEDPQTKC EYMLNSMPKRLCLVCGDIASGYHYGVASCEACKAFFKRTIQGNIEYSCPATNECEITK RRRKSCQACRFMKCLKVGMLKEGVRLDRVRGGRQKYKRRIDAENSPYLNPQLVQPAKK PYNKIVSHLLVAEPEKIYAMPDPTVPDSDIKALTTLCDLADRELWIIGWAKHIPGFS TLSLADQMSLLQSAWMEILILGWYRSLSFEDELVYADDYIMDEDQSKLAGLLDLNNA ILQLVKKYKSMKLEKEEFVTLKAIALANSDSMHIEDVEAVQKLQDVLHEALQDYEAGQ HMEDPRRAGKMLMTLPLLRQTSTKAVQHFYNIKLEGKVPMHKLFLEMLEAKV (SEQ IDNO: 33)
Mouse polynucleotide sequence:
GCCCTGTCTCTGTCAAGGAAACTTTGATTTATAGGTGGGGTGCACAAATAATGGTTGT CGGGCGCACATGGATTCGGTAGAACTTTGCCTGCCTGAATCTTTTTCCCTGCACTACG AAGAAGAGCTTCTCTGCAGAATGTCAAACAAAGATCGACACATTGATTCCAGCTGTTC GTCCTTCATCAAGACGGAACCCTCCAGCCCAGCCTCCCTGACGGACAGCGTCAACCAC CACAGCCCTGGTGGGTCTTCCGACGCCAGTGGGAGTTACAGTTCAACCATGAATGGCC ATCAGAACGGACTGGACTCGCCACCTCTCTACCCCTCTGCTCCGATCCTGGGAGGCAG CGGGCCTGTCCGGAAACTGTATGATGACTGCTCCAGCACCATCGTAGAGGATCCCCAG ACCAAGTGTGAATATATGCTCAACTCCATGCCCAAGAGACTGTGCTTAGTGTGTGGCG ACATCGCCTCTGGGTACCACTATGGGGTTGCATCATGTGAAGCCTGCAAGGCATTCTT CAAGAGGACGATTCAAGGTAACATAGAGTACAGCTGCCCAGCCACGAATGAATGTGAG ATCACAAAGCGCAGACGCAAATCCTGCCAGGCCTGCCGCTTCATGAAGTGTCTCAAAG TGGGCATGCTGAAAGAAGGGGTCCGTCTTGACAGAGTGCGTGGAGGTCGGCAGAAGTA CAAGCGCAGAATAGATGCTGAGAACAGCCCATACCTGAACCCTCAGCTGGTGCAGCCA GCCAAAAAGCCATATAACAAGATTGTCTCGCATTTGTTGGTGGCTGAACCAGAGAAGA TCTATGCCATGCCTGACCCTACTGTCCCCGACAGTGACATCAAAGCCCTCACCACACT CTGTGACTTGGCTGACCGAGAGTTGGTGGTTATCATTGGATGGGCAAAACATATTCCA GGCTTCTCCACACTGTCCCTTGCAGACCAGATGAGCCTCCTCCAGAGTGCATGGATGG AGATTCTGATCCTCGGCGTTGTGTACCGATCGCTTTCGTTTGAGGATGAACTTGTCTA TGCAGACGATTATATAATGGATGAAGACCAGTCTAAATTAGCAGGCCTTCTTGACCTA AATAATGCTATCCTGCAGCTGGTGAAGAAGTACAAGAGCATGAAGCTAGAGAAGGAAG AATTCGTCACCCTCAAAGCAATAGCTCTTGCTAATTCAGATTCCATGCATATAGAAGA TGTGGAAGCTGTGCAGAAACTTCAGGATGTGTTACATGAGGCCCTGCAGGATTACGAG GCTGGCCAGCACATGGAAGACCCTCGCCGTGCAGGCAAGATGCTGATGACGCTGCCGC TGCTGAGGCAGACCTCCACCAAGGCAGTCCAGCACTTCTACAACATCAAACTCGAAGG CAAAGTGCCCATGCACAAACTTTTTTTGGAAATGCTGGAGGCCAAGGTCTGACTAAAA GCCCCCCCTGGGCCCTCCCATCCTGCACGTTGAAAAGGGAAGATAAACCCAAGAATGA TGTCGAAGAATCTTAGAGTTTAGTGAACAACATTAAAAATCAACAGACTGCACTGATA T (SEQ ID NO: 34) ESR1
Human polypeptide sequence: MTMTLHTKASGMALLHQIQGNELEPLNRPQLKIPLERPLGEVYLDSSKPAVYNYPEGA AYEFNAAAAANAQVYGQTGLPYGPGSEAAAFGSNGLGGFPPLNSVSPSPLMLLHPPPQ LSPFLQPHGQQVPYYLENEPSGYTVREAGPPAFYRPNSDNRRQGGRERLASTNDKGSM AMESAKETRYCAVCNDYASGYHYGVWSCEGCKAFFKRSIQGHNDYMCPATNQCTIDKN RRKSCQACRLRKCYEVGMMKGGIRKDRRGGRMLKHKRQRDDGEGRGEVGSAGDMRAAN L PSPLMIKRSKKNSLALSLTADQMVSALLDAEPPILYSEYDPTRPFSEASMMGLLTN LADRELVHMINWAKRVPGFVDLTLHDQVHLLECA LEILMIGLV RSMEHPGKLLFAP NLLLDRNQGKCVEGMVEIFDMLLATSSRFRMMNLQGEEFVCLKSIILLNSGVYTFLSS TLKSLEEKDHIHRVLDKITDTLIHLMAKAGLTLQQQHQRLAQLLLILSHIRHMSNKGM EHLYSMKCKNWPLYDLLLEMLDAHRLHAPTSRGGASVEETDQSHLATAGSTSSHSLQ KYYITGEAEGFPATV (SEQ ID NO: 35)
Human polynucleotide sequence: GAGTTGTGCCTGGAGTGATGTTTAAGCCAATGTCAGGGCAAGGCAACAGTCCCTGGCC GTCCTCCAGCACCTTTGTAATGCATATGAGCTCGGGAGACCAGTACTTAAAGTTGGAG GCCCGGGAGCCCAGGAGCTGGCGGAGGGCGTTCGTCCTGGGAGCTGCACTTGCTCCGT CGGGTCGCCGGCTTCACCGGACCGCAGGCTCCCGGGGCAGGGCCGGGGCCAGAGCTCG CGTGTCGGCGGGACATGCGCTGCGTCGCCTCTAACCTCGGGCTGTGCTCTTTTTCCAG GTGGCCCGCCGGTTTCTGAGCCTTCTGCCCTGCGGGGACACGGTCTGCACCCTGCCCG CGGCCACGGACCATGACCATGACCCTCCACACCAAAGCATCTGGGATGGCCCTACTGC ATCAGATCCAAGGGAACGAGCTGGAGCCCCTGAACCGTCCGCAGCTCAAGATCCCCCT GGAGCGGCCCCTGGGCGAGGTGTACCTGGACAGCAGCAAGCCCGCCGTGTACAACTAC CCCGAGGGCGCCGCCTACGAGTTCAACGCCGCGGCCGCCGCCAACGCGCAGGTCTACG GTCAGACCGGCCTCCCCTACGGCCCCGGGTCTGAGGCTGCGGCGTTCGGCTCCAACGG CCTGGGGGGTTTCCCCCCACTCAACAGCGTGTCTCCGAGCCCGCTGATGCTACTGCAC CCGCCGCCGCAGCTGTCGCCTTTCCTGCAGCCCCACGGCCAGCAGGTGCCCTACTACC TGGAGAACGAGCCCAGCGGCTACACGGTGCGCGAGGCCGGCCCGCCGGCATTCTACAG GCCAAATTCAGATAATCGACGCCAGGGTGGCAGAGAAAGATTGGCCAGTACCAATGAC AAGGGAAGTATGGCTATGGAATCTGCCAAGGAGACTCGCTACTGTGCAGTGTGCAATG ACTATGCTTCAGGCTACCATTATGGAGTCTGGTCCTGTGAGGGCTGCAAGGCCTTCTT CAAGAGAAGTATTCAAGGACATAACGACTATATGTGTCCAGCCACCAACCAGTGCACC ATTGATAAAAACAGGAGGAAGAGCTGCCAGGCCTGCCGGCTCCGCAAATGCTACGAAG TGGGAATGATGAAAGGTGGGATACGAAAAGACCGAAGAGGAGGGAGAATGTTGAAACA CAAGCGCCAGAGAGATGATGGGGAGGGCAGGGGTGAAGTGGGGTCTGCTGGAGACATG AGAGCTGCCAACCTTTGGCCAAGCCCGCTCATGATCAAACGCTCTAAGAAGAACAGCC TGGCCTTGTCCCTGACGGCCGACCAGATGGTCAGTGCCTTGTTGGATGCTGAGCCCCC CATACTCTATTCCGAGTATGATCCTACCAGACCCTTCAGTGAAGCTTCGATGATGGGC TTACTGACCAACCTGGCAGACAGGGAGCTGGTTCACATGATCAACTGGGCGAAGAGGG TGCCAGGCTTTGTGGATTTGACCCTCCATGATCAGGTCCACCTTCTAGAATGTGCCTG GCTAGAGATCCTGATGATTGGTCTCGTCTGGCGCTCCATGGAGCACCCAGTGAAGCTA CTGTTTGCTCCTAACTTGCTCTTGGACAGGAACCAGGGAAAATGTGTAGAGGGCATGG TGGAGATCTTCGACATGCTGCTGGCTACATCATCTCGGTTCCGCATGATGAATCTGCA GGGAGAGGAGTTTGTGTGCCTCAAATCTATTATTTTGCTTAATTCTGGAGTGTACACA TTTCTGTCCAGCACCCTGAAGTCTCTGGAAGAGAAGGACCATATCCACCGAGTCCTGG ACAAGATCACAGACACTTTGATCCACCTGATGGCCAAGGCAGGCCTGACCCTGCAGCA GCAGCACCAGCGGCTGGCCCAGCTCCTCCTCATCCTCTCCCACATCAGGCACATGAGT AACAAAGGCATGGAGCATCTGTACAGCATGAAGTGCAAGAACGTGGTGCCCCTCTATG ACCTGCTGCTGGAGATGCTGGACGCCCACCGCCTACATGCGCCCACTAGCCGTGGAGG GGCATCCGTGGAGGAGACGGACCAAAGCCACTTGGCCACTGCGGGCTCTACTTCATCG CATTCCTTGCAAAAGTATTACATCACGGGGGAGGCAGAGGGTTTCCCTGCCACAGTCT GAGAGCTCCCTGGCTCCCACACGGTTCAGATAATCCCTGCTGCATTTTACCCTCATCA TGCACCACTTTAGCCAAATTCTGTCTCCTGCATACACTCCGGCATGCATCCAACACCA ATGGCTTTCTAGATGAGTGGCCATTCATTTGCTTGCTCAGTTCTTAGTGGCACATCTT CTGTCTTCTGTTGGGAACAGCCAAAGGGATTCCAAGGCTAAATCTTTGTAACAGCTCT CTTTCCCCCTTGCTATGTTACTAAGCGTGAGGATTCCCGTAGCTCTTCACAGCTGAAC TCAGTCTATGGGTTGGGGCTCAGATAACTCTGTGCATTTAAGCTACTTGTAGAGACCC AGGCCTGGAGAGTAGACATTTTGCCTCTGATAAGCACTTTTTAAATGGCTCTAAGAAT AAGCCACAGCAAAGAATTTAAAGTGGCTCCTTTAATTGGTGACTTGGAGAAAGCTAGG TCAAGGGTTTATTATAGCACCCTCTTGTATTCCTATGGCAATGCATCCTTTTATGAAA GTGGTACACCTTAAAGCTTTTATATGACTGTAGCAGAGTATCTGGTGATTGTCAATTC ACTTCCCCCTATAGGAATACAAGGGGCCACACAGGGAAGGCAGATCCCCTAGTTGGCC AAGACTTATTTTAACTTGATACACTGCAGATTCAGAGTGTCCTGAAGCTCTGCCTCTG GCTTTCCGGTCATGGGTTCCAGTTAATTCATGCCTCCCATGGACCTATGGAGAGCAAC AAGTTGATCTTAGTTAAGTCTCCCTATATGAGGGATAAGTTCCTGATTTTTGTTTTTA TTTTTGTGTTACAAAAGAAAGCCCTCCCTCCCTGAACTTGCAGTAAGGTCAGCTTCAG GACCTGTTCCAGTGGGCACTGTACTTGGATCTTCCCGGCGTGTGTGTGCCTTACACAG GGGTGAACTGTTCACTGTGGTGATGCATGATGAGGGTAAATGGTAGTTGAAAGGAGCA GGGGCCCTGGTGTTGCATTTAGCCCTGGGGCATGGAGCTGAACAGTACTTGTGCAGGA TTGTTGTGGCTACTAGAGAACAAGAGGGAAAGTAGGGCAGAAACTGGATACAGTTCTG AGCACAGCCAGACTTGCTCAGGTGGCCCTGCACAGGCTGCAGCTACCTAGGAACATTC CTTGCAGACCCCGCATTGCCTTTGGGGGTGCCCTGGGATCCCTGGGGTAGTCCAGCTC TTATTCATTTCCCAGCGTGGCCCTGGTTGGAAGAAGCAGCTGTCAAGTTGTAGACAGC TGTGTTCCTACAATTGGCCCAGCACCCTGGGGCACGGGAGAAGGGTGGGGACCGTTGC TGTCACTACTCAGGCTGACTGGGGCCTGGTCAGATTACGTATGCCCTTGGTGGTTTAG AGATAATCCAAAATCAGGGTTTGGTTTGGGGAAGAAAATCCTCCCCCTTCCTCCCCCG CCCCGTTCCCTACCGCCTCCACTCCTGCCAGCTCATTTCCTTCAATTTCCTTTGACCT ATAGGCTAAAAAAGAAAGGCTCATTCCAGCCACAGGGCAGCCTTCCCTGGGCCTTTGC TTCTCTAGCACAATTATGGGTTACTTCCTTTTTCTTAACAAAAAAGAATGTTTGATTT CCTCTGGGTGACCTTATTGTCTGTAATTGAAACCCTATTGAGAGGTGATGTCTGTGTT AGCCAATGACCCAGGTAGCTGCTCGGGCTTCTCTTGGTATGTCTTGTTTGGAAAAGTG GATTTCATTCATTTCTGATTGTCCAGTTAAGTGATCACCAAAGGACTGAGAATCTGGG' AGGGCAAAAAAAAAAAAAAAAGTTTTTATGTGCACTTAAATTTGGGGACAATTTTATG TATCTGTGTTAAGGATATGCTTAAGAACATAATTCTTTTGTTGCTGTTTGTTTAAGAA GCACCTTAGTTTGTTTAAGAAGCACCTTATATAGTATAATATATATTTTTTTGAAATT ACATTGCTTGTTTATCAGACAATTGAATGTAGTAATTCTGTTCTGGATTTAATTTGAC TGGGTTAACATGCAAAAACCAAGGAAAAATATTTAGTTTTTTTTTTTTTTTTTGTATA CTTTTCAAGCTACCTTGTCATGTATACAGTCATTTATGCCTAAAGCCTGGTGATTATT CATTTAAATGAAGATCACATTTCATATCAACTTTTGTATCCACAGTAGACAAAATAGC ACTAATCCAGATGCCTATTGTTGGATATTGAATGACAGACAATCTTATGTAGCAAAGA TTATGCCTGAAAAGGAAAATTATTCAGGGCAGCTAATTTTGCTTTTACCAAAATATCA GTAGTAATATTTTTGGACAGTAGCTAATGGGTCAGTGGGTTCTTTTTAATGTTTATAC TTAGATTTTCTTTTAAAAAAATTAAAATAAAACAAAAAAAATTTCTAGGACTAGACGA TGTAATACCAGCTAAAGCCAAACAATTATACAGTGGAAGGTTTTACATTATTCATCCA ATGTGTTTCTATTCATGTTAAGATACTACTACATTTGAAGTGGGCAGAGAACATCAGA TGATTGAAATGTTCGCCCAGGGGTCTCCAGCAACTTTGGAAATCTCTTTGTATTTTTA CTTGAAGTGCCACTAATGGACAGCAGATATTTTCTGGCTGATGTTGGTATTGGGTGTA GGAACATGATTTAAAAAAAAAACTCTTGCCTCTGCTTTCCCCCACTCTGAGGCAAGTT AAAATGTAAAAGATGTGATTTATCTGGGGGGCTCAGGTATGGTGGGGAAGTGGATTCA GGAATCTGGGGAATGGCAAATATATTAAGAAGAGTATTGAAAGTATTTGGAGGAAAAT GGTTAATTCTGGGTGTGCACCAAGGTTCAGTAGAGTCCACTTCTGCCCTGGAGACCAC AAATCAACTAGCTCCATTTACAGCCATTTCTAAAATGGCAGCTTCAGTTCTAGAGAAG AAAGAACAACATCAGCAGTAAAGTCCATGGAATAGCTAGTGGTCTGTGTTTCTTTTCG CCATTGCCTAGCTTGCCGTAATGATTCTATAATGCCATCATGCAGCAAT.TATGAGAGG CTAGGTCATCCAAAGAGAAGACCCTATCAATGTAGGTTGCAAAATCTAACCCCTAAGG AAGTGCAGTCTTTGATTTGATTTCCCTAGTAACCTTGCAGATATGTTTAACCAAGCCA TAGCCCATGCCTTTTGAGGGCTGAACAAATAAGGGACTTACTGATAATTTACTTTTGA TCACATTAAGGTGTTCTCACCTTGAAATCTTATACACTGAAATGGCCATTGATTTAGG CCACTGGCTTAGAGTACTCCTTCCCCTGCATGACACTGATTACAAATACTTTCCTATT CATACTTTCCAATTATGAGATGGACTGTGGGTACTGGGAGTGATCACTAACACCATAG TAATGTCTAATATTCACAGGCAGATCTGCTTGGGGAAGCTAGTTATGTGAAAGGCAAA TAAAGTCATACAGTAGCTCAAAAGGCAACCATAATTCTCTTTGGTGCAAGTCTTGGGA GCGTGATCTAGATTACACTGCACCATTCCCAAGTTAATCCCCTGAAAACTTACTCTCA ACTGGAGCAAATGAACTTTGGTCCCAAATATCCATCTTTTCAGTAGCGTTAATTATGC TCTGTTTCCAACTGCATTTCCTTTCCAATTGAATTAAAGTGTGGCCTCGTTTTTAGTC ATTTAAAATTGTTTTCTAAGTAATTGCTGCCTCTATTATGGCACTTCAATTTTGCACT GTCTTTTGAGATTCAAGAAAAATTTCTATTCATTTTTTTGCATCCAATTGTGCCTGAA CTTTTAAAATATGTAAATGCTGCCATGTTCCAAACCCATCGTCAGTGTGTGTGTTTAG AGCTGTGCACCCTAGAAACAACATACTTGTCCCATGAGCAGGTGCCTGAGACACAGAC CCCTTTGCATTCACAGAGAGGTCATTGGTTATAGAGACTTGAATTAATAAGTGACATT ATGCCAGTTTCTGTTCTCTCACAGGTGATAAACAATGCTTTTTGTGCACTACATACTC TTCAGTGTAGAGCTCTTGTTTTATGGGAAAAGGCTCAAATGCCAAATTGTGTTTGATG GATTAATATGCCCTTTTGCCGATGCATACTATTACTGATGTGACTCGGTTTTGTCGCA GCTTTGCTTTGTTTAATGAAACACACTTGTAAACCTCTTTTGCACTTTGAAAAAGAAT CCAGCGGGATGCTCGAGCACCTGTAAACAATTTTCTCAACCTATTTGATGTTCAAATA AAGAATTAAACT (SEQ ID NO: 36)
Mouse polypeptide sequence:
MTMTLHTKASGMALLHQIQGNELEPLNRPQLKMPMERALGEVYVDNSKPTVFNYPEGA AYEFNAAAAAAAAASAPVYGQSGIAYGPGSEAAAFSANSLGAFPQLNSVSPSPLMLLH PPPQLSPFLHPHGQQVPYYLENEPSAYAVRDTGPPAFYRSNSDNRRQNGRERLSSSNE KGNMIMESAKETRYCAVCNDYASGYHYGV SCEGCKAFFKRSIQGHNDYMCPATNQCT IDKNRRKSCQACRLRKCYEVGMMKGGIRKDRRGGRMLKHKRQRDDLEGRNEMGASGDM RAANLWPSPLVIKHTKKNSPALSLTADQMVSALLDAEPPMIYSEYDPSRPFSEASMMG LLTNLADRELVHMINWAKRVPGFGDLNLHDQVHLLECAWLEILMIGLVWRSMEHPGKL LFAPNLLLDRNQGKCVEGMVEIFDMLLATSSRFRMMNLQGEEFVCLKSIILLNSGVYT FLSSTLKSLEEKDHIHRVLDKITDTLIHLJYIAKAGLTLQQQHRRLAQLLLILSHIRHMS NKGMEHLYNMKCKNWPLYDLLLEMLDAHRLHAPASRMGVPPEEPSQTQLATTSSTSA HSLQTYYIPPEAEGFPNTI (SEQ ID NO: 37)
Mouse polynucleotide sequence:
ATGACCATGACCCTTCACACCAAAGCCTCGGGAATGGCCTTGCTGCACCAGATCCAAG GGAACGAGCTGGAGCCCCTCAACCGCCCGCAGCTCAAGATGCCCATGGAGAGGGCCCT GGGCGAGGTATACGTGGACAACAGCAAGCCCACTGTGTTCAACTACCCCGAGGGCGCC GCCTACGAGTTCAACGCCGCCGCCGCCGCCGCCGCCGCCGCCTCGGCGCCGGTCTACG GCCAGTCGGGCATCGCCTACGGCCCCGGGTCGGAGGCGGCCGCCTTCAGTGCCAACAG CCTGGGGGCTTTCCCCCAGCTCAACAGCGTGTCGCCTAGCCCGCTGATGCTGCTGCAC CCGCCGCCGCAGCTGTCTCCTTTCCTGCACCCGCACGGCCAGCAGGTGCCCTACTACC TGGAGAACGAGCCCAGCGCCTACGCCGTGCGCGACACCGGCCCTCCCGCCTTCTACAG GTCTAATTCTGACAATCGACGCCAGAATGGCCGAGAGAGACTGTCCAGCAGTAACGAG AAAGGAAACATGATCATGGAGTCTGCCAAGGAGACTCGCTACTGTGCCGTGTGCAATG ACTATGCCTCTGGCTACCATTATGGGGTCTGGTCCTGCGAAGGCTGCAAGGCTTTCTT AAGAGAAGCATTCAAGGACACAATGACTACATGTGTCCAGCTACAAACCAATGCACC ATTGACAAGAACCGGAGGAAGAGTTGCCAGGCCTGTCGGCTGCGCAAGTGTTACGAAG TGGGCATGATGAAAGGCGGCATACGGAAAGACCGCCGAGGAGGGAGAATGTTGAAGCA CAAGCGTCAGAGAGATGACTTGGAAGGCCGAAATGAAATGGGTGCTTCAGGAGACATG AGGGCTGCCAACCTTTGGCCAAGCCCTCTTGTGATTAAGCACACTAAGAAGAATAGCC CTGCCTTGTCCTTGACAGCTGACCAGATGGTCAGTGCCTTGTTGGATGCTGAACCGCC CATGATCTATTCTGAATATGATCCTTCTAGACCCTTCAGTGAAGCCTCAATGATGGGC TTATTGACCAACCTAGCAGATAGGGAGCTGGTTCATATGATCAACTGGGCAAAGAGAG TGCCAGGCTTTGGGGACTTGAATCTCCATGATCAGGTCCACCTTCTCGAGTGTGCCTG GCTGGAGATTCT.GATGATTGGTCTCGTCTGGCGCTCCATGGAACACCCGGGGAAGCTC CTGTTTGCTCCTAACTTGCTCCTGGACAGGAATCAAGGTAAATGTGTGGAAGGCATGG TGGAGATCTTTGACATGTTGCTTGCTACGTCAAGTCGGTTCCGCATGATGAACCTGCA GGGTGAAGAGTTTGTGTGCCTCAAATCCATCATTTTGCTTAATTCCGGAGTGTACACG TTTCTGTCCAGCACCTTGAAGTCTCTGGAAGAGAAGGACCACATCCACCGTGTCCTGG ACAAGATCACAGACACTTTGATCCACCTGATGGCCAAAGCTGGCCTGACTCTGCAGCA GCAGCATCGCCGCCTAGCTCAGCTCCTTCTCATTCTTTCCCATATCCGGCACATGAGT AACAAAGGCATGGAGCATCTCTACAACATGAAATGCAAGAACGTTGTGCCCCTCTATG ACCTGCTCCTGGAGATGTTGGATGCCCACCGCCTTCATGCCCCAGCCAGTCGCATGGG AGTGCCCCCAGAGGAGCCCAGCCAGACCCAGCTGGCCACCACCAGCTCCACTTCAGCA CATTCCTTACAAACCTACTACATACCCCCGGAAGCAGAGGGCTTCCCCAACACGATCT GA (SEQ ID NO: 38)
ESR2
Human polypeptide sequence: MDIKNSPSSLNSPSSYNCSQSILPLEHGSIYIPSSYVDSHHEYPAMTFYSPAVMNYSI PSNVTNLEGGPGRQTTSPNVLWPTPGHLSPLWHRQLSHLYAEPQKSPWCEARSLEHT LPVNRETLKRKVSGNRCASPVTGPGSKRDAHFCAVCSDYASGYHYGV SCEGCKAFFK RSIQGHNDYICPATNQCTIDKNRRKSCQACRLRKCYEVGMVKCGSRRERCGYRLVRRQ RSADEQLHCAGKAKRSGGHAPRVRELLLDALSPEQLVLTLLEAEPPHVLISRPSAPFT EASMMMSLTKLADKELVHMISWAKKIPGFVELSLFDQVRLLESCWMEVLMMGLMWRSI DHPGKLIFAPDLVLDRDEGKCVEGILEIFDMLLATTSRFRELKLQHKEYLCVKAMILL NSSMYPLVTATQDADSSRKLAHLLNAVTDALV VIAKSGISSQQQSMRLANLLMLLSH VRHASNKGMEHLLNMKCKNWPVYDLLLEMLNAHVLRGCKSSITGSECSPAEDSKSKE GSQNPQSQ (SEQ ID NO: 39)
Human polynucleotide sequence:
ATGAATTACAGCATTCCCAGCAATGTCACTAACTTGGAAGGTGGGCCTGGTCGGCAGA CCACAAGCCCAAATGTGTTGTGGCCAACACCTGGGCACCTTTCTCCTTTAGTGGTCCA TCGCCAGTTATCACATCTGTATGCGGAACCTCAAAAGAGTCCCTGGTGTGAAGCAAGA TCGCTAGAACACACCTTACCTGTAAACAGAGAGACACTGAAAAGGAAGGTTAGTGGGA ACCGTTGCGCCAGCCCTGTTACTGGTCCAGGTTCAAAGAGGGATGCTCACTTCTGCGC TGTCTGCAGCGATTACGCATCGGGATATCACTATGGAGTCTGGTCGTGTGAAGGATGT AAGGCCTTTTTTAAAAGAAGCATTCAAGGACATAATGATTATATTTGTCCAGCTACAA ATCAGTGTACAATCGATAAAAACCGGCGCAAGAGCTGCCAGGCCTGCCGACTTCGGAA GTGTTACGAAGTGGGAATGGTGAAGTGTGGCTCCCGGAGAGAGAGATGTGGGTACCGC CTTGTGCGGAGACAGAGAAGTGCCGACGAGCAGCTGCACTGTGCCGGCAAGGCCAAGA GAAGTGGCGGCCACGCGCCCCGAGTGCGGGAGCTGCTGCTGGACGCCCTGAGCCCCGA GCAGCTAGTGCTCACCCTCCTGGAGGCTGAGCCGCCCCATGTGCTGATCAGCCGCCCC AGTGCGCCCTTCACCGAGGCCTCCATGATGATGTCCCTGACCAAGTTGGCCGACAAGG AGTTGGTACACATGATCAGCTGGGCCAAGAAGATTCCCGGCTTTGTGGAGCTCAGCCT GTTCGACCAAGTGCGGCTCTTGGAGAGCTGTTGGATGGAGGTGTTAATGATGGGGCTG ATGTGGCGCTCAATTGACCACCCCGGCAAGCTCATCTTTGCTCCAGATCTTGTTCTGG ACAGGGATGAGGGGAAATGCGTAGAAGGAATTCTGGAAATCTTTGACATGCTCCTGGC AACTACTTCAAGGTTTCGAGAGTTAAAACTCCAACACAAAGAATATCTCTGTGTCAAG GCCATGATCCTGCTCAATTCCAGTATGTACCCTCTGGTCACAGCGACCCAGGATGCTG ACAGCAGCCGGAAGCTGGCTCACTTGCTGAACGCCGTGACCGATGCTTTGGTTTGGGT GATTGCCAAGAGCGGCATCTCCTCCCAGCAGCAATCCATGCGCCTGGCTAACCTCCTG ATGCTCCTGTCCCACGTCAGGCATGCGAGTAACAAGGGCATGGAACATCTGCTCAACA TGAAGTGCAAAAATGTGGTCCCAGTGTATGACCTGCTGCTGGAGATGCTGAATGCCCA CGTGCTTCGCGGGTGCAAGTCCTCCATCACGGGGTCCGAGTGCAGCCCGGCAGAGGAC
AGTAAAAGCAAAGAGGGCTCCCAGAACCCACAGTCTCAGTGA
(SEQ IDNO: 40) Mouse polypeptide sequence:
MEIKNSPSSLTSPASYNCSQSILPLEHGPIYIPSSYVESRHEYSAMTFYSPAVMNYSV PSSTGNLEGGPVRQTASPNVLWPTSGHLSPLATHCQSSLLYAEPQKSP CEARSLEHT LPVNRETLKRKLGGSGCASPVTSPSAKRDAHFCAVCSDYASGYHYGVWSCEGCKAFFK RSIQGHNDYICPATNQCTIDKNRRKSCQACRLRKCYEVGMVKCGSRRERCGYRIVRRQ RSASEQVHCLNKAKRTSGHTPRVKELLLNSLSPEQLVLTLLEAEPPNVLVSRPSMPFT EASMMMSLTKLADKELVHMIG AKKIPGFVELSLLDQVRLLESCWMEVLMVGLMWRSI DHPGKLIFAPDLVLDRDEGKCVEGILEIFGMLLATTARFRELKLQHKEYLCVKAMILL NSSMYPLATASQEAESSRKLTHLLNAVTDALVWVISKSGISSQQQSVRLANLLMLLSH VRHISNKGMEHLLSMKCKNWPVYDLLLEMLNAHTLRGYKSSISGSECCSTEDSKSKE GSQNLQSQ (SEQ IDNO: 41)
Mouse polynucleotide sequence:
ATGACATTCTACAGTCCTGCTGTGATGAACTACAGTGTTCCCAGCAGCACCGGTAACC TGGAAGGTGGGCCTGTTCGCCAGACTGCAAGCCCAAATGTGCTATGGCCAACTTCTGG ACACCTCTCTCCTTTAGCCACCCACTGCCAATCATCGCTTCTCTATGCAGAACCTCAA AAGAGTCCTTGGTGTGAAGCAAGATCACTAGAACACACCTTGCCTGTAAACAGAGAGA • CCCTGAAGAGGAAGCTTGGCGGGAGCGGTTGTGCCAGCCCTGTTACTAGTCCAAGCGC CAAGAGGGATGCTCACTTCTGCGCCGTCTGCAGTGATTATGCATCTGGGTATCATTAC GGTGTCTGGTCCTGTGAAGGATGTAAGGCCTTTTTTAAAAGAAGCATTCAAGGACATA ATGACTATATCTGTCCAGCCACGAATCAGTGTACCATAGACAAGAACCGGCGTAAAAG CTGCCAGGCCTGCCGACTTCGCAAGTGTTACGAAGTAGGAATGGTCAAGTGTGGATCC AGGAGAGAAAGGTGTGGGTACCGAATAGTACGAAGACAGAGAAGTGCCAGCGAGCAGG TGCATTGCCTGAACAAAGCCAAGAGAACCAGTGGGCACACACCCCGGGTGAAGGAGCT ACTGCTGAACTCTCTGAGTCCCGAGCAGCTGGTGCTCACCCTGCTGGAAGCTGAGCCA CCCAATGTGCTAGTGAGCCGTCCCAGCATGCCCTTCACCGAGGCCTCCATGATGATGT CCCTCACGAAGCTGGCTGACAAGGAACTGGTGCACATGATTGGCTGGGCCAAGAAAAT CCCTGGCTTTGTGGAGCTCAGCCTGTTGGACCAAGTCCGCCTCTTGGAAAGCTGCTGG ATGGAGGTGCTGATGGTGGGGCTGATGTGGCGCTCCATCGACCACCCCGGCAAGCTCA TCTTTGCTCCAGACCTCGTTCTGGACAGGGATGAGGGGAAGTGCGTGGAAGGGATTCT GGAAATCTTTGGCATGCTCCTGGCGACGACGGCACGGTTCCGTGAGTTAAAACTGCAG CACAAAGAATATCTGTGTGTGAAGGCCATGATTCTCCTCAACTCCAGTATGTACCCCT TGGCTACCGCAAGCCAGGAAGCAGAGAGTAGCCGGAAGCTGACACACCTATTGAACGC AGTGACAGATGCCCTGGTCTGGGTGATTTCGAAGAGTGGAATCTCTTCCCAGCAGCAG TCAGTCCGTCTGGCCAACCTCCTGATGCTTCTTTCTCATGTCAGGCACATCAGTAACA AGGGCATGGAACATCTGCTCAGCATGAAGTGCAAAAATGTGGTCCCGGTGTACGACCT GCTGCTGGAGATGCTGAATGCTCACACGCTTCGAGGGTACAAGTCCTCAATCTCGGGG TCTGAGTGCTGCTCGACAGAGGACAGTAAGAGCAAAGAGGGCTCCCAGAACCTCCAGT CACAGTGA (SEQ IDNO: 42)
FXR
Human polypeptide sequence:
MGSKMNLIEHSHLPTTDEFSFSENLFGVLTEQVAGPLGQNLEVEPYSQYSNVQFPQVQ
PQISSSSYYSNLGFYPQQPEEWYSPGIYELRRMPAETLYQGETEVAEMPVTKKPRMGA SAGRIKGDELCWCGDRASGYHYNALTCEGCKGFFRRSITKNAVYKCKNGGNCVMDMY MRRKCQECRLRKCKEMGMLAECLLTEIQCKSKRLRKNVKQHADQTVNEDSEGRDLRQV TSTTKSCREKTELTPDQQTLLHFIMDSYNKQRMPQEITNKILKEEFSAEENFLILTEM ATNHVQVLVEFTKKLPGFQTLDHEDQI LLKGSAVEAMFLRSAEIFNKKLPSGHSDLL EERIRNSGISDEYITPMFSFYKSIGELKMTQEEYALLTAIVILSPDRQYIKDREAVEK LQEPLLDVLQKLCKIHQPENPQHFACLLGRLTELRTFNHHHAEMLMSWRVNDHKFTPL LCEI DVQ (SEQ ID NO: 43)
Human polynucleotide sequence:
ATGGGATCAAAAATGAATCTCATTGAACATTCCCATTTACCTACCACAGATGAATTTT CTTTTTCTGAAAATTTATTTGGTGTTTTAACAGAACAAGTGGCAGGTCCTCTGGGACA GAACCTGGAAGTGGAACCATACTCGCAATACAGCAATGTTCAGTTTCCCCAAGTTCAA CCACAGATTTCCTCGTCATCCTATTATTCCAACCTGGGTTTCTACCCCCAGCAGCCTG AAGAGTGGTACTCTCCTGGAATATATGAACTCAGGCGTATGCCAGCTGAGACTCTCTA CCAGGGAGAAACTGAGGTAGCAGAGATGCCTGTAACAAAGAAGCCCCGCATGGGCGCG TCAGCAGGGAGGATCAAAGGGGATGAGCTGTGTGTTGTTTGTGGAGACAGAGCCTCTG GATACCACTATAATGCACTGACCTGTGAGGGGTGTAAAGGTTTCTTCAGGAGAAGCAT TACCAAAAACGCTGTGTACAAGTGTAAAAACGGGGGCAACTGTGTGATGGATATGTAC ATGCGAAGAAAGTGTCAAGAGTGTCGACTAAGGAAATGCAAAGAGATGGGAATGTTGG CTGAATGCTTGTTAACTGAAATTCAGTGTAAATCTAAGCGACTGAGAAAAAATGTGAA GCAGCATGCAGATCAGACCGTGAATGAAGACAGTGAAGGTCGTGACTTGCGACAAGTG ACCTCGACAACAAAGTCATGCAGGGAGAAAACTGAACTCACCCCAGATCAACAGACTC TTCTACATTTTATTATGGATTCATATAACAAACAGAGGATGCCTCAGGAAATAACAAA TAAAATTTTAAAAGAAGAATTCAGTGCAGAAGAAAATTTTCTCATTTTGACGGAAATG GCAACCAATCATGTACAGGTTCTTGTAGAATTCACAAAAAAGCTACCAGGATTTCAGA CTTTGGACCATGAAGACCAGATTGCTTTGCTGAAAGGGTCTGCGGTTGAAGCTATGTT CCTTCGTTCAGCTGAGATTTTCAATAAGAAACTTCCGTCTGGGCATTCTGACCTATTG GAAGAAAGAATTCGAAATAGTGGTATCTCTGATGAATATATAACACCTATGTTTAGTT TTTATAAAAGTATTGGGGAACTGAAAATGACTCAAGAGGAGTATGCTCTGCTTACAGC AATTGTTATCCTGTCTCCAGATAGACAATACATAAAGGATAGAGAGGCAGTAGAGAAG CTTCAGGAGCCACTTCTTGATGTGCTACAAAAGTTGTGTAAGATTCACCAGCCTGAAA ATCCTCAACACTTTGCCTGTCTCCTGGGTCGCCTGACTGAATTACGGACATTCAATCA TCACCACGCTGAGATGCTGATGTCATGGAGAGTAAACGACCACAAGTTTACCCCACTT CTCTGTGAAATCTGGGACGTGCAGTGA (SEQ ID NO: 44)
Mouse polypeptide sequence: MVMQFQGLENPIQISLHHSHRLSGFVPDGMSVKPAKGMLTEHAAGPLGQNLDLESYSP YNNVPFPQVQPQISSSSYYSNLGFYPQQPEDWYSPGIYELRRMPAETGYQGETEVSEM PVTKKPRMAAASAGRIKGDELCWCGDRASGYHYNALTCEGCKGFFRRSITKNAVYKC KNGGNCVMDMYMRRKCQECRLRKCREMGMLAECLLTEIQCKSKRLRKNVKQHADQTVN EDDSEGRDLRQVTSTTKFCREKTELTADQQTLLDYIMDSYNKQRMPQEITNKILKEEF SAEENFLILTEMATSHVQILVEFTKKLPGFQTLDHEDQIALLKGSAVEAMFLRSAEIF NKKLPAGHADLLEERIRKSGISDEYITPMFSFYKSVGELKMTQEEYALLTAIVILSPD RQYIKDREAVEKLQEPLLDVLQKLCKMYQPENPQHFACLLGRLTELRTFNHHHAEMLM S RVNDHKFTPLLCEI DVQ (SEQ IDNO: 45)
Mouse polynucleotide sequence:
ATGGTGATGCAGTTTCAGGGCTTAGAAAATCCAATTCAGATTAGTCTTCACCACAGCC
ACCGGCTGTCAGGATTTGTGCCGGACGGGATGAGTGTGAAGCCAGCTAAAGGTATGCT AACAGAACACGCGGCAGGCCCTCTGGGGCAGAATCTGGATTTGGAATCGTACTCCCCA
TACAACAATGTCCCGTTTCCTCAAGTTCAGCCACAGATTTCCTCCTCGTCTTACTATT CCAACCTGGGCTTCTACCCCCAACAACCGGAAGACTGGTATTCTCCTGGCATCTATGA ACTCAGGCGAATGCCCGCTGAGACTGGGTACCAGGGAGAGACTGAGGTATCAGAGATG CCTGTGACAAAGAAGCCGCGAATGGCCGCGGCATCGGCAGGCAGAATAAAAGGGGATG AGCTGTGTGTTGTCTGTGGAGACAGGGCCTCTGGGTACCACTACAACGCGCTCACCTG TGAGGGCTGCAAAGGTTTCTTCCGAAGAAGCATTACCAAGAACGCCGTGTACAAGTGT AAGAACGGGGGCAACTGCGTGATGGACATGTACATGCGCAGGAAGTGCCAGGAGTGCC GGCTAAGGAAGTGCAGAGAGATGGGGATGTTGGCTGAATGTTTGTTAACTGAAATCCA GTGTAAATCTAAACGGCTAAGGAAAAATGTGAAGCAGCACGCTGATCAGACAGTGAAT GAGGACGACAGCGAAGGGCGTGACTTGCGACAAGTGACCTCCACAACCAAGTTTTGCA GGGAGAAAACGGAACTCACGGCAGACCAGCAGACCCTCCTGGATTATATTATGGATTC GTACAACAAACAGAGAATGCCTCAGGAAATCACAAATAAAATCTTAAAAGAAGAATTT AGTGCAGAAGAAAATTTTCTCATATTAACAGAAATGGCAACCAGCCATGTACAGATTC TCGTAGAATTCACAAAAAAGCTTCCAGGGTTTCAGACACTGGACCACGAAGATCAGAT TGCTTTGCTCAAAGGGTCCGCAGTGGAGGCCATGTTTCTTCGTTCGGCGGAGATTTTC AATAAGAAACTTCCTGCCGGACATGCAGACCTGTTGGAAGAAAGAATTCGAAAGAGTG GTATCTCTGATGAGTATATAACCCCGATGTTCAGTTTCTATAAAAGTGTTGGAGAACT CAAAATGACTCAGGAGGAGTACGCTCTGCTCACAGCGATCGTCATCCTCTCTCCAGAC AGACAATACATCAAGGACAGAGAGGCGGTGGAGAAGCTGCAGGAGCCCCTGCTTGATG TGCTACAAAAGCTGTGCAAGATGTACCAGCCTGAGAACCCACAGCATTTCGCCTGCCT CCTGGGTCGCCTGACGGAACTCCGGACATTCAACCATCACCACGCTGAGATGCTGATG TCTTGGAGAGTGAATGATCACAAGTTCACCCCGCTCCTCTGTGAGATCTGGGATGTGC AGTGA (SE(5 ID NO: 46) GCR
Human polypeptide sequence:
MDSKESLTPGREENPSSVLAQERGDVMDFYKTLRGGATVKVSASSPSLAVASQSDSKQ RRLLVDFPKGSVSNAQQPDLSKAVSLSMGLYMGETETKVMGNDLGFPQQGQISLSSGE TDLKLLEESIANLNRSTSVPENPKSSASTAVSAAPTEKEFPKTHSDVSSEQQHLKGQT GTNGGNVKLYTTDQSTFDILQDLEFSSGSPGKETNESPWRSDLLIDENCLLSPLAGED DSFLLEGNSNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEKEDFIELCTPG VIKQEKLGTVYCQASFPGANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQK PIFNVIPPIPVGSENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPP SSSSTATTGPPPKLCLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNYLCAGRNDCI IDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIKGIQQATTGVSQETSENPGNKTIVP ATLPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRIMTTLNMLGGRQVIAAVK AKA IPGFRNLHLDDQMTLLQYSWMFLMAFALG RSYRQSSANLLCFAPDLIINEQRMTLPC MYDQCKHMLYVSSELHRLQVSYEEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKE LGKAIVKREGNSSQNWQRFYQLTKLLDSMHEWENLLNYCFQTFLDKTMSIEFPEMLA EIITNQIPKYSNGNIKKLLFHQK (SEQ ID NO: 47) Human polynucleotide sequence:
TTTTTAGAAAAAAAAAATATATTTCCCTCCTGCTCCTTCTGCGTTCACAAGCTAAGTT GTTTATCTCGGCTGCGGCGGGAACTGCGGACGGTGGCGGGCGAGCGGCTCCTCTGCCA GAGTTGATATTCACTGATGGACTCCAAAGAATCATTAACTCCTGGTAGAGAAGAAAAC CCCAGCAGTGTGCTTGCTCAGGAGAGGGGAGATGTGATGGACTTCTATAAAACCCTAA GAGGAGGAGCTACTGTGAAGGTTTCTGCGTCTTCACCCTCACTGGCTGTCGCTTCTCA ATCAGACTCCAAGCAGCGAAGACTTTTGGTTGATTTTCCAAAAGGCTCAGTAAGCAAT GCGCAGCAGCCAGATCTGTCCAAAGCAGTTTCACTCTCAATGGGACTGTATATGGGAG AGACAGAAACAAAAGTGATGGGAAATGACCTGGGATTCCCACAGCAGGGCCAAATCAG CCTTTCCTCGGGGGAAACAGACTTAAAGCTTTTGGAAGAAAGCATTGCAAACCTCAAT AGGTCGACCAGTGTTCCAGAGAACCCCAAGAGTTCAGCATCCACTGCTGTGTCTGCTG CCCCCACAGAGAAGGAGTTTCCAAAAACTCACTCTGATGTATCTTCAGAACAGCAACA TTTGAAGGGCCAGACTGGCACCAACGGTGGCAATGTGAAATTGTATACCACAGACCAA AGCACCTTTGACATTTTGCAGGATTTGGAGTTTTCTTCTGGGTCCCCAGGTAAAGAGA CGAATGAGAGTCCTTGGAGATCAGACCTGTTGATAGATGAAAACTGTTTGCTTTCTCC TCTGGCGGGAGAAGACGATTCATTCCTTTTGGAAGGAAACTCGAATGAGGACTGCAAG CCTCTCATTTTACCGGACACTAAACCCAAAATTAAGGATAATGGAGATCTGGTTTTGT CAAGCCCCAGTAATGTAACACTGCCCCAAGTGAAAACAGAAAAAGAAGATTTCATCGA ACTCTGCACCCCTGGGGTAATTAAGCAAGAGAAACTGGGCACAGTTTACTGTCAGGCA AGCTTTCCTGGAGCAAATATAATTGGTAATAAAATGTCTGCCATTTCTGTTCATGGTG TGAGTACCTCTGGAGGACAGATGTACCACTATGACATGAATACAGCATCCCTTTCTCA ACAGCAGGATCAGAAGCCTATTTTTAATGTCATTCCACCAATTCCCGTTGGTTCCGAA AATTGGAATAGGTGCCAAGGATCTGGAGATGACAACTTGACTTCTCTGGGGACTCTGA ACTTCCCTGGTCGAACAGTTTTTTCTAATGGCTATTCAAGCCCCAGCATGAGACCAGA TGTAAGCTCTCCTCCATCCAGCTCCTCAACAGCAACAACAGGACCACCTCCCAAACTC TGCCTGGTGTGCTCTGATGAAGCTTCAGGATGTCATTATGGAGTCTTAACTTGTGGAA GCTGTAAAGTTTTCTTCAAAAGAGCAGTGGAAGGACAGCACAATTACCTATGTGCTGG AAGGAATGATTGCATCATCGATAAAATTCGAAGAAAAAACTGCCCAGCATGCCGCTAT CGAAAATGTCTTCAGGCTGGAATGAACCTGGAAGCTCGAAAAACAAAGAAAAAAATAA AAGGAATTCAGCAGGCCACTACAGGAGTCTCACAAGAAACCTCTGAAAATCCTGGTAA CAAAACAATAGTTCCTGCAACGTTACCACAACTCACCCCTACCCTGGTGTCACTGTTG GAGGTTATTGAACCTGAAGTGTTATATGCAGGATATGATAGCTCTGTTCCAGACTCAA CTTGGAGGATCATGACTACGCTCAACATGTTAGGAGGGCGGCAAGTGATTGCAGCAGT GAAATGGGCAAAGGCAATACCAGGTTTCAGGAACTTACACCTGGATGACCAAATGACC CTACTGCAGTACTCCTGGATGTTTCTTATGGCATTTGCTCTGGGGTGGAGATCATATA GACAATCAAGTGCAAACCTGCTGTGTTTTGCTCCTGATCTGATTATTAATGAGCAGAG AATGACTCTACCCTGCATGTACGACCAATGTAAACACATGCTGTATGTTTCCTCTGAG TTACACAGGCTTCAGGTATCTTATGAAGAGTATCTCTGTATGAAAACCTTACTGCTTC TCTCTTCAGTTCCTAAGGACGGTCTGAAGAGCCAAGAGCTATTTGATGAAATTAGAAT GACCTACATCAAAGAGCTAGGAAAAGCCATTGTCAAGAGGGAAGGAAACTCCAGCCAG AACTGGCAGCGGTTTTATCAACTGACAAAACTCTTGGATTCTATGCATGAAGTGGTTG AAAATCTCCTTAACTATTGCTTCCAAACATTTTTGGATAAGACCATGAGTATTGAATT CCCCGAGATGTTAGCTGAAATCATCACCAATCAGATACCAAAATATTCAAATGGAAAT ATCAAAAAACTTCTGTTTCATCAAAAGTGACTGCCTTAATAAGAATGGTTGCCTTAAA GAAAGTCGAATTAATAGCTTTTATTGTATAAACTATCAGTTTGTCCTGTAGAGGTTTT GTTGTTTTATTTTTTATTGTTTTCATCTGTTGTTTTGTTTTAAATACGCACTACATGT GGTTTATAGAGGGCCAAGACTTGGCAACAGAAGCAGTTGAGTCGTCATCACTTTTCAG TGATGGGAGAGTAGATGGTGAAATTTATTAGTTAATATATCCCAGAAATTAGAAACCT TAATATGTGGACGTAATCTCCACAGTCAAAGAAGGATGGCACCTAAACCACCAGTGCC CAAAGTCTGTGTGATGAACTTTCTCTTCATACTTTTTTTCACAGTTGGCTGGATGAAA TTTTCTAGACTTTCTGTTGGTGTATCCCCCCCCTGTATAGTTAGGATAGCATTTTTGA TTTATGCATGGAAACCTGAAAAAAAGTTTACAAGTGTATATCAGAAAAGGGAAGTTGT GCCTTTTATAGCTATTACTGTCTGGTTTTAACAATTTCCTTTATATTTAGTGAACTAC GCTTGCTCATTTTTTCTTACATAATTTTTTATTCAAGTTATTGTACAGCTGTTTAAGA TGGGCAGCTAGTTCGTAGCTTTCCCAAATAAACTCTAAACATTAATCAATCATCTGTG TGAAAATGGGTTGGTGCTTCTAACCTGATGGCACTTAGCTATCAGAAGACCACAAAAA TTGACTCAAATCTCCAGTATTCTTGTCAAAAAAAAAAAAAAAAAAGCTCATATTTTGT ATATATCTGCTTCAGTGGAGAATTATATAGGTTGTGCAAATTAACAGTCCTAACTGGT ATAGAGCACCTAGTCCAGTGACCTGCTGGGTAAACTGTGGATGATGGTTGCAAAAGAC TAATTTAAAAAATAACTACCAAGAGGCCCTGTCTGTACCTAACGCCCTATTTTTGCAA TGGCTATATGGCAAGAAAGCTGGTAAACTATTTGTCTTTCAGGACCTTTTGAAGTAGT TTGTATAACTTCTTAAAAGTTGTGATTCCAGATAACCAGCTGTAACACAGCTGAGAGA CTTTTAATCAGACAAAGTAATTCCTCTCACTAAACTTTACCCAAAAACTAAATCTCTA ATATGGCAAAAATGGCTAGACACCCATTTTCACATTCCCATCTGTCACCAATTGGTTA ATCTTTCCTGATGGTACAGGAAAGCTCAGCTACTGATTTTTGTGATTTAGAACTGTAT GTCAGACATCCATGTTTGTAAAACTACACATCCCTAATGTGTGCCATAGAGTTTAACA CAAGTCCTGTGAATTTCTTCACTGTTGAAAATTATTTTAAACAAAATAGAAGCTGTAG TAGCCCTTTCTGTGTGCACCTTACCAACTTTCTGTAAACTCAAAACTTAACATATTTA CTAAGCCACAAGAAATTTGATTTCTATTCAAGGTGGCCAAATTATTTGTGTAATAGAA AACTGAAAATCTAATATTAAAAATATGGAACTTCTAATATATTTTTATATTTAGTTAT AGTTTCAGATATATATCATATTGGTATTCACTAATCTGGGAAGGGAAGGGCTACTGCA GCTTTACATGCAATTTATTAAAATGATTGTAAAATAGCTTGTATAGTGTAAAATAAGA ATGATTTTTAGATGAGATTGTTTTATCATGACATGTTATATATTTTTTGTAGGGGTCA AAGAAATGCTGATGGATAACCTATATGATTTATAGTTTGTACATGCATTCATACAGGC AGCGATGGTCTCAGAAACCAAACAGTTTGCTCTAGGGGAAGAGGGAGATGGAGACTGG TCCTGTGTGCAGTGAAGGTTGCTGAGGCTCTGACCCAGTGAGATTACAGAGGAAGTTA TCCTCTGCCTCCCATTCTGACCACCCTTCTCATTCCAACAGTGAGTCTGTCAGCGCAG GTTTAGTTTACTCAATCTCCCCTTGCACTAAAGTATGTAAAGTATGTAAACAGGAGAC AGGAAGGTGGTGCTTACATCCTTAAAGGCACCATCTAATAGCGGGTTACTTTCACATA CAGCCCTCCCCCAGCAGTTGAATGACAACAGAAGCTTCAGAAGTTTGGCAATAGTTTG CATAGAGGTACCAGCAATATGTAAATAGTGCAGAATCTCATAGGTTGCCAATAATACA CTAATTCCTTTCTATCCTACAACAAGAGTTTATTTCCAAATAAAATGAGGACATGTTT TTGTTTTCTTTGAATGCTTTTTGAATGTTATTTGTTATTTTCAGTATTTTGGAGAAAT TATTTAATAAAAAAACAATCATTTGCTTTTTG (SEQ ID NO: 48)
Mouse polypeptide sequence:
MDSKESLAPPGRDEVPSSLLGRGRGSVMDLYKTLRGGATVKVSASSPSVAAASQADSK QQRILLDFSKGSASNAQQQQQQQQPQPDLSKAVSLSMGLYMGETETKVMGNDLGYPQQ GQLGLSSGETDFRLLEESIANLNRSTSRPENPKSSTPAAGCATPTEKEFPQTHSDPSS EQQNRKSQPGTNGGSVKLYTTDQSTFDILQDLEFSAGSPGKETNESPWRSDLLIDENL LSPLAGEDDPFLLEGDVNEDCKPLILPDTKPKIQDTGDTILSSPSSVALPQVKTEKDD FIELCTPGVIKQEKLGPVYCQASFSGTNIIGNKMSAISVHGVSTSGGQMYHYDMNTAS LSQQQDQKPVFNVIPPIPVGSEN NRCQGSGEDNLTSLGAMNFAGRSVFSNGYSSPGM RPDVSSPPSSSSTATGPPPKLCLVCSDEASVCHYGVLTCGSCKVFFKRAVEGQHNYLC AGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIKGIQQATAGVSQDTSENA NKTIVPAALPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSAWRIMTTLNMLGGRQVIAA VKWAKAIPGFRNLHLDDQMTLLQYSWMFLMAFALG RSYRQASGNLLCFAPDLIINEQ RMTLPCMYDQCKHMLFISTELQRLQVSYEEYLCMKTLLLLSSVPKEGLKSQELFDEIR MTYIKELGKAIVKREGNSSQNWQRFYQLTKLLDSMHDWENLLSYCFQTFLDKSMSIE FPEMLAEIITNQIPKYSNGNIKKLLFHQK (SEQ ID NO: 49)
Mouse polynucleotide sequence:
ATGGACTCCAAAGAATCCTTAGCTCCCCCTGGTAGAGACGAAGTCCCCAGCAGTTTGC TTGGCCGGGGGAGGGGAAGCGTGATGGACTTGTATAAAACCCTGAGGGGTGGAGCTAC AGTCAAGGTTTCTGCGTCTTCACCCTCAGTGGCTGCTGCTTCTCAGGCAGATTCCAAG CAGCAGAGGATTCTCCTTGATTTTTCAAAAGGCTCAGCAAGCAATGCACAGCAGCAGC AGCAGCAGCAGCAGCCGCAGCCAGATTTATCCAAAGCCGTTTCACTGTCCATGGGACT GTATATGGGAGAGACCGAAACAAAAGTGATGGGGAATGACTTGGGCTACCCACAGCAG GGCCAGCTTGGCCTCTCCTCTGGGGAAACAGACTTTCGGCTTCTGGAAGAAAGCATTG CAAACCTCAATAGGTCGACCAGCCGTCCAGAGAATCCCAAGAGTTCAACACCTGCAGC TGGGTGTGCTACCCCGACAGAGAAGGAGTTTCCCCAGACTCACTCTGATCCATCTTCA GAACAGCAAAATAGAAAAAGCCAGCCTGGCACCAACGGTGGCAGTGTGAAATTGTATA CCACAGACCAAAGCACCTTTGACATCTTGCAGGATTTGGAGTTTTCTGCCGGGTCCCC AGGTAAAGAGACAAACGAGAGTCCTTGGAGGTCAGACCTGTTGATAGATGAAAACTTG CTTTCTCCTTTGGCGGGAGAAGATGATCCATTCCTTCTGGAAGGGGACGTGAATGAGG ATTGCAAGCCTCTTATTTTACCGGACACTAAACCTAAAATTCAGGATACTGGAGATAC AATCTTATCAAGCCCCAGCAGTGTGGCACTGCCCCAAGTGAAAACAGAGAAAGATGAT TTCATTGAGCTTTGCACCCCTGGGGTAATTAAGCAAGAGAAACTGGGCCCGGTTTATT GCCAGGCAAGCTTTTCTGGGACAAATATAATTGGGAATAAAATGTCTGCCATTTCTGT TCATGGCGTGAGTACCTCTGGAGGACAGATGTACCACTATGACATGAATACAGCATCC CTTTCTCAGCAGCAGGATCAGAAGCCTGTTTTTAATGTCATTCCACCAATTCCTGTTG GTTCTGAAAACTGGAATAGGTGCCAAGGGTCTGGAGAGGACAACCTGACTTCCTTGGG GGCTATGAACTTCGCAGGCCGCTCAGTGTTTTCTAATGGATATTCAAGCCCTGGAATG AGACCAGATGTGAGTTCTCCTCCGTCCAGCTCCTCCACAGCAACGGGACCACCTCCCA AACTCTGCCTGGTGTGCTCCGATGAAGCTTCGGGATGCCATTATGGGGTGCTGACGTG TGGAAGCTGTAAAGTCTTCTTTAAAAGAGCAGTGGAAGGTAGACAGCACAATTACCTT TGTGCTGGAAGAAATGATTGCATCATTGATAAAATTCGAAGAAAAAACTGTCCAGCAT GCCGCTATCGAAAATGTCTTCAAGCTGGAATGAACCTGGAAGCTCGAAAAACGAAGAA AAAAATTAAAGGAATTCAGCAAGCCACTGCAGGAGTCTCACAAGACACTTCTGAAAAC GCTAACAAAACAATAGTTCCTGCCGCGCTGCCACAGCTTACCCCTACCCTGGTGTCAC TGCTGGAGGTGATCGAGCCTGAGGTGTTATATGCAGGATATGACAGCTCTGTTCCAGA CTCAGCATGGAGAATTATGACCACGCTCAACATGTTAGGTGGGCGCCAAGTGATTGCC GCAGTGAAATGGGCAAAGGCGATACCAGGATTCAGAAACTTACACCTGGATGACCAAA TGACCCTTCTACAGTACTCATGGATGTTTCTCATGGCATTTGCCCTGGGTTGGAGATC ATACAGACAAGCAAGTGGAAACCTGCTATGCTTTGCTCCTGATCTGATTATTAATGAG CAGAGAATGACTCTACCCTGCATGTATGACCAATGTAAACACATGCTGTTTATCTCCA CTGAATTACAAAGATTGCAGGTATCCTATGAAGAGTATCTCTGTATGAAAACCTTACT GCTTCTCTCCTCAGTTCCTAAGGAAGGTCTGAAGAGCCAAGAGTTATTTGATGAGATT CGAATGACTTATATCAAAGAGCTAGGAAAAGCCATTGTCAAAAGGGAAGGAAACTCCA GTCAGAATTGGCAGCGGTTTTATCAACTGACAAAACTTTTGGACTCCATGCATGATGT GGTTGAAAATCTCCTTAGCTACTGCTTCCAAACATTTTTGGATAAGTCCATGAGTATT GAATTC (SEQ ID NO: 50) GORG
Human polypeptide sequence:
MDRAPQRQHRASRELLAAKKTHTSQIEVIPCKICGDKSSGIHYGVITCEGCKGFFRRS QRCNAAYSCTRQQNCPIDRTSRNRCQHCRLQKCLALGMSRDAVKFGRMSKKQRDSLHA EVQKQLQQRQQQQQEPWKTPPAGAQGADTLTYTLGLPDGQLPLGSSPDLPEASACPP GLLKASGSGPSYSNNLAKAGLNGASCHLEYSPERGKAEGRESFYSTGSQLTPDRCGLR FEEHRHPGLGELGQGPDSYGSPSFRSTPEAPYASLTEIEHLVQSVCKSYRETCQLRLE DLLRQRSNIFSREEVTGYQRKSMWEM ERCAHHLTEAIQYWEFAKRLSGFMELCQND QIVLLKAGAMEWLVRMCRAYNADNRTVFFEGKYGGMELFRALGCSELISSIFDFSHS LSALHFSEDEIALYTALVLINAHRPGLQEKRKVEQLQYNLELAFHHHLCKTHRQSILA KLPPKGKLRSLCSQHVERLQIFQHLHPIWQAAFPPLYKELFSTETESPVGCPSDLEE GLLASPYGLLATSLDPVPPSPFSFPMNPGGWSPPALWK (SEQ IDNO: 51)
Human polynucleotide sequence:
ATGGACAGGGCCCCACAGAGACAGCACCGAGCCTCACGGGAGCTGCTGGCTGCAAAGA AGACCCACACCTCACAAATTGAAGTGATCCCTTGCAAAATCTGTGGGGACAAGTCGTC TGGGATCCACTACGGGGTTATCACCTGTGAGGGGTGCAAGGGCTTCTTCCGCCGGAGC CAGCGCTGTAACGCGGCCTACTCCTGCACCCGTCAGCAGAACTGCCCCATCGACCGCA CCAGCCGAAACCGATGCCAGCACTGCCGCCTGCAGAAATGCCTGGCGCTGGGGATGTC CCGAGATGCTGTCAAGTTCGGCCGCATGTCCAAGAAGCAGAGGGACAGCCTGCATGCA GAAGTGCAGAAACAGCTGCAGCAGCGGCAACAGCAGCAACAGGAACCAGTGGTCAAGA CCCCTCCAGCAGGGGCCCAAGGAGCAGATACCCTCACCTACACCTTGGGGCTCCCAGA CGGGCAGCTGCCCCTGGGCTCCTCGCCTGACCTGCCTGAGGCTTCTGCCTGTCCCCCT GGCCTCCTGAAAGCCTCAGGCTCTGGGCCCTCATATTCCAACAACTTGGCCAAGGCAG GGCTCAATGGGGCCTCATGCCACCTTGAATACAGCCCTGAGCGGGGCAAGGCTGAGGG CAGAGAGAGCTTCTATAGCACAGGCAGCCAGCTGACCCCTGACCGATGTGGACTTCGT TTTGAGGAACACAGGCATCCTGGGCTTGGGGAACTGGGACAGGGCCCAGACAGCTACG GCAGCCCCAGTTTCCGCAGCACACCGGAGGCACCCTATGCCTCCCTGACAGAGATAGA •GCACCTGGTGCAGAGCGTCTGCAAGTCCTACAGGGAGACATGCCAGCTGCGGCTGGAG GACCTGCTGCGGCAGCGCTCCAACATCTTCTCCCGGGAGGAAGTGACTGGCTACCAGA GGAAGTCCATGTGGGAGATGTGGGAACGGTGTGCCCACCACCTCACCGAGGCCATTCA GTACGTGGTGGAGTTCGCCAAGAGGCTCTCAGGCTTTATGGAGCTCTGCCAGAATGAC CAGATTGTGCTTCTCAAAGCAGGAGCAATGGAAGTGGTGCTGGTTAGGATGTGCCGGG CCTACAATGCTGACAACCGCACGGTCTTTTTTGAAGGCAAATACGGTGGCATGGAGCT GTTCCGAGCCTTGGGCTGCAGCGAGCTCATCAGCTCCATCTTTGACTTCTCCCACTCC CTAAGTGCCTTGCACTTTTCCGAGGATGAGATTGCCCTCTACACAGCCCTTGTTCTCA TCAATGCCCATCGGCCAGGGCTCCAAGAGAAAAGGAAAGTAGAACAGCTGCAGTACAA TCTGGAGCTGGCCTTTCATCATCATCTCTGCAAGACTCATCGCCAAAGCATCCTGGCA AAGCTGCCACCCAAGGGGAAGCTTCGGAGCCTGTGTAGCCAGCATGTGGAAAGGCTGC AGATCTTCCAGCACCTCCACCCCATCGTGGTCCAAGCCGCTTTCCCTCCACTCTACAA GGAGCTCTTCAGCACTGAAACCGAGTCACCTGTGGGCTGTCCAAGTGACCTGGAAGAG GGACTCCTTGCCTCTCCCTATGGCCTGCTGGCCACCTCCCTGGACCCCGTTCCACCCT CACCCTTTTCCTTTCCCATGAACCCTGGAGGGTGGTCCCCACCAGCTCTTTGGAAGTG A (SEQ ID NO: 52)
Mouse polypeptide sequence:
MDRAPQRHHRTSRELLAAKKTHTSQIEVIPCKICGDKSSGIHYGVITCEGCKGFFRRS QQCNVAYSCTRQQNCPIDRTSRNRCQHCRLQKCLALGMSRDAVKFGRMSKKQRDSLHA EVQKQLQQQQQQEQVAKTPPAGSRGADTLTYTLGLSDGQLPLGASPDLPEASACPPGL LRASGSGPPYSNTLAKTEVQGASCHLEYSPERGKAEGRDSIYSTDGQLTLGRCGLRFE ETRHPELGEPEQGPDSHCIPSFCSAPEVPYASLTDIEYLVQNVCKSFRETCQLRLEDL LRQRTNLFSREEVTSYQRKSMWEMWERCAHHLTEAIQYWEFAKRLSGFMELCQNDQI ILLTAGAMEλ/VLVRMCRAYNANNHTVFFEGKYGGVELFRALGCSELISSIFDFSHFLS ALCFSEDEIALYTALVLINANRPGLQEKRRVEHLQYNLELAFHHHLCKTHRQGLLAKL PPKGKLRSLCSQHVEKLQIFQHLHPIWQAAFPPLYKELFSTDVESPEGLSK (SEQ ID NO: 53)
Mouse polynucleotide sequence:
ATGGACAGGGCCCCACAGAGACACCACCGGACATCTCGGGAGCTGCTGGCTGCAAAGA AGACCCACACCTCACAAATTGAAGTGATCCCTTGCAAGATCTGTGGGGACAAGTCATC TGGGATCCACTACGGGGTTATCACCTGTGAGGGGTGCAAGGGCTTCTTCCGCCGCAGC CAGCAGTGTAATGTGGCCTACTCCTGCACGCGTCAGCAGAACTGCCCCATTGACCGAA CCAGCCGCAACCGATGCCAGCATTGCCGCCTGCAGAAGTGCCTGGCTCTGGGCATGTC CCGAGATGCTGTCAAGTTTGGCCGAATGTCCAAGAAGCAGAGGGACAGTCTACATGCA GAAGTGCAGAAACAACTGCAACAGCAGCAGCAACAGGAACAAGTGGCCAAGACTCCTC CAGCTGGGAGCCGCGGAGCAGACACACTTACATACACTTTAGGGCTCTCAGATGGGCA GCTACCACTGGGCGCCTCACCTGACCTACCCGAGGCCTCTGCTTGTCCCCCTGGCCTC CTGAGAGCCTCAGGCTCTGGCCCACCATATTCCAATACCTTGGCCAAAACAGAGGTCC AGGGGGCCTCCTGCCACCTTGAGTATAGTCCAGAACGAGGCAAAGCTGAAGGCAGAGA CAGCATCTATAGCACTGACGGCCAACTTACTCTTGGAAGATGTGGACTTCGTTTTGAG GAAACCAGGCATCCTGAACTTGGGGAACCAGAACAGGGTCCAGACAGCCACTGCATTC CCAGTTTCTGCAGTGCCCCAGAGGTACCATATGCCTCTCTGACAGACATAGAGTACCT GGTACAGAATGTCTGCAAGTCCTTCCGAGAGACATGCCAGCTGCGACTGGAGGACCTT CTACGGCAGCGCACCAACCTCTTTTCACGGGAGGAGGTGACCAGCTACCAGAGGAAGT CAATGTGGGAGATGTGGGAGCGCTGTGCCCACCACCTCACTGAGGCCATTCAGTATGT GGTGGAGTTTGCCAAGCGGCTTTCAGGCTTCATGGAGCTCTGCCAGAATGACCAGATC ATACTACTGACAGCAGGAGCAATGGAAGTCGTCCTAGTCAGAATGTGCAGGGCCTACA ATGCCAACAACCACACAGTCTTTTTTGAAGGCAAATACGGTGGTGTGGAGCTGTTTCG AGCCTTGGGCTGCAGCGAGCTCATCAGCTCCATATTTGACTTTTCCCACTTCCTCAGC GCCCTGTGTTTTTCTGAGGATGAGATTGCCCTCTACACGGCCCTGGTTCTCATCAATG CCAACCGTCCTGGGCTCCAAGAGAAGAGGAGAGTGGAACATCTGCAATACAATTTGGA ACTGGCTTTCCATCATCATCTCTGCAAGACTCATCGACAAGGCCTCCTAGCCAAGCTG CCACCCAAAGGAAAACTCCGGAGCCTGTGCAGCCAACATGTGGAAAAGCTGCAGATCT TCCAGCACCTCCACCCCATCGTGGTCCAAGCCGCCTTCCCNCCACTCTATAAGGAACT CTTCAGCACTGATGTTGAATCCCCTGAGGGGCTGTCAAAGTGA
(SEQ ID NO: 54)
HN4A
Human polypeptide sequence:
MDMADYSAALDPAYTTLEFENVQVLTMGNDTSPSEGTNLNAPNSLGVSALCAICGDRA TGKHYGASSCDGCKGFFRRSVRKNHMYSCRFSRQCWDKDKRNQCRYCRLKKCFRAGM KKEAVQNERDRISTRRSSYEDSSLPSINALLQAEVLSRQITSPVSGINGDIRAKKIAS IADVCESMKEQLLVLVEWAKYIPAFCELPLDDQVALLRAHAGEHLLLGATKRSMVFKD VLLLGNDYIVPRHCPELAEMSRVSIRILDELVLPFQELQIDDNEYAYLKAIIFFDPDA KGLSDPGKIKRLRSQVQVSLEDYINDRQYDSRGRFGELLLLLPTLQSITWQMIEQIQF IKLFGMAKIDNLLQEMLLGGSPSDAPHAHHPLHPHLMQEHMGTNVIVANTMPTHLSNG QMCEWPRPRGQAATPETPQPSPPGGSGSEPYKLLPGAVATIVKPLSAIPQPTITKQEV I (SEQ IDNO: 55)
Human polynucleotide sequence:
ATGGACATGGCCGACTACAGTGCTGCACTGGACCCAGCCTACACCACCCTGGAATTTG AGAATGTGCAGGTGTTGACGATGGGCAATGACACGTCCCCATCAGAAGGCACCAACCT CAACGCGCCCAACAGCCTGGGTGTCAGCGCCCTGTGTGCCATCTGCGGGGACCGGGCC ACGGGCAAACACTACGGTGCCTCGAGCTGTGACGGCTGCAAGGGCTTCTTCCGGAGGA GCGTGCGGAAGAACCACATGTACTCCTGCAGATTTAGCCGGCAGTGCGTGGTGGACAA GGACAAGAGGAACCAGTGCCGCTACTGCAGGCTCAAGAAATGCTTCCGGGCTGGCATG AAGAAGGAAGCCGTCCAGAATGAGCGGGACCGGATCAGCACTCGAAGGTCAAGCTATG AGGACAGCAGCCTGCCCTCCATCAATGCGCTCCTGCAGGCGGAGGTCCTGTCCCGACA GATCACCTCCCCCGTCTCCGGGATCAACGGCGACATTCGGGCGAAGAAGATTGCCAGC ATCGCAGATGTGTGTGAGTCCATGAAGGAGCAGCTGCTGGTTCTCGTTGAGTGGGCCA AGTACATCCCAGCTTTCTGCGAGCTCCCCCTGGACGACCAGGTGGCCCTGCTCAGAGC CCATGCTGGCGAGCACCTGCTGCTCGGAGCCACCAAGAGATCCATGGTGTTCAAGGAC GTGCTGCTCCTAGGCAATGACTACATTGTCCCTCGGCACTGCCCGGAGCTGGCGGAGA TGAGCCGGGTGTCCATACGCATCCTTGACGAGCTGGTGCTGCCCTTCCAGGAGCTGCA GATCGATGACAATGAGTATGCCTACCTCAAAGCCATCATCTTCTTTGACCCAGATGCC AAGGGGCTGAGCGATCCAGGGAAGATCAAGCGGCTGCGTTCCCAGGTGCAGGTGAGCT TGGAGGACTACATCAACGACCGCCAGTATGACTCGCGTGGCCGCTTTGGAGAGCTGCT GCTGCTGCTGCCCACCTTGCAGAGCATCACCTGGCAGATGATCGAGCAGATCCAGTTC ATCAAGCTCTTCGGCATGGCCAAGATTGACAACCTGTTGCAGGAGATGCTGCTGGGAG GGTCCCCCAGCGATGCACCCCATGCCCACCACCCCCTGCACCCTCACCTGATGCAGGA ACATATGGGAACCAACGTCATCGTTGCCAACACAATGCCCACTCACCTCAGCAACGGA CAGATGTGTGAGTGGCCCCGACCCAGGGGACAGGCAGCCACCCCTGAGACCCCACAGC CCTCACCGCCAGGTGGCTCAGGGTCTGAGTCCTATAAGCTCCTGCCGGGAGCCGTCGC CACAATCGTCAAGCCCCTCTCTGCCATCCCCCAGCCGACCATCACCAAGCAGGAAGTT ATCTAG (SEQ ID NO: 56)
Mouse polypeptide sequence:
MDMADYSAALDPAYTTLEFENVQVLTMGNDTSPSEGANLNSSNSLSVSALCAICGDRA
TGKHYGASSCDGCKGFFRRSVRKNHMYSCRFSRQCWDKDKRNQCRYCRLKKCFRAGM KKEAVQNERDRISTRRSSYEDSSLPSINALLQAEVLSQQITSPISGINGDIRAKKIAN ITDVCESMKEQLLVLVEWAKYIPAFCELLLDDQVALLRAHAGEHLLLGATKRSMVFKD VLLLGNDYIVPRHCPELAEMSRVSIRILDELVLPFQELQIDDNEYACLKAIIFFDPDA KGLSDPGKIKRLRSQVQVSLEDYINDRQYDSRGRFGELLLLLPTLQSITWQMIEQIQF IKLFGMAKIDNLLQEMLLGGSASDAPHTHHPLHPHLMQEHMGTNVIVANTMPSHLSNG QMCEWPRPRGQAATPETPQPSPPSGSGSESYKLLPGAITTIVKPPSAIPQPTITKQEA I (SEQ IDNO: 57)
Mouse polynucleotide sequence:
ATGGATATGGCCGACTACAGCGCTGCCCTGGACCCAGCCTACACCACCCTGGAGTTTG AAAATGTGCAGGTGTTGACCATGGGCAATGACACGTCCCCATCTGAAGGTGCCAACCT CAATTCATCCAACAGCCTGAGCGTCAGTGCCCTGTGCGCCATCTGTGGCGACCGGGCC ACCGGCAAACACTACGGAGCCTCGAGCTGTGACGGCTGCAAGGGGTTCTTCAGGAGGA GCGTGAGGAAGAACCACATGTACTCCTGCAGGTTTAGCCGACAATGTGTGGTAGACAA AGATAAGAGGAACCAGTGTCGTTACTGCAGGCTTAAGAAGTGCTTCCGGGCTGGCATG AAGAAGGAAGCTGTCCAAAATGAGCGGGACCGGATCAGCACGCGGAGGTCAAGCTACG AGGACAGCAGCCTGCCCTCCATCAACGCGCTCCTGCAGGCAGAGGTTCTGTCCCAACA GATCACCTCTCCCATCTCTGGGATCAATGGCGACATTCGGGCAAAGAAGATTGCCAAC ATCACAGACGTGTGTGAGTCTATGAAGGAGCAGCTGCTGGTCCTGGTCGAGTGGGCCA AGTACATCCCGGCCTTCTGCGAACTCCTTCTGGATGACCAGGTGGCGCTGCTCAGGGC CCACGCCGGTGAGCATCTGCTGCTTGGAGCCACCAAGAGGTCCATGGTGTTTAAGGAC GTGCTGCTCCTAGGCAATGACTACATCGTCCCTCGGCACTGTCCAGAGCTAGCGGAGA TGAGCCGTGTGTCCATCCGCATCCTCGATGAGCTGGTCCTGCCCTTCCAAGAGCTGCA GATTGATGACAATGAATATGCCTGCCTCAAAGCCATCATCTTCTTTGATCCAGATGCC AAGGGGCTGAGTGACCCGGGCAAGATCAAGCGGCTGCGGTCACAGGTGCAAGTGAGCC TGGAGGATTACATCAACGACCGGCAGTACGACTCTCGGGGCCGCTTTGGAGAGCTGCT GCTGCTGTTGCCCACGCTGCAGAGCATCACCTGGCAGATGATCGAACAGATCCAGTTC ATCAAGCTCTTCGGCATGGCCAAGATTGACAACCTGCTGCAGGAGATGCTTCTCGGAG GGTCTGCCAGTGATGCACCCCACACCCACCACCCCCTGCACCCTCACCTGATGCAAGA ACACATGGGCACCAATGTCATTGTTGCTAACACGATGCCCTCTCACCTCAGCAATGGA CAGATGTGTGAGTGGCCCCGACCCAGGGGGCAGGCAGCCACTCCCGAGACTCCACAGC CATCACCACCAAGTGGCTCGGGATCTGAATCCTACAAGCTCCTGCCAGGAGCCATCAC CACCATCGTCAAGCCTCCCTCTGCCATTCCCCAGCCAACGATCACCAAGCAAGAAGCC ATCTAG
(SEQ ID NO: 58)
HN4G Human polypeptide sequence:
MNTTDNGVNCLCAICGDRATGKHYGASTCDGCKGFFRRSIRKSHIYSCRFSRQCWDK DKRNQCRYCRLRKCFRAGMKKEAVQNERDRISTRRSTFDGSNIPSINTLAQAEVRSRQ ISVSSPGSSTDINVKKIASIGDVCESMKQQLLVLVEWAKYIPAFCELPLDDQVALLRA HAGEHLLLGATKRSMIYKDILLLGNNYVIHRNSCEVEISRVANRVLDELVRPFQEIQI DDNEYACLKAIVFFDPDAKGLSDPVKIKNMRFQVQIGLEDYINDRQYDSRGRFGELLL LLPTLQSITWQMIEQIQFVKLFGMVKIDNLLQEMLLGGASNDGSHLHHPMHPHLSQDP LTGQTILLGPMSTLVHADQISTPETPLPSPPQGSGQEQYKIAANQASVISHQHLSKQK Q (SEQ IDNO: 59)
Human polynucleotide sequence:
ATGAATACCACAGACAACGGTGTCAACTGTCTGTGTGCTATCTGTGGGGACAGAGCAA CAGGAAAACACTATGGGGCATCCACCTGTGATGGGTGCAAGGGTTTCTTCAGACGCAG CATTCGTAAGAGTCACATTTATTCTTGCAGGTTCAGTCGGCAATGTGTTGTTGACAAG GACAAAAGGAATCAATGTAGATATTGTCGATTAAGAAAGTGTTTTAGAGCGGGAATGA AAAAAGAAGCTGTACAAAATGAACGTGACAGAATAAGCACCAGAAGAAGCACATTTGA TGGCAGCAACATCCCCTCCATTAACACACTGGCACAAGCTGAAGTTCGGTCTCGCCAG ATCTCAGTCTCAAGCCCTGGGTCAAGCACTGACATAAACGTTAAGAAAATTGCAAGTA TTGGTGATGTCTGTGAATCTATGAAACAGCAGCTCTTAGTCTTGGTGGAATGGGCTAA ATATATTCCTGCCTTCTGTGAATTACCATTGGATGATCAGGTGGCACTGTTGAGAGCT CACGCAGGGGAGCACTTACTGCTTGGAGCTACAAAGAGATCCATGATGTATAAAGATA TTTTGCTTTTGGGAAACAACTATGTTATTCACCGCAACAGCTGTGAAGTTGAGATTAG CCGTGTGGCCAATCGTGTTCTAGATGAGCTGGTTAGACCATTTCAAGAAATCCAGATT GATGACAATGAGTATGCTTGTTTAAAGGCAATTGTATTTTTTGATCCAGATGCAAAAG GGCTAAGCGATCCAGTAAAAATTAAGAACATGAGGTTCCAAGTGCAGATCGGTTTGGA GGACTACATCAATGATCGGCAGTATGACTCCCGGGGGAGGTTTGGAGAGTTGCTTCTG CTCCTGCCCACACTGCAGAGCATCACGTGGCAAATGATTGAGCAAATACAGTTTGTTA AACTTTTTGGGATGGTTAAAATTGACAATCTACTTCAGGAAATGCTATTAGGTGGGGC TTCCAATGATGGCAGTCATCTCCATCATCCAATGCATCCACATTTGTCTCAAGACCCA TTAACTGGACAAACTATACTTTTAGGTCCCATGTCAACACTGGTTCATGCAGACCAGA TCTCAACTCCTGAAACCCCACTCCCTTCCCCACCACAAGGCTCTGGGCAAGAACAGTA CAAAATAGCTGCAAACCAAGCATCAGTCATTTCACACCAGCATCTCTCCAAACAAAAG CAATTGTGA
(SEQ ID NO: 60)
Mouse polypeptide sequence: MNTTDSGVNCLCAICGDRATGKHYGASSCDGCKGFFRRSIRKSHVYSCRFSRQCWDK DKRNQCRYCRLRKCFRAGMKKEAVQNERDRISTRRSTYEGSNIPSINTLAQAEVRSCQ ISVPSPSSSTDINIKKIASISDVCESMKQQLLVLVEWAKYIPAFCELPLDDQVALLRA HAGEHLLLGATKRSMMYKDILLLGNHYVIHRNSCEVEVSRVANRVLDELVRPFQEIQI DDNEYACLKAIVFFDPDAKGLSDPVKIKNMRFQVQISLEDYINDRQYDSRGRFGELLL LLPTLQSITWQMIEQIQFVKLFGMVKIDNLLQEMLLGGAANDGSHLHHPMHPHLSQDP LTGQTILLGPMSTLVHTDQIATPETPLPSPPQGSGQEPYKITANQASVISHQSLSKQK QL (SEQ IDNO: 61) Mouse polynucleotide sequence:
ATGGACAGTTCTGCCCCAGAGACCACAAGTATGAATACCACAGACAGTGGTGTCAACT GTTTATGTGCCATCTGTGGTGACAGAGCAACAGGAAAGCACTATGGGGCATCCAGTTG TGATGGCTGCAAAGGCTTTTTCAGGCGCAGCATTCGGAAGAGTCATGTTTATTCCTGC AGGTTCAGTCGGCAGTGTGTTGTTGACAAGGACAAAAGGAATCAATGCAGATACTGTC GATTAAGAAAGTGTTTTAGAGCAGGAATGAAAAAAGAAGCGGTGCAAAATGAACGCGA CAGAATCAGTACAAGAAGAAGTACCTACGAGGGCAGCAACATCCCCTCCATAAACACT CTGGCACAAGCGGAAGTGAGGTCTTGCCAGATTTCAGTCCCAAGCCCCAGTTCCAGCA CTGACATAAATATTAAGAAAATCGCAAGCATCAGTGACGTTTGTGAGTCCATGAAACA ACAGCTCTTAGTCTTGGTGGAATGGGCCAAATACATCCCTGCCTTCTGTGAACTGCCC TTGGATGACCAGGTGGCCCTCTTGAGAGCCCATGCTGGAGAACATCTGCTGCTTGGAG CTACAAAGAGATCCATGATGTATAAAGATATTTTGCTTTTGGGAAACCACTATGTTAT TCACCGCAACAGCTGTGAAGTTGAAGTCAGTCGTGTAGCCAACAGAGTTCTCGATGAG CTGGTTAGACCCTTCCAAGAGATCCAGATAGATGACAACGAGTACGCGTGCTTGAAGG CCATTGTGTTTTTTGACCCAGATGCAAAGGGATTGAGTGACCCTGTGAAGATTAAGAA CATGCGGTTCCAGGTGCAGATCAGCTTGGAGGACTACATCAATGACCGGCAGTATGAC TCTCGTGGCAGGTTTGGAGAGCTGCTGTTGCTGCTGCCAACACTGCAGAGCATTACCT GGCAGATGATTGAACAAATTCAGTTCGTCAAACTGTTCGGCATGGTCAAAATTGACAA CCTCCTTCAGGAAATGCTGCTGGGTGGTGCTGCCAATGATGGTAGTCATCTCCATCAT CCAATGCACCCACATTTATCTCAAGATCCACTAACTGGGCAAACTATACTTTTAGGTC CCATGTCCACACTGGTTCATACAGACCAGATTGCAACTCCAGAGACCCCACTCCCTTC CCCACCACAAGGCTCTGGACAAGAACCGTACAAAATTACTGCAAATCAAGCTTCAGTC ATTTCACATCAATCCCTCTCTAAGCAAAAGCAGCTGTGA
(SEQ ID NO: 62)
MCR
Human polypeptide sequence: METKGYHSLPEGLDMERRWGQVSQAVERSSLGPTERTDENNYMEIVNVSCVSGAIPNN STQGSSKEKQELLPCLQQDNNRPGILTSDIKTELESKELSATVAESMGLYMDSVRDAD YSYEQQNQQGSMSPAKIYQNVEQLVKFYKGNGHRPSTLSCVNTPLRSFMSDSGSSVNG GVMRAIVKSPIMCHEKSPSVCSPLNMTSSVCSPAGINSVSSTTASFGSFPVHSPITQG TPLTCSPNAENRGSRSHSPAHASNVGSPLSSPLSSMKSSISSPPSHCSVKSPVSSPNN VTLRSSVSSPANINNSRCSVSSPSNTNNRSTLSSPAASTVGSICSPVNNAFSYTASGT SAGSSTLRDWPSPDTQEKGAQEVPFPKTEEVESAISNGVTGQLNIVQYIKPEPDGAF SSSCLGGNSKINSDSSFSVPIKQESTKHSCSGTSFKGNPTVNPFPFMDGSYFSFMDDK DYYSLSGILGPPVPGFDGNCEGSGFPVGIKQEPDDGSYYPEASIPSSAIVGVNSGGQS FHYRIGAQGTISLSRSARDQSFQHLSSFPPVNTLVESWKSHGDLSSRRSDGYPVLEYI PENVSSSTLRSVSTGSSRPSKICLVCGDEASGCHYGWTCGSCKVFFKRAVEGQHNYL CAGRNDCIIDKIRRKNCPACRLQKCLQAGMNLGARKSKKLGKLKGIHEEQPQQQQPPP PPPPPQSPEEGTTYIAPAKEPSVNTALVPQLSTISRALTPSPVMVLENIEPEIVYAGY DSSKPDTAENLLSTLNRLAGKQMIQWK AKVLPGFKNLPLEDQITLIQYSWMCLSSF ALSWRSYKHTNSQFLYFAPDLVFNEEKMHQSAMYELCQGMHQISLQFVRLQLTFEEYT IMKVLLLLSTIPKDGLKSQAAFEEMRTNYIKELRKMVTKCPNNSGQS QRFYQLTKLL DSMHDLVSDLLEFCFYTFRESHALKVEFPAMLVEIISDQLPKVESGNAKPLYFHRK (SEQ IDNO: 63)
Human polynucleotide sequence:
ATGGAGACCAAAGGCTACCACAGTCTCCCTGAAGGTCTAGATATGGAAAGACGGTGGG GTCAAGTTTCTCAGGCTGTGGAGCGTTCTTCCCTGGGACCTACAGAGAGGACCGATGA GAATAACTACATGGAGATTGTCAACGTAAGCTGTGTTTCCGGTGCTATTCCAAACAAC AGTACTCAAGGAAGCAGCAAAGAAAAACAAGAACTACTCCCTTGCCTTCAGCAAGACA ATAATCGGCCTGGGATTTTAACATCTGATATTAAAACTGAGCTGGAATCTAAGGAACT TTCAGCAACTGTAGCTGAGTCCATGGGTTTATATATGGATTCTGTAAGAGATGCTGAC TATTCCTATGAGCAGCAGAACCAACAAGGAAGCATGAGTCCAGCTAAGATTTATCAGA ATGTTGAACAGCTGGTGAAATTTTACAAAGGAAATGGCCATCGTCCTTCCACTCTAAG TTGTGTGAACACGCCCTTGAGATCATTTATGTCTGACTCTGGGAGCTCCGTGAATGGT GGCGTCATGCGCGCCATTGTTAAAAGCCCTATCATGTGTCATGAGAAAAGCCCGTCTG TTTGCAGCCCTCTGAACATGACATCTTCGGTTTGCAGCCCTGCTGGAATCAACTCTGT GTCCTCCACCACAGCCAGCTTTGGCAGTTTTCCAGTGCACAGCCCAATCACCCAGGGA ACTCCTCTGACATGCTCCCCTAATGCTGAAAATCGAGGCTCCAGGTCGCACAGCCCTG CACATGCTAGCAATGTGGGCTCTCCTCTCTCAAGTCCGTTAAGTAGCATGAAATCCTC AATTTCCAGCCCTCCAAGTCACTGCAGTGTAAAATCTCCAGTCTCCAGTCCCAATAAT GTCACTCTGAGATCCTCTGTGTCTAGCCCTGCAAATATTAACAACTCAAGGTGCTCTG TTTCCAGCCCTTCGAACACTAATAACAGATCCACGCTTTCCAGTCCGGCAGCCAGTAC TGTGGGATCTATCTGTAGCCCTGTAAACAATGCCTTCAGCTACACTGCTTCTGGCACC TCTGCTGGATCCAGTACATTGCGGGATGTGGTTCCCAGTCCAGACACGCAGGAGAAAG GTGCTCAAGAGGTCCCTTTTCCTAAGACTGAGGAAGTAGAGAGTGCCATCTCAAATGG TGTGACTGGCCAGCTTAATATTGTCCAGTACATAAAACCAGAACCAGATGGAGCTTTT AGCAGCTCATGTCTAGGAGGAAATAGCAAAATAAATTCGGATTCTTCATTCTCAGTAC CAATAAAGCAAGAATCAACCAAGCATTCATGTTCAGGCACCTCTTTTAAAGGGAATCC AACAGTAAACCCGTTTCCATTTATGGATGGCTCGTATTTTTCCTTTATGGATGATAAA GACTATTATTCCCTATCAGGAATTTTAGGACCACCTGTGCCCGGCTTTGATGGTAACT GTGAAGGCAGCGGATTCCCAGTGGGTATTAAACAAGAACCAGATGACGGGAGCTATTA CCCAGAGGCCAGCATCCCTTCCTCTGCTATTGTTGGGGTGAATTCAGGTGGACAGTCC TTCCACTACAGGATTGGTGCTCAAGGTACAATATCTTTATCACGATCGGCTAGAGACC AATCTTTCCAACACCTGAGTTCCTTTCCTCCTGTCAATACTTTAGTGGAGTCATGGAA ATCACACGGCGACCTGTCGTCTAGAAGAAGTGATGGGTATCCGGTCTTAGAATACATT CCAGAAAATGTATCAAGCTCTACTTTACGAAGTGTTTCTACTGGATCTTCAAGACCTT CAAAAATATGTTTGGTGTGTGGGGATGAGGCTTCAGGATGCCATTATGGGGTAGTCAC CTGTGGCAGCTGCAAAGTTTTCTTCAAAAGAGCAGTGGAAGGGCAACACAACTATTTA TGTGCTGGAAGAAATGATTGCATCATTGATAAGATTCGACGAAAGAATTGTCCTGCTT GCAGACTTCAGAAATGTCTTCAAGCTGGAATGAATTTAGGAGCACGAAAGTCAAAGAA GTTGGGAAAGTTAAAAGGGATTCACGAGGAGCAGCCACAGCAGCAGCAGCCCCCACCC CCACCCCCACCCCCGCAAAGCCCAGAGGAAGGGACAACGTACATCGCTCCTGCAAAAG AACCCTCGGTCAACACAGCACTGGTTCCTCAGCTCTCCACAATCTCACGAGCGCTCAC ACCTTCCCCCGTTATGGTCCTTGAAAACATTGAACCTGAAATTGTATATGCAGGCTAT GACAGCTCAAAACCAGATACAGCCGAAAATCTGCTCTCCACGCTCAACCGCTTAGCAG GCAAACAGATGATCCAAGTCGTGAAGTGGGCAAAGGTACTTCCAGGATTTAAAAACTT GCCTCTTGAGGACCAAATTACCCTAATCCAGTATTCTTGGATGTGTCTATCATCATTT GCCTTGAGCTGGAGATCGTACAAACATACGAACAGCCAATTTCTCTATTTTGCACCAG ACCTAGTCTTTAATGAAGAGAAGATGCATCAGTCTGCCATGTATGAACTATGCCAGGG GATGCACCAAATCAGCCTTCAGTTCGTTCGACTGCAGCTCACCTTTGAAGAATACACC ATCATGAAAGTTTTGCTGCTACTAAGCACAATTCCAAAGGATGGCCTCAAAAGCCAGG CTGCATTTGAAGAAATGAGGACAAATTACATCAAAGAACTGAGGAAGATGGTAACTAA GTGTCCCAACAATTCTGGGCAGAGCTGGCAGAGGTTCTACCAACTGACCAAGCTGCTG GACTCCATGCATGACCTGGTGAGCGACCTGCTGGAATTCTGCTTCTACACCTTCCGAG AGTCCCATGCGCTGAAGGTAGAGTTCCCCGCAATGCTGGTGGAGATCATCAGCGACCA GCTGCCCAAGGTGGAGTCGGGGAACGCCAAGCCGCTCTACTTCCACCGGAAGTGA (SEQ IDNO: 64)
Mouse polypeptide sequence: METKGYHSLPEGLDMERRWSQVSQTLERSSLGPAERTNENSYMEIVNVSCVSGATPNN STQGSSKEKHELLPCLQQDNSRSGILPSDIKTELESKELSATVAESMGLYMDSVRDAE YTYDQQNQQGSLSPAKIYQNMEQLVKFYKENGHRSSTLSAISRPLRSFMPDSGTSMNG GALRAIVKSPIICHEKSPSVCSPLNMPSSVCSPAGINSMSSSTASFGSFPVHSPITQG TSLTCSPSVENRGSRSHSPVHASNVGSPLSSPLSSMKSPISSPPSHCSVKSPVSSPNN VPLRSSVSSPANLNNSRCSVSSPSNTNNRSTLSSPTASTVGSIGSPISNAFSYTTSGA SAGAGAIQDMVPSPDTHEKGAHDVPFPKTEEVEKAISNGVTGQLNIVQYIKPEPDGAF SSSCLGGNNKINPSSPFSVPIKQESSKHSCSGASFKGNPTVNPFPFMDGSYFSFMDDK DYYSLSGILGPPVPGFDSSCEGSAFPGGIKQEPDDGSYFPETSIPSSAIIGVNSGGQS FHYRIGAQGTISLSRSPRDQSFQHLSSFPPVNALVES KPHGDLSSRRSDGYPVLEYI PENVSSEFMSLNLKL SIKKYSRIPALQDEVGEKRN ESPNKILKLQIYVILYPNKPN TTAAEWSKKGFGSLEGKILLSISTVRKTLQRVFLGWAGSSILDALKHAVADLGSYRL (SEQ IDNO: 65)
Mouse polynucleotide sequence:
ATGGAAACCAAAGGCTACCACAGTCTCCCTGAAGGCCTAGATATGGAAAGGCGCTGGA GTCAAGTGTCTCAGACCTTGGAGCGTTCTTCTCTTGGACCTGCAGAGAGGACCAATGA GAACAGCTACATGGAGATTGTCAACGTCAGCTGCGTTTCCGGTGCTACTCCGAACAAC AGTACTCAAGGGAGCAGCAAAGAAAAACACGAATTACTCCCTTGTCTTCAGCAAGACA ATAGTCGGTCTGGGATTTTGCCATCAGATATTAAAACTGAGCTGGAATCCAAGGAACT TTCAGCCACGGTGGCTGAGTCCATGGGTTTATACATGGATTCTGTGAGAGATGCCGAG TACACTTATGATCAGCAAAACCAACAAGGAAGCCTGAGCCCGGCAAAGATTTATCAAA ACATGGAGCAGCTGGTGAAGTTTTACAAAGAGAATGGTCACAGGTCCTCCACACTGAG TGCTATAAGCAGGCCTTTGAGGTCATTCATGCCTGACTCTGGGACCTCCATGAATGGT GGGGCCTTGCGTGCCATCGTTAAGAGCCCAATCATCTGTCATGAGAAGAGCCCCTCTG TTTGCAGCCCGCTCAACATGCCGTCTTCAGTATGCAGCCCCGCGGGCATCAACTCCAT GTCCTCCTCCACAGCTAGCTTTGGCAGTTTCCCAGTGCACAGTCCCATCACTCAAGGA ACCTCACTGACATGCTCCCCCAGTGTTGAAAATAGAGGCTCAAGGTCACACAGCCCCG TACATGCGAGCAATGTGGGCTCTCCTCTTTCAAGTCCATTAAGCAGCATGAAATCCCC AATTTCCAGCCCTCCAAGTCACTGCAGTGTAAAATCTCCAGTATCCAGTCCAAACAAT GTCCCTCTGCGCTCCTCTGTGTCAAGCCCGGCAAATCTTAACAATTCAAGGTGCTCTG TTTCCAGCCCTTCCAACACCAACAATAGATCTACACTCTCCAGCCCGACAGCTAGCAC AGTGGGGTCCATTGGCAGCCCCATCAGCAATGCCTTCAGCTATACCACTTCAGGCGCT TCGGCTGGAGCCGGTGCCATCCAGGATATGGTTCCCAGTCCAGACACCCACGAGAAAG GTGCTCACGACGTTCCTTTCCCTAAGACAGAGGAAGTCGAGAAGGCCATTTCCAATGG TGTGACTGGTCAGCTCAACATTGTCCAGTACATAAAACCAGAACCAGATGGGGCTTTC AGCAGTTCCTGCCTAGGAGGAAACAACAAAATCAACCCCAGTTCTCCGTTCTCTGTAC CAATAAAGCAAGAGTCAAGCAAGCACTCATGTTCAGGCGCCTCTTTTAAAGGGAACCC CACAGTCAACCCATTTCCATTCATGGATGGCTCGTACTTTTCTTTTATGGATGATAAA GACTATTATTCCCTATCAGGAATCTTAGGACCACCTGTGCCCGGCTTTGATAGTAGCT GTGAAGGCAGTGCGTTCCCGGGGGGGATTAAGCAAGAACCAGATGATGGGAGCTATTT CCCTGAAACCAGCATCCCATCATCTGCCATCATTGGTGTGAATTCAGGTGGACAGTCC TTTCACTACCGGATTGGTGCTCAAGGTACAATATCTTTATCACGGTCACCTAGAGACC AATCTTTCCAACACTTGAGTTCCTTTCCGCCTGTCAATGCATTAGTGGAGTCATGGAA ACCACACGGTGACCTGTCATCTAGGAGAAGTGATGGGTACCCGGTCCTAGAGTACATT CCAGAAAACGTGTCAAGTGAGTTTATGTCACTGAATTTGAAGCTGTGGAGTATTAAAA AATACAGCAGAATCCCTGCCCTCCAGGATGAGGTAGGTGAGAAAAGAAACTGGGAATC TCCGAATAAGATCTTGAAGTTGCAGATTTATGTCATTCTATACCCAAACAAGCCAAAC ACCACAGCAGCAGAATGGAGCAAGAAGGGCTTTGGGAGCCTTGAAGGAAAAATCTTAC TGTCCATCAGCACTGTTAGAAAAACACTTCAAAGGGTGTTTCTGGGATGGGCTGGCAG CAGCATCTTGGATGCTCTGAAACATGCTGTTGCTGACCTAGGAAGTTACCGCCTCTGA (SEQ ID NO: 66)
NR21
Human polypeptide sequence:
MSKPAGSTSRILDIPCKVCGDRSSGKHYGVYACDGCSGFFKRSIRRNRTYVCKSGNQG GCPVDKTHRNQCRACRLKKCLEVNMNKDAVQHERGPRTSTIRKQVALYFRGHKEENGA AAHFPSAALPAPAFFTAVTQLEPHGLELAAVSTTPERQTLVSLAQPTPKYPHEVNGTP MYLYEVATESVCESAARLLFMSIKWAKSVPAFSTLSLQDQLMLLEDAWRELFVLGIAQ AIPVDANTLLAVSGMNGDNTDSQKLNKIISEIQALQEWARFRQLRLDATEFACLKC IVTFKAVPTHSGSELRSFRNAAAIAALQDEAQLTLNSYIHTRYPTQPCRFGKLLLLLP ALRSISPSTIEEVFFKKTIGNVPITRLLSDMYKSSDI (SEQ ID NO: 67)
Human polynucleotide sequence:
ATGAGCAAGCCAGCCGGATCAACAAGCCGCATTTTAGATATCCCCTGCAAAGTGTGTG GCGACCGCAGCTCGGGGAAGCACTACGGGGTCTACGCCTGCGACGGCTGCTCAGGTTT
TTTCAAACGGAGCATCCGAAGGAATAGGACCTATGTCTGCAAATCTGGAAACCAGGGA
GGCTGTCCGGTGGACAAGACGCACAGAAACCAGTGCAGGGCGTGTCGGCTGAAGAAGT
GTTTGGAAGTCAACATGAACAAAGACGCCGTGCAGCACGAGCGGGGGCCTCGGACGTC
CACCATCCGCAAGCAAGTGGCCCTCTACTTCCGTGGACACAAGGAGGAGAACGGGGCC GCCGCGCACTTTCCCTCGGCGGCGCTCCCTGCGCCGGCCTTCTTCACCGCGGTCACGC
AGCTGGAGCCGCACGGCCTGGAGCTGGCCGCGGTGTCCACCACTCCAGAGCGGCAGAC
CCTCGTGAGCCTGGCTCAGCCCACGCCCAAGTACCCCCATGAAGTGAATGGGACCCCA
ATGTATCTCTATGAAGTGGCCACGGAGTCGGTGTGTGAATCAGCTGCCAGACTTCTCT
TCATGAGCATCAAGTGGGCTAAGAGTGTGCCAGCCTTCTCCACGCTGTCTTTGCAAGA CCAGCTGATGCTTTTGGAAGATGCTTGGAGAGAACTGTTTGTTCTAGGAATAGCACAA
TGGGCCATTCCGGTTGATGCTAACACTCTACTGGCTGTATCTGGCATGAACGGTGACA ACACAGATTCCCAGAAGCTGAACAAGATCATATCTGAAATACAGGCTTTACAAGAGGT GGTGGCTCGATTTAGACAACTCCGGTTAGATGCTACTGAATTTGCCTGTCTAAAATGC ATCGTCACTTTCAAAGCCGTTCCTACACATAGTGGTTCTGAACTGAGAAGTTTCCGGA ATGCTGCCGCCATTGCAGCCCTTCAAGATGAGGCTCAGCTAACGCTCAACAGCTACAT CCATACCAGATATCCCACTCAACCCTGTCGCTTTGGAAAACTCCTGTTGCTTTTGCCA GCTTTACGTTCTATTAGCCCATCAACTATAGAAGAAGTGTTTTTCAAAAAAACCATCG GCAATGTGCCAATTACAAGACTGCTTTCAGATATGTACAAATCCAGTGATATCTAA (SEQ ID NO: 68) Mouse polypeptide sequence:
MSKPAGSTSRILDIPCKVCGDRSSGKHYGVYACDGCSGFFKRSIRRNRTYVCKSGNQG GCPVDKTHRNQCRACRLKKCLEVNMNKDAVQHERGPRTSTIRKQVALYFRGHKEDNGA AAHFPSTALPAPAFFTAVTQLEPHGLELAAVSATPERQTLVSLAQPTPKYPHEVNGTP MYLYEVATESVCESAARLLFMSIKWAKSVPAFSTLSLQDQLMLLEDAWRELFVLGIAQ WAIPVDANTLLAVSGMNTDNTDSQKLNKII'SEIQALQEWARFRQLRLDATEFACLKC IVTFKAVPTHSGSELRSFRNAAAIAALQDEAQLTLNSYIHTRYPTQPCRFGKLLLLLP ALRSISPSTIEEVFFKKTIGNVPITRLLSDMYKSSDI (SEQ ID NO: 69)
Mouse polynucleotide sequence:
ATGAGCAAGCCCGCCGGATCAACAAGCCGCATTTTAGATATCCCTTGCAAAGTGTGTG GTGACCGCAGCTCCGGGAAGCACTACGGGGTCTACGCTTGCGACGGCTGCTCCGGATT CTTCAAGAGGAGCATTCGAAGGAATAGGACCTATGTCTGCAAGTCTGGAAACCAGGGA GGATGCCCCGTAGACAAGACACACAGAAACCAATGCAGGGCGTGTCGACTGAAGAAGT GTTTGGAAGTCAACATGAACAAAGATGCCGTGCAGCACGAGCGGGGTCCTCGGACGTC CACCATCCGCAAACAGGTGGCTCTCTACTTCCGTGGACACAAGGAAGACAATGGGGCC GCTGCGCACTTCCCCTCCACGGCGCTGCCAGCCCCTGCTTTCTTCACAGCGGTCACGC AGCTGGAGCCGCACGGTCTGGAGTTGGCCGCTGTGTCTGCCACTCCTGAACGGCAGAC TCTCGTGAGCCTGGCTCAGCCCACGCCCAAGTATCCCCATGAAGTGAATGGGACCCCA ATGTATCTCTACGAAGTGGCCACTGAGTCCGTGTGTGAATCAGCTGCCAGGCTTCTCT TTATGAGCATCAAGTGGGCAAAGAGTGTGCCAGCCTTTTCCACTTTGTCTTTACAAGA TCAGCTGATGCTTTTGGAAGACGCGTGGAGAGAACTGTTTGTTCTAGGAATAGCACAA TGGGCCATTCCGGTTGATGCTAACACTCTACTGGCTGTATCTGGCATGAATACTGACA ACACAGACTCCCAGAAGCTGAACAAGATCATATCTGAAATACAGGCTTTGCAAGAGGT GGTGGCTCGGTTCAGACAGCTCCGATTAGACGCCACTGAATTTGCCTGTCTGAAATGT ATTGTCACTTTCAAAGCTGTTCCTACACACAGTGGTTCTGAACTGAGAAGTTTCCGGA ATGCTGCCGCCATTGCCGCTCTCCAAGATGAGGCTCAGCTAACTCTCAACAGCTACAT TCATACCAGATACCCCACCCAACCCTGCCGATTCGGGAAACTCCTGTTGCTTTTACCA GCTTTACGGTCAATTAGCCCATCTACCATAGAAGAAGTGTTTTTCAAAAAAACCATCG GCAATGTGCCGATTACAAGACTACTTTCAGATATGTACAAATCCAGTGACATCTAA (SEQ ID NO: 70) NR23
Human polypeptide sequence:
METRPTALMSSTVAAAAPAAGAASRKESPGRWGLGEDPTGVSPSLQCRVCGDSSSGKH YGIYACNGCSGFFKRSVRRRLIYRCQVGAGMCPVDKAHRNQCQACRLKKCLQAGMNQD AVQNERQPRSTAQVHLDSMESNTESRPESLVAPPAPAGRSPRGPTPMSAARALGHHFM ASLITAETCAKLEPEDADENIDVTSNDPEFPSSPYSSSSPCGLDSIHETSARLLFMAV KAKNLPVFSSLPFRDQVILLEEAWSELFLLGAIQWSLPLDSCPLLAPPEASAAGGAQ GRLTLASMETRVLQETISRFRALAVDPTEFACMKALVLFKPETRGLKDPEHVEALQDQ SQVMLSQHSKAHHPSQPVRFGKLLLLLPSLRFITAERIELLFFRKTIGNTPMEKLLCD MFKN
(SEQ ID NO: 71)
Human polynucleotide sequence:
ATGGAGACCAGACCAACAGCTCTGATGAGCTCCACAGTGGCTGCAGCTGCGCCTGCAG CTGGGGCTGCCTCCAGGAAGGAGTCTCCAGGCAGATGGGGCCTGGGGGAGGATCCCAC AGGCGTGAGCCCCTCGCTCCAGTGCCGCGTGTGCGGAGACAGCAGCAGCGGGAAGCAC TATGGCATCTATGCCTGCAACGGCTGCAGCGGCTTCTTCAAGAGGAGCGTACGGCGGA GGCTCATCTACAGGTGCCAGGTGGGGGCAGGGATGTGCCCCGTGGACAAGGCCCACCG CAACCAGTGCCAGGCCTGCCGGCTGAAGAAGTGCCTGCAGGCGGGGATGAACCAGGAC GCCGTGCAGAACGAGCGCCAGCCGCGAAGCACAGCCCAGGTCCACCTGGACAGCATGG AGTCCAACACTGAGTCCCGGCCGGAGTCCCTGGTGGCTCCCCCGGCCCCGGCAGGGCG CAGCCCACGGGGCCCCACACCCATGTCTGCAGCCAGAGCCCTGGGCCACCACTTCATG GCCAGCCTTATAACAGCTGAAACCTGTGCTAAGCTGGAGCCAGAGGATGCTGATGAGA ATATTGATGTCACCAGCAATGACCCTGAGTTCCCCTCCTCTCCATACTCCTCTTCCTC CCCCTGCGGCCTGGACAGCATCCATGAGACCTCGGCTCGCCTACTCTTCATGGCCGTC AAGTGGGCCAAGAACCTGCCTGTGTTCTCCAGCCTGCCCTTCCGGGATCAGGTGATCC TGCTGGAAGAGGCGTGGAGTGAACTCTTTCTCCTCGGGGCCATCCAGTGGTCTCTGCC TCTGGACAGCTGTCCTCTGCTGGCACCGCCCGAGGCTTCTGCTGCCGGTGGTGCCCAG GGCCGGCTCACGCTGGCCAGCATGGAGACGCGTGTCCTGCAGGAAACTATCTCTCGGT TCCGGGCATTGGCGGTGGACCCCACGGAGTTTGCCTGCATGAAGGCCTTGGTCCTCTT CAAGCCAGAGACGCGGGGCCTGAAGGATCCTGAGCACGTAGAGGCCTTGCAGGACCAG TCCCAAGTGATGCTGAGCCAGCACAGCAAGGCCCACCACCCCAGCCAGCCCGTGAGGT GA
(SEQ IDNO: 72)
Mouse polypeptide sequence: MSSTVAASTMPVSVAASKKESPGRWGLGEDPTGVGPSLQCRVCGDSSSGKHYGIYACN GCSGFFKRSVRRRLIYRCQVGAGMCPVDKAHRNQCQACRLKKCLQAGMNQDAVQNERQ PRSMAQVHLDAMETGSDPRSEPWASPALAGPSPRGPTSVSATRAMGHHFMASLITAE TCAKLEPEDAEENIDVTSNDPEFPASPCSLDGIHETSARLLFMAVKWAKNLPVFSNLP FRDQVILLEEAWNELFLLGAIQWSLPLDSCPLLAPPEASGSSQGRLALASAETRFLQE TISRFRALAVDPTEFACLKALVLFKPETRGLKDPEHVEALQDQSQVMLSQHSKAHHPS QPVRFGKLLLLLPSLRFLTAERIELLFFRKTIGNTPMEKLLCDMFKN (SEQ IDNO: 73)
Mouse polynucleotide sequence:
ATGAGCTCTACAGTGGCTGCCTCCACTATGCCTGTGTCTGTGGCGGCCTCCAAGAAGG AGTCTCCAGGTAGATGGGGCCTTGGAGAGGATCCAACAGGTGTGGGCCCCTCGCTCCA GTGCCGAGTGTGTGGGGACAGCAGCAGTGGGAAACATTATGGCATCTATGCCTGCAAT GGCTGCAGTGGCTTCTTCAAGAGGAGTGTGAGAAGGAGGCTCATCTACAGGTGCCAAG TCGGGGCAGGGATGTGCCCAGTGGATAAGGCCCATCGCAATCAGTGCCAGGCCTGCCG GCTGAAGAAGTGCTTACAAGCAGGCATGAACCAAGATGCTGTGCAGAATGAGCGCCAA CCTCGGAGCATGGCTCAGGTCCACCTGGATGCCATGGAAACAGGCAGTGACCCCCGAT CAGAACCAGTGGTAGCCTCTCCTGCTCTGGCAGGGCCCAGTCCCCGGGGCCCCACGTC TGTGTCTGCAACCAGAGCCATGGGCCACCACTTTATGGCCAGCCTTATCACCGCCGAA ACTTGTGCTAAACTGGAGCCAGAGGACGCTGAAGAGAATATTGATGTCACCAGCAATG ACCCCGAGTTCCCCGCATCCCCCTGCAGTCTGGATGGCATCCATGAGACATCTGCTCG CCTGCTCTTCATGGCTGTCAAATGGGCCAAAAACTTGCCTGTGTTTTCCAACCTGCCT TTCCGGGACCAGGTGATCTTGCTGGAAGAGGCATGGAATGAGCTTTTCCTTCTTGGAG CCATACAGTGGTCTCTGCCCCTGGACAGCTGCCCACTGCTGGCACCACCTGAGGCGTC CGGCAGCTCTCAGGGCAGGCTGGCCTTGGCCAGTGCAGAGACGCGCTTCCTGCAGGAA ACCATCTCCCGGTTCCGAGCTCTGGCAGTGGATCCCACAGAGTTTGCCTGCCTGAAGG CCCTGGTCCTCTTCAAACCTGAAACACGAGGCCTGAAGGATCCTGAGCACGTGGAGGC TTTGCAGGACCAGTCCCAGGTGATGCTAAGCCAGCATAGCAAGGCTCACCACCCCAGC CAGCCTGTGAGGTTTGGGAAATTGCTCCTCCTGCTCCCATCTTTGAGGTTCCTCACGG CTGAGCGCATTGAGCTTCTCTTCTTCAGAAAGACCATAGGGAACACTCCGATGGAGAA GCTCCTGTGTGACATGTTCAAAAACTAG (SEQ IDNO: 74)
NR41 Human polypeptide sequence:
MPCIQAQYGTPAPSPGPRDHLASDPLTPEFIKPTMDLASPEAAPAAPTALPSFSTFMD GYTGEFDTFLYQLPGTVQPCSSASSSASSTSSSSATSPASASFKFEDFQVYGCYPGPL SGPVDEALSSSGSDYYGSPCSAPSPSTPSFQPPQLSP DGSFGHFSPSQTYEGLRAWT EQLPKASGPPQPPAFFSFSPPTGPSPSLAQSPLKLFPSQATHQLGEGESYSMPTAFPG LAPTSPHLEGSGILDTPVTSTKARSGAPGGSEGRCAVCGDNASCQHYGVRTCEGCKGF FKRTVQKNAKYICLANKDCPVDKRRRNRCQFCRFQKCLAVGMVKEWRTDSLKGRRGR LPSKPKQPPDASPANLLTSLVRAHLDSGPSTAKLDYSKFQELVLPHFGKEDAGDVQQF YDLLSGSLEVIRKAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIF CSGLVLHRLQCARGFGDWIDSILAFSRSLHSLLVDVPAFACLSALVLITDRHGLQEPR RVEELQNRIASCLKEHVAAVAGEPQPASCLSRLLGKLPELRTLCTQGLQRIFYLKLED LVPPPPIIDKIFMDTLPF (SEQ ID NO: 75) Human polynucleotide sequence:
ATGCCCTGTATCCAAGCCCAATATGGGACACCAGCACCGAGTCCGGGACCCCGTGACC ACCTGGCAAGCGACCCCCTGACCCCTGAGTTCATCAAGCCCACCATGGACCTGGCCAG CCCCGAGGCAGCCCCCGCTGCCCCCACTGCCCTGCCCAGCTTCAGCACGTTCATGGAC GGCTACACAGGAGAGTTTGACACCTTCCTCTACCAGCTGCCAGGAACAGTCCAGCCAT GCTCCTCAGCCTCCTCCTCGGCCTCCTCCACATCCTCGTCCTCAGCCACCTCCCCTGC CTCTGCCTCCTTCAAGTTCGAGGACTTCCAGGTGTACGGCTGCTACCCCGGCCCCCTG AGCGGCCCAGTGGATGAGGCCCTGTCCTCCAGTGGCTCTGACTACTATGGCAGCCCCT GCTCGGCCCCGTCGCCCTCCACGCCCAGCTTCCAGCCGCCCCAGCTCTCTCCCTGGGA TGGCTCCTTCGGCCACTTCTCGCCCAGCCAGACTTACGAAGGCCTGCGGGCATGGACA GAGCAGCTGCCCAAAGCCTCTGGGCCCCCACAGCCTCCAGCCTTCTTTTCCTTCAGTC CTCCCACTGGCCCCAGCCCCAGCCTGGCCCAGAGCCCCCTGAAGTTGTTCCCCTCACA GGCCACCCACCAGCTGGGGGAGGGAGAGAGCTATTCCATGCCTACGGCCTTCCCAGGT TTGGCACCCACTTCTCCACACCTTGAGGGCTCGGGGATACTGGATACACCCGTGACCT CAACCAAGGCCCGGAGCGGGGCCCCAGGTCCAAGTGAAGGCCGCTGTGCTGTGTGTGG GGACAACGCTTCATGCCAGCATTATGGTGTCCGCACATGTGAGGGCTGCAAGGGCTTC TTCAAGCGCACAGTGCAGAAAAACGCCAAGTACATCTGCCTGGCTAACAAGGACTGCC CTGTGGACAAGAGGCGGCGAAACCGCTGCCAGTTCTGCCGCTTCCAGAAGTGCCTGGC GGTGGGCATGGTGAAGGAAGTTGTCCGAACAGACAGCCTGAAGGGGCGGCGGGGCCGG CTACCTTCAAAACCCAAGCAGCCCCCAGATGCCTCCCCTGCCAATCTCCTCACTTCCC TGGTCCTTGCACACCTGGATTCAGGGCCCAGCACTGCCAAACTGGACTACTCCAAGTT CCAGGAGCTGGTGCTGCCCCACTTTGGGAAGGAAGATGCTGGGGATGTACAGCAGTTC TACGACCTGCTCTCCGGTTCTCTGGAGGTCATCCGAAAGTGGGCGGAGAAGATCCCTG GCTTTGCTGAGCTGTCACCGGCTGACCAGGACCTGTTGCTGGAGTCGGCCTTCCTGGA GCTCTTCATCCTCCGCCTGGCGTACAGGTCTAAGCCAGGCGAGGGCAAGCTCATCTTC TGCTCAGGCCTGGTGCTACACCGGCTGCAGTGTGCCCGTGGCTTCGGGGACTGGATTG ACAGTATCCTGGCCTTCTCAAGGTCCCTGCACAGCTTGCTTGTCGATGTCCCTGCCTT CGCCTGCCTCTCTGCCCTTGTCCTCATCACCGACCGGCATGGGCTGCAGGAGCCGCGG CGGGTGGAGGAGCTGCAGAACCGCATCGCCAGCTGCCTGAAGGAGCACGTGGCAGCTG TGGCGGGCGAGCCCCAGCCAGCCAGCTGCCTGTCACGTCTGTTGGGCAAACTGCCCGA GCTGCGGACCCTGTGCACCCAGGGCCTGCAGCGCATCTTCTACCTCAAGCTGGAGGAC TTGGTGCCCCCTCCACCCATCATTGACAAGATCTTCATGGACACGCTGCCCTTCTGA (SEQ ID NO: 76)
Mouse polypeptide sequence:
MPCIQAQYGTPATSPGPRDHLTGDPLALEFGKPTMDLASPETAPAAPATLPSFSTFMD GYTGEFDTFLYQLPGTTQPCSSACSSASSTSSSSSSATSPASASFKFEDFQVYGCYPG TLSGPLDETLSSSGSEYYGSPCSAPSPSTPNFQPSQLSP DGSFGHFSPSQTYEGL A TEQLPKASSGPPPPPTFFSFSPPTGPSPSLAQSSLKLFPPPATHQLGEGESYSMPAA FPGLAPTSPNRDTSGILDAPVTSTKSRSGASGGSEGRCAVCGDNASCQHYGVRTCEGC KGFFKRTVQKSAKYICLANKDCPVDKRRRNRCQFCRFQKCLAVGMVKEWRTDSLKGR RGRLPSKPKQPPDASPTNLLTSLIRAHLDSGPSTAKLDYSKFQELVLPRFGKEDAGDV QQFYDLLSGSLDVIRKWAEKIPGFIELCPGDQDLLLESAFLELFILRLAYRSKPGEGK LIFCSGLVLHQLQCARGFGDWIDNILAFSRSLHSLGVDVPAFACLSALVLITDRHGLQ DPRRVEELQNRIASCLKEHMATVAGDPQPASCLSRLLGKLPELRTLCTQGLQRIFCLK LEDLVPPPPIVDKIFMDTLSF (SEQ IDNO: 77)
Mouse polynucleotide sequence:
ATGCCCTGTATTCAAGCTCAATATGGAACACCAGCAACGAGCCCAGGACCGCGTGACC ACCTGACCGGTGATCCCCTGGCCCTTGAGTTCGGCAAGCCTACCATGGACCTGGCCAG CCCCGAGACAGCACCTGCCGCACCTGCTACACTGCCCAGCTTCAGCACCTTCATGGAC GGGTACACCGGAGAGTTTGACACCTTCCTCTACCAGCTGCCGGGGACGACCCAGCCGT GCTCCTCAGCTTGTTCCTCTGCCTCCTCCACGTCTTCTTCCTCATCCTCGGCCACCTC CCCCGCTTCGGCGTCCTTCAAGTTTGAGGACTTCCAGGTGTACGGCTGCTACCCGGGC ACCCTGAGCGGCCCATTAGATGAGACCCTATCCTCCAGCGGCTCTGAGTACTATGGCA GTCCCTGCTCAGCCCCCTCGCCATCTACACCCAACTTCCAGCCGTCCCAGCTTTCTCC CTGGGACGGCTCATTTGGCCACTTCTCCCCGAGCCAGACTTATGAAGGCCTCTGGGCA TGGACAGAGCAGTTGCCTAAGGCTTCTTCAGGGCCTCCGCCACCTCCAACCTTCTTCT CCTTCAGTCCTCCCACTGGCCCCAGCCCCAGCCTGGCCCAGAGTTCTCTGAAATTGTT CCCACCACCAGCCACCCACCAGCTTGGGGAGGGGGAGAGCTATTCCATGCCAGCAGCT TTCCCCGGCTTGGCACCCACCTCTCCGAACCGTGACACTTCCGGCATTCTGGACGCAC CCGTGACCTCCACCAAGTCCCGGAGCGGGGCTTCAGGTGGCAGCGAGGGCCGCTGTGC AGTCTGTGGTGACAATGCTTCGTGTCAGCACTATGGGGTCCGCACCTGTGAGGGCTGC AAGGGCTTCTTCAAGCGCACAGTACAGAAAAGCGCCAAGTACATCTGCCTGGCAAACA AGGATTGCCCTGTGGACAAGAGGCGGCGGAACCGCTGCCAGTTCTGCCGCTTCCAGAA GTGCCTGGCTGTGGGCATGGTGAAGGAAGTTGTACGGACAGACAGCCTAAAAGGGCGG CGGGGCCGGCTACCTTCAAAACCCAAGCAGCCTCCAGATGCCTCCCCTACCAATCTTC TCACTTCCCTCATCCGGGCACACTTGGACTCCGGGCCTAGCACTGCCAAATTGGACTA TTCCAAGTTCCAGGAACTGGTGCTGCCCCGCTTCGGGAAGGAAGATGCCGGTGACGTG CAACAATTTTATGACTTGCTCTCTGGTTCCCTGGACGTTATCCGAAAGTGGGCAGAAA AAATCCCTGGCTTCATTGAGCTTTGCCCAGGAGACCAAGACCTGTTGCTAGAGTCTGC CTTCCTGGAACTCTTCATCCTCCGCCTGGCATACCGATCTAAACCCGGTGAGGGGAAG CTCATCTTCTGCTCAGGCCTGGTACTACACCAGCTGCAGTGTGCCCGTGGCTTTGGTG ATTGGATTGACAACATCCTGGCCTTCTCACGGTCCCTGCACAGCTTGGGTGTTGATGT TCCCGCCTTTGCCTGCCTGTCCGCTCTGGTCCTCATCACTGATCGACACGGGCTCCAG GACCCTCGTCGGGTGGAAGAGCTGCAGAATCGCATTGCTAGCTGTCTGAAGGAGCACA TGGCTACCGTGGCAGGAGACCCACAGCCGGCCAGCTGCCTGTCACGTCTGCTGGGCAA ACTGCCTGAGCTTCGGACCCTGTGCACTCAAGGCCTGCAGCGCATCTTTTGCCTCAAG TTGGAGGACTTGGTACCCCCTCCACCTATTGTGGACAAGATCTTTATGGACACATTGT CTTTCTGA (SEQ ID NO: 78) NR42
Human polypeptide sequence: MPCVQAQYGSSPQGASPASQSYSYHSSGEYSSDFLTPEFVKFSMDLTNTEITATTSLP SFSTFMDNYSTGYDVKPPCLYQMPLSGQQSSIKVEDIQMHNYQQHSHLPPQSEEMMPH SGSVYYKPSSPPTPTTPGFQVQHSPMWDDPGSLHNFHQNYVATTHMIEQRKTPVSRLS LFSFKQSPPGTPVSSCQMRFDGPLHVPMNPEPAGSHHWDGQTFAVPNPIRKPASMGF PGLQIGHASQLLDTQVPSPPSRGSPSNEGLCAVCGDNAACQHYGVRTCEGCKGFFKRT VQKNAKYVCLANKNCPVDKRRRNRCQYCRFQKCLAVGMVKEWRTDSLKGRRGRLPSK PKSPQEPSPPSPPVSLISALVRAHVDSNPAMTSLDYSRFQANPDYQMSGDDTQHIQQF YDLLTGSMEIIRGWAEKIPGFADLPKADQDLLFESAFLELFVLRLAYRSNPVEGKLIF CNGWLHRLQCVRGFGEWIDSIVEFSSNLQNMNIDISAFSCIAALAMVTERHGLKEPK RVEELQNKIVNCLKDHVTFNNGGLNRPNYLSKLLGKLPELRTLCTQGLQRIFYLKLED LVPPPAIIDKLFLDTLPF (SEQ ID NO: 79)
Human polynucleotide sequence: ATGCCTTGTGTTCAGGCGCAGTATGGGTCCTCGCCTCAAGGAGCCAGCCCCGCTTCTC AGAGCTACAGTTACCACTCTTCGGGAGAATACAGCTCCGATTTCTTAACTCCAGAGTT TGTCAAGTTTAGCATGGACCTCACCAACACTGAAATCACTGCCACCACTTCTCTCCCC AGCTTCAGTACCTTTATGGACAACTACAGCACAGGCTACGACGTCAAGCCACCTTGCT TGTACCAAATGCCCCTGTCCGGACAGCAGTCCTCCATTAAGGTAGAAGACATTCAGAT GCACAACTACCAGCAACACAGCCACCTGCCCCCCCAGTCTGAGGAGATGATGCCGCAC TCCGGGTCGGTTTACTACAAGCCCTCCTCGCCCCCGACGCCCACCACCCCGGGCTTCC AGGTGCAGCACAGCCCCATGTGGGACGACCCGGGATCTCTCCACAACTTCCACCAGAA CTACGTGGCCACTACGCACATGATCGAGCAGAGGAAAACGCCAGTCTCCCGCCTCTCC CTCTTCTCCTTTAAGCAATCGCCCCCTGGCACCCCGGTGTCTAGTTGCCAGATGCGCT TCGACGGGCCCCTGCACGTCCCCATGAACCCGGAGCCCGCCGGCAGCCACCACGTGGT GGACGGGCAGACCTTCGCTGTGCCCAACCCCATTCGCAAGCCCGCGTCCATGGGCTTC CCGGGCCTGCAGATCGGCCACGCGTCTCAGCTGCTCGACACGCAGGTGCCCTCACCGC CGTCGCGGGGCTCCCCCTCCAACGAGGGGCTGTGCGCTGTGTGTGGGGACAACGCGGC CTGCCAACACTACGGCGTGCGCACCTGTGAGGGCTGCAAAGGCTTCTTTAAGCGCACA GTGCAAAAAAATGCAAAATACGTGTGTTTAGCAAATAAAAACTGCCCAGTGGACAAGC GTCGCCGGAATCGCTGTCAGTACTGCCGATTTCAGAAGTGCCTGGCTGTTGGGATGGT CAAAGAAGTGGTTCGCACAGACAGTTTAAAAGGCCGGAGAGGTCGTTTGCCCTCGAAA CCGAAGAGCCCACAGGAGCCCTCTCCCCCTTCGCCCCCGGTGAGTCTGATCAGTGCCC TCGTCAGGGCCCATGTCGACTCCAACCCGGCTATGACCAGCCTGGACTATTCCAGGTT CCAGGCGAACCCTGACTATCAAATGAGTGGAGATGACACCCAGCATATCCAGCAATTC TATGATCTCCTGACTGGCTCCATGGAGATCATCCGGGGCTGGGCAGAGAAGATCCCTG GCTTCGCAGACCTGCCCAAAGCCGACCAAGACCTGCTTTTTGAATCAGCTTTCTTAGA ACTGTTTGTCCTTCGATTAGCATACAGGTCCAACCCAGTGGAGGGTAAACTCATCTTT TGCAATGGGGTGGTCTTGCACAGGTTGCAATGCGTTCGTGGCTTTGGGGAATGGATTG ATTCCATTGTTGAATTCTCCTCCAACTTGCAGAATATGAACATCGACATTTCTGCCTT CTCCTGCATTGCTGCCCTGGCTATGGTCACAGAGAGACACGGGCTCAAGGAACCCAAG AGAGTGGAAGAACTGCAAAACAAGATTGTAAATTGTCTCAAAGACCACGTGACTTTCA ACAATGGGGGGTTGAACCGCCCCAATTATTTGTCCAAACTGTTGGGGAAGCTCCCAGA ACTTCGTACCCTTTGCACACAGGGGCTACAGCGCATTTTCTACCTGAAATTGGAAGAC TTGGTGCCACCGCCAGCAATAATTGACAAACTTTTCCTGGACACTTTACCTTTCTAA (SEQ IDNO: 80)
Mouse polypeptide sequence: MPCVQAQYGSSPQGASPASQSYSYHSSGEYSSDFLTPEFVKFSMDLTNTEITATTSLP SFSTFMDNYSTGYDVKPPCLYQMPLSGQQSSIKVEDIQMHNYQQHSHLPPQSEEMMPH SGSVYYKPSSPPTPSTPSFQVQHSPMWDDPGSLHNFHQNYVATTHMIEQRKTPVSRLS LFSFKQSPPGTPVSSCQMRFDGPLHVPMNPEPAGSHHWDGQTFAVPNPIRKPASMGF PGLQIGHASQLLDTQVPSPPSRGSPSNEGLCAVCGDNAACQHYGVRTCEGCKGFFKRT VQKNAKYVCLANKNCPVDKRRRNRCQYCRFQKCLAVGMVKEWRTDSLKGRRGRLPSK PKSPQDPSPPSPPVSLISALVRAHVDSNPAMTSLDYSRFQANPDYQMSGDDTQHIQQF YDLLTGSMEIIRGWAEKIPGFADLPKADQDLLFESAFLELFVLRLAYRSNPVEGKLIF CNGWLHRLQCVRGFGEWIDSIVEFSSNLQNMNIDISAFSCIAALAMVTERHGLKEPK RVEELQNKIVNCLKDHVTFNNGGLNRPNYLSKLLGKLPELRTLCTQGLQRIFYLKLED LVPPPAIIDKLFLDTLPF (SEQ ID NO: 81)
Mouse polynucleotide sequence:
ATGCCTTGTGTTCAGGCGCAGTATGGGTCCTCGCCTCAAGGAGCCAGCCCCGCTTCTC AGAGCTACAGTTACCACTCTTCGGGAGAATACAGCTCCGATTTCTTAACTCCAGAGTT TGTCAAGTTTAGCATGGACCTCACCAACACTGAAATTACTGCCACCACTTCTCTCCCC AGCTTCAGTACCTTTATGGACAACTACAGCACAGGCTACGACGTCAAGCCACCTTGCT TGTACCAAATGCCCCTGTCCGGACAGCAGTCCTCCATTAAGGTAGAAGACATTCAGAT GCACAACTACCAGCAACACAGCCACCTGCCCCCTCAGTCCGAGGAGATGATGCCACAC AGCGGGTCGGTTTACTACAAGCCCTCTTCGCCCCCGACACCCAGCACCCCGAGCTTCC AGGTGCAGCATAGCCCGATGTGGGACGATCCGGGCTCCCTTCACAACTTCCACCAGAA CTACGTGGCCACTACGCATATGATCGAGCAGAGGAAGACACCTGTCTCCCGCCTGTCA CTCTTCTCCTTTAAGCAGTCGCCCCCGGGCACTCCTGTGTCTAGCTGCCAGATGCGCT TCGACGGGCCTCTGCACGTCCCCATGAACCCGGAGCCCGCGGGCAGCCACCACGTAGT GGATGGGCAGACCTTCGCCGTGCCCAACCCCATTCGCAAGCCGGCATCCATGGGCTTC CCGGGCCTGCAGATCGGCCACGCATCGCAGTTGCTTGACACGCAGGTGCCCTCGCCGC CGTCCCGGGGCTCTCCCTCCAATGAGGGTCTGTGCGCTGTTTGCGGTGACAACGCGGC CTGTCAGCACTACGGTGTTCGCACTTGTGAGGGCTGCAAAGGTTTCTTTAAGCGCACG GTGCAAAAAAACGCGAAATATGTGTGTTTAGCAAATAAAAACTGCCCAGTGGACAAGC GCCGCCGAAATCGTTGTCAGTACTGTCGGTTTCAGAAGTGCCTAGCTGTTGGGATGGT TAAAGAAGTGGTTCGCACGGACAGTTTAAAAGGCCGGAGAGGTCGTTTACCCTCGAAG CCGAAGAGCCCACAGGATCCCTCTCCCCCCTCACCTCCGGTGAGTCTGATCAGTGCCC TCGTCAGAGCCCACGTCGATTCCAATCCGGCAATGACCAGCCTGGACTATTCCAGGTT CCAGGCAAACCCTGACTATCAGATGAGTGGAGATGATACCCAACATATCCAGCAGTTC TACGATCTCCTGACCGGCTCTATGGAGATCATCAGAGGGTGGGCAGAGAAGATCCCTG GCTTTGCTGACCTGCCCAAAGCCGACCAGGACCTGCTTTTTGAATCAGCTTTCTTAGA ATTATTTGTTCTGCGCTTAGCATACAGGTCCAACCCAGTGGAGGGTAAACTCATCTTT TGCAATGGGGTGGTCTTGCACAGGTTGCAATGCGTGCGTGGCTTTGGGGAATGGATTG ATTCCATTGTTGAATTCTCCTCCAACTTGCAGAATATGAACATCGACATTTCTGCCTT CTCCTGCATTGCTGCCCTGGCTATGGTCACAGAGAGACACGGGCTCAAGGAACCCAAG AGAGTGGAAGAGCTACAAAACAAAATTGTAAATTGTCTTAAAGACCATGTGACTTTCA ATAATGGGGGTTTGAACCGACCCAACTACCTGTCTAAACTGTTGGGGAAGCTGCCAGA ACTCCGCACCCTTTGCACACAGGGCCTCCAGCGCATTTTCTACCTGAAATTGGAAGAC TTGGTACCACCACCAGCAATAATTGACAAACTTTTCCTGGACACCTTACCTTTCTAA (SEQ ID NO: 82)
NR43
Human polypeptide sequence:
MPCVQAQYSPSPPGSSYAAQTYSSEYTTEIMNPDYTKLTMDLGSTEITATATTSLPSI STFVEGYSSNYELKPSCVYQMQRPLIKVEEGRAPSYHHHHHHHHHHHHHHQQQHQQPS IPPASSPEDEVLPSTSMYFKQSPPSTPTTPAFPPQAGALWDEALPSAPGCIAPGPLLD PPMKAVPTVAGARFPLFHFKPSPPHPPAPSPAGGHHLGYDPTAAAALSLPLGAAAAAG SQAAALEGHPYGLPLAKRAAPLAFPPLGLTPSPTASSLLGESPSLPSPPSRSSSSGEG TCAVCGDNAACQHYGyRTCEGCKGFFKRTVQKNAKYVCLANKNCPVDKRRRNRCQYCR FQKCLSVGMVKEWRTDSLKGRRGRLPSKPKSPLQQEPSQPSPPSPPICMMNALVRAL TDSTPRDLDYSRYCPTDQAAAGTDAEHVQQFYNLLTASIDVSRS AEKIPGFTDLPKE DQTLLIESAFLELFVLRLSIRSNTAEDKFVFCNGLVLHRLQCLRGFGE LDSIKDFSL NLQSLNLDIQALACLSALSMITERHGLKEPKRVEELCNKITSSLKDHQSKGQALEPTE SKVLGALVELRKICTLGLQRIFYLKLEDLVSPPSIIDKLFLDTLPF (SEQ ID NO: 83)
Human polynucleotide sequence: CCCACTGCGGAAGAGGGCAGCCCGGCAAGCCCGGGCCCTGAGCCTGGACCCTTAGCGG TGCCGGGCAGCACTGCCGGCGCTTCGCCTCGCCGGACGTCCGCTCCTCCTACACTCTC AGCCTCCGCTGGAGAGACCCCCAGCCCCACCATTCAGCGCGCAAGATACCCTCCAGAT ATGCCCTGCGTCCAAGCCCAATATAGCCCTTCCCCTCCAGGTTCCAGTTATGCGGCGC AGACATACAGCTCGGAATACACCACGGAGATCATGAACCCCGACTACACCAAGCTGAC CATGGACCTTGGCAGCACTGAGATCACGGCTACAGCCACCACGTCCCTGCCCAGCATC AGTACCTTCGTGGAGGGCTACTCGAGCAACTACGAACTCAAGCCTTCCTGCGTGTACC AAATGCAGCGGCCCTTGATCAAAGTGGAGGAGGGGCGGGCGCCCAGCTACCATCACCA TCACCACCACCACCACCACCACCACCACCATCACCAGCAGCAGCATCAGCAGCCATCC ATTCCTCCAGCCTCCAGCCCGGAGGACGAGGTGCTGCCCAGCACCTCCATGTACTTCA AGCAGTCCCCACCGTCCACCCCCACCACGCCGGCCTTCCCCCCGCAGGCGGGGGCGTT ATGGGACGAGGCACTGCCCTCGGCGCCCGGCTGCATCGCACCCGGCCCGCTGCTGGAC CCGCCGATGAAGGCGGTCCCCACGGTGGCCGGCGCGCGCTTCCCGCTCTTCCACTTCA AGCCCTCGCCGCCGCATCCCCCCGCGCCCAGCCCGGCCGGCGGCCACCACCTCGGCTA CGACCCGACGGCCGCTGCCGCGCTCAGCCTGCCGCTGGGAGCCGCAGCCGCCGCGGGC AGCCAGGCCGCCGCGCTTGAGAGCCACCCGTACGGGCTGCCGCTGGCCAAGAGGGCGG CCCCGCTGGCCTTCCCGCCTCTCGGCCTCACGCCCTCCCCTACCGCGTCCAGCCTGCT GGGCGAGAGTCCCAGCCTGCCGTCGCCGCCCAGCAGGAGCTCGTCGTCTGGCGAGGGC ACGTGTGCCGTGTGCGGGGACAACGCCGCCTGCCAGCACTACGGCGTGCGAACCTGCG AGGGCTGCAAGGGCTTTTTCAAGAGAACAGTGCAGAAAAATGCAAAATATGTTTGCCT GGCAAATAAAAACTGCCCAGTAGACAAGAGACGTCGAAACCGATGTCAGTACTGTCGA TTTCAGAAGTGTCTCAGTGTTGGAATGGTAAAAGAAGTTGTCCGTACAGATAGTCTGA AAGGGAGGAGAGGTCGTCTGCCTTCCAAACCAAAGAGCCCATTACAACAGGAACCTTC TCAGCCCTCTCCACCTTCTCCTCCAATCTGCATGATGAATGCCCTTGTCCGAGCTTTA ACAGACTCAACACCCAGAGATCTTGATTATTCCAGATACTGTCCCACTGACCAGGCTG CTGCAGGCACAGATGCTGAGCATGTGCAACAATTCTACAACCTCCTGACAGCCTCCAT TGATGTATCCAGAAGCTGGGCAGAAAAGATTCCGGGATTTACTGATCTCCCCAAAGAA GATCAGACATTACTTATTGAATCAGCCTTTTTGGAGCTGTTTGTCCTCAGACTTTCCA TCAGGTCAAACACTGCTGAAGATAAGTTTGTGTTCTGCAATGGACTTGTCCTGCATCG ACTTCAGTGCCTTCGTGGATTTGGGGAGTGGCTCGACTCTATTAAAGACTTTTCCTTA AATTTGCAGAGCCTGAACCTTGATATCCAAGCCTTAGCCTGCCTGTCAGCACTGAGCA TGATCACAGAAAGACATGGGTTAAAAGAACCAAAGAGAGTCGAAGAGCTATGCAACAA GATCACAAGCAGTTTAAAAGACCACCAGAGTAAGGGACAGGCTCTGGAGCCCACCGAG TCCAAGGTCCTGGGTGCCCTGGTAGAACTGAGGAAGATCTGCACCCTGGGCCTCCAGC GCATCTTCTACCTGAAGCTGGAAGACTTGGTGTCTCCACCTTCCATCATTGACAAGCT CTTCCTGGACACCCTACCTTTCTAA (SEQ ID NO: 84)
Mouse polypeptide sequence: MPCVQAQYSPSPPGSTYATQTYGSEYTTEIMNPDYTKLTMDLGSTGIMATATTSLPSF STFMEGYPSSCELKPSCLYQMPPSGPRPLIKMEEGREHGYHHHHHHHHHHHHHQQQQP SIPPPSGPEDEVLPSTSMYFKQSPPSTPTTPGFPPQAGALWDDELPSAPGCIAPGPLL DPQMKAVPPMAAAARFPIFFKPSPPHPPAPSPAGGHHLGYDPTAAAALSLPLGAAAAA GSQAAALEGHPYGLPLAKRTATLTFPPLGLTASPTASSLLGESPSLPSPPNRSSSSGE GTCAVCGDNAACQHYGVRTCEGCKGFFKRTVQKNAKYVCLANKNCPVDKRRRNRCQYC RFQKCLSVGMVKEWRTDSLKGRRGRLPSKPKSPLQQEPSQPSPPSPPICMMNALVRA LTDATPRDLDYSRVSSMNAFEPL (SEQ ID NO: 85)
Mouse polynucleotide sequence:
ATGCCCTGCGTGCAAGCCCAGTATAGCCCTTCACCTCCGGGGTCCACTTACGCCACGC AGACTTATGGCTCGGAATACACCACAGAAATCATGAACCCCGACTACACCAAGCTGAC CATGGACCTCGGTAGCACGGGGATCATGGCCACCGCCACTACATCCCTGCCCAGCTTC AGTACCTTCATGGAGGGCTACCCCAGCAGCTGCGAACTCAAGCCCTCCTGCCTGTACC AAATGCCGCCTTCTGGGCCTCGGCCTTTGATCAAGATGGAAGAGGGTCGCGAGCATGG CTACCACCACCACCATCACCATCACCATCATCACCACCACCACCAGCAACAGCAGCCG TCCATTCCTCCTCCCTCCGGCCCCGAGGACGAGGTACTGCCCAGCACCTCCATGTACT TCAAGCAGTCTCCGCCGTCTACACCGACCACTCCAGGCTTCCCCCCGCAGGCGGGGGC GCTGTGGGACGACGAGCTGCCCTCTGCGCCTGGCTGCATCGCTCCGGGACCGCTGCTG GACCCGCAGATGAAGGCGGTACCCCCCATGGCCGCTGCTGCGCGCTTCCCGATCTTCT TCAAGCCCTCACCGCCACACCCTCCCGCGCCCAGTCCAGCCGGCGGCCACCACCTCGG CTATGACCCCACGGCCGCAGCTGCACTCAGTCTGCCCCTGGGAGCCGCGGCCGCAGCA GGCAGCCAAGCTGCTGCGCTCGAGGGCCACCCATACGGGCTCCCGCTGGCCAAGAGGA CGGCCACGCTGACCTTCCCTCCGCTGGGCCTCACAGCCTCCCCCACCGCGTCCAGCCT GCTGGGAGAGAGCCCCAGCCTCCCATCGCCACCCAATAGGAGCTCATCATCTGGGGAA GGCACATGTGCCGTGTGCGGCGACAACGCTGCCTGCCAGCACTACGGAGTCCGCACCT GCGAGGGCTGCAAGGGCTTCTTCAAGAGAACGGTGCAGAAAAATGCAAAATATGTTTG CCTGGCAAATAAAAACTGCCCAGTGGACAAGAGACG.CCGAAACCGATGTCAGTACTGC AGATTTCAGAAGTGTCTCAGTGTCGGGATGGTTAAGGAAGTTGTGCGTACAGACAGTC TGAAAGGGAGGAGAGGTCGTCTGCCTTCCAAACCAAAGAGCCCACTACAACAGGAGCC" CTCGCAGCCCTCCCCGCCATCTCCTCCGATCTGTATGATGAATGCCCTTGTCCGAGCT TTAACAGATGCAACACCCAGAGATCTTGATTATTCCAGAGTAAGTTCTATGAATGCTT TTGAACCATTATGA
(SEQ IDNO: 86)
NR52
Human polypeptide sequence:
MSSNSDTGDLQESLKHGLTPIGAGLPDRHGSPIPARGRLVMLPKVETEALGLARSHGE QGQMPENMQVSQFKMVNYSYDEDLEELCPVCGDKVSGYHYGLLTCESCKGFFKRTVQN NKRYTCIENQNCQIDKTQRKRCPYCRFQKCLSVGMKLEAVRADRMRGGRNKFGPMYKR DRALKQQKKALIRANGLKLEAMSQVIQAMPSDLTISSAIQNIHSASKGLPLNHAALPP TDYDRSPFVTSPISMTMPPHGSLQGYQTYGHFPSRAIKSEYPDPYTSSPESIMGYSYM DSYQTSSPASIPHLILELLKCEPDEPQVQAKIMAYLQQEQANRSKHEKLSTFGLMCKM ADQTLFSIVEWARSSIFFRELKVDDQMKLLQNC SELLILDHIYRQWHGKEGSIFLV TGQQVDYSIIASQAGATLNNLMSHAQELVAKLRSLQFDQREFVCLKFLVLFSLDVKNL ENFQLVEGVQEQVNAALLDYTMCNYPQQTEKFGQLLLRLPEIRAISMQAEEYLYYKHL NGDVPYNNLLIEMLHAKRA (SEQ ID NO: 87)
Human polynucleotide sequence: ATGTCTTCTAATTCAGATACTGGGGATTTACAAGAGTCTTTAAAGCACGGACTTACAC CTATTGTGTCTCAATTTAAAATGGTGAATTACTCCTATGATGAAGATCTGGAAGAGCT TTGTCCCGTGTGTGGAGATAAAGTGTCTGGGTACCATTATGGGCTCCTCACCTGTGAA AGCTGCAAGGGATTTTTTAAGCGAACAGTCCAAAATAATAAAAGGTACACATGTATAG AAAACCAGAACTGCCAAATTGACAAAACACAGAGAAAGCGTTGTCCTTACTGTCGTTT TCAAAAATGTCTAAGTGTTGGAATGAAGCTAGAAGCTGTAAGGGCCGACCGAATGCGT GGAGGAAGGAATAAGTTTGGGCCAATGTACAAGAGAGACAGGGCCCTGAAGCAACAGA AAAAAGCCCTCATCCGAGCCAATGGACTTAAGCTAGAAGCCATGTCTCAGGTGATCCA AGCTATGCCCTCTGACCTGACCATTTCCTCTGCAATTCAAAACATCCACTCTGCCTCC AAAGGCCTACCTCTGAACCATGCTGCCTTGCCTCCTACAGACTATGACAGAAGTCCCT TTGTAACATCCCCCATTAGCATGACAATGCCCCCTCACGGCAGCCTGCAAGGTTACCA AACATATGGCCACTTTCCTAGCCGGGCCATCAAGTCTGAGTACCCAGACCCCTATACC AGCTCACCCGAGTCCATAATGGGCTATTCATATATGGATAGTTACCAGACGAGCTCTC CAGCAAGCATCCCACATCTGATACTGGAACTTTTGAAGTGTGAGCCAGATGAGCCTCA AGTCCAGGCTAAAATCATGGCCTATTTGCAGCAAGAGCAGGCTAACCGAAGCAAGCAC GAAAAGCTGAGCACCTTTGGGCTTATGTGCAAAATGGCAGATCAAACTCTCTTCTCCA TTGTCGAGTGGGCCAGGAGTAGTATCTTCTTCAGAGAACTTAAGGTTGATGACCAAAT GAAGCTGCTTCAGAACTGCTGGAGTGAGCTCTTAATCCTCGACCACATTTACCGACAA GTGGTACATGGAAAGGAAGGATCCATCTTCCTGGTTACTGGGCAACAAGTGGACTATT CCATAATAGCATCACAAGCCGGAGCCACCCTCAACAACCTCATGAGTCATGCACAGGA GTTAGTGGCAAAACTTCGTTCTCTCCAGTTTGATCAACGAGAGTTCGTATGTCTGAAA TTCTTGGTGCTCTTTAGTTTAGATGTCAAAAACCTTGAAAACTTCCAGCTGGTAGAAG GTGTCCAGGAACAAGTCAATGCCGCCCTGCTGGACTACACAATGTGTAACTACCCGCA GCAGACAGAGAAATTTGGACAGCTACTTCTTCGACTACCCGAAATCCGGGCCATCAGT ATGCAGGCTGAAGAATACCTCTACTACAAGCACCTGAACGGGGATGTGCCCTATAATA ACCTTCTCATTGAAATGTTGCATGCCAAAAGAGCATAA (SEQ ID NO: 88)
Mouse polypeptide sequence: MSASLDTGDFQEFLKHGLTAIASAPGSETRHSPKREEQLREKRAGLPDRHRRPI ARS RLVMLPKVETEAPGLVRSHGEQGQMPENMQVSQFKMVNYSYDEDLEELCPVCGDKVSG YHYGLLTCESCKGFFKRTVQNQKRYTCIENQNCQIDKTQRKRCPYCRFKKCIDVGMKL EAVRADRMRGGRNKFGPMYKRDRALKQQKKALIRANGLKLEAMSQVIQAMPSDLTSAI QNIHSASKGLPLSHVALPPTDYDRSPFVTSPISMTMPPHSSLHGYQPYGHFPSRAIKS EYPDPYSSSPESMMGYSYMDGYQTNSPASIPHLILELLKCEPDEPQVQAKIMAYLQQE QSNRNRQEKLSAFGLLCKMADQTLFSIVE ARSSIFFRELKVDDQMKLLQNCWSELLI LDHIYRQVAHGKEGTIFLVTGEHVDYSTIISHTEVAFNNLLSLAQELWRLRSLQFDQ REFVCLKFLVLFSSDVKNLENLQLVEGVQEQVNAALLDYTVCNYPQQTEKFGQLLLRL PEIRAISKQAEDYLYYKHVNGDVPYNNLLIEMLHAKRA (SEQ IDNO: 89)
Mouse polynucleotide sequence:
ATGTCTGCTAGTTTGGATACTGGAGATTTTCAAGAATTTCTTAAGCATGGACTTACAG CTATTGCGTCTGCACCAGGGTCAGAGACTCGCCACTCCCCCAAACGTGAGGAACAACT CCGGGAAAAACGTGCTGGGCTTCCGGACCGACACCGACGCCCCATTCCCGCCCGCAGC CGCCTTGTCATGCTGCCCAAAGTGGAGACGGAAGCCCCAGGACTGGTCCGATCGCATG GGGAACAGGGGCAGATGCCAGAAAACATGCAAGTGTCTCAATTTAAAATGGTGAATTA CTCCTATGATGAAGATCTGGAAGAGCTATGTCCTGTGTGTGGCGATAAAGTGTCTGGG TACCATTACGGTCTCCTCACGTGCGAAAGCTGCAAGGGTTTTTTTAAGCGAACTGTCC AAAACCAAAAAAGGTACACGTGCATAGAGAACCAGAATTGCCAAATTGACAAAACGCA GAGAAAACGATGTCCCTACTGTCGATTCAAAAAATGTATCGATGTTGGGATGAAGCTG GAAGCCGTAAGAGCCGACCGCATGCGAGGGGGCAGAAATAAGTTTGGGCCAATGTACA AGAGAGACAGGGCTTTGAAqCAGCAGAAGAAAGCCCTCATTCGAGCCAATGGACTTAA GCTGGAAGCCATGTCTCAGGTGATCCAAGCAATGCCCTCAGACCTGACCTCTGCAATT CAGAACATTCATTCCGCCTCCAAAGGCCTACCTCTGAGCCATGTAGCCTTGCCTCCGA CAGACTATGACAGAAGTCCCTTTGTCACATCTCCCATTAGCATGACAATGCCACCTCA CAGCAGCCTGCATGGTTACCAACCCTATGGTCACTTTCCTAGTCGGGCCATCAAGTCT GAGTACCCAGACCCCTACTCCAGCTCACCTGAGTCAATGATGGGTTACTCCTACATGG ATGGTTACCAGACAAACTCCCCGGCCAGCATCCCACACCTGATACTGGAACTTTTGAA GTGTGAACCAGATGAGCCTCAAGTTCAAGCGAAGATCATGGCTTACCTCCAGCAAGAG CAGAGTAACCGAAACAGGCAAGAAAAGCTGAGCGCATTTGGGCTTTTATGCAAAATGG CGGACCAGACCCTGTTCTCCATTGTTGAGTGGGCCAGGAGTAGTATCTTCTTCAGGGA ACTGAAGGTTGATGACCAAATGAAGCTGCTTCAAAACTGCTGGAGTGAGCTCTTGATT CTCGATCACATTTACCGACAAGTGGCGCATGGGAAGGAAGGGACAATCTTCCTGGTTA CTGGAGAACACGTGGACTACTCCACCATCATCTCACACACAGAAGTCGCGTTCAACAA CCTCCTGAGTCTCGCACAGGAGCTGGTGGTGAGGCTCCGTTCCCTTCAGTTCGATCAG CGGGAGTTTGTATGTCTCAAGTTCCTGGTGCTGTTCAGCTCAGATGTGAAGAACCTGG AGAACCTGCAGCTGGTGGAAGGTGTCCAAGAGCAGGTGAATGCCGCCCTGCTGGACTA CACGGTTTGCAACTACCCACAACAGACTGAGAAATTCGGACAGCTACTTCTTCGGCTA CCCGAGATCCGGGCAATCAGCAAGCAGGCAGAAGACTACCTGTACTATAAGCACGTGA ACGGGGATGTGCCCTATAATAACCTCCTCATTGAGATGCTGCATGCCAAAAGAGCCTA A (SEQ ID NO: 90) NR61
Human polypeptide sequence:
MERDEPPPSGGGGGGGSAGFLEPPAALPPPPRNGFCQDELAELDPGTISVSDDRAEQR TCLICGDRATGLHYGIISCEGCKGFFKRSICNKRVYRCSRDKNCVMSRKQRNRCQYCR LLKCLQMGMNRKAIREDGMPGGRNKSIGPVQISEEEIERIMSGQEFEEEANHWSNHGD SDHSSPGNRASESNQPSPGSTLSSSRSVELNGFMAFREQYMGMSVPPHYQYIPHLFSY SGHSPLLPQQARSLDPQSYSLIHQLLSAEDLEPLGTPMLIEDGYAVTQAELFALLCRL ADELLFRQIAWIKKLPFFCELSIKDYTCLLSST QELILLSSLTVYSKQIFGELADVT AKYSPSDEELHRFSDEGMEVIERLIYLYHKFHQLKVSNEEYACMKAINFLNQDIRGLT SASQLEQLNKRY YICQDFTEYKYTHQPNRFPDLMMCLPEIRYIAGKMVNVPLEQLPL LFKWLHSCKTSVGKE (SEQ ID NO: 91) Human polynucleotide sequence:
ATGGAGCGGGACGAACCGCCGCCTAGCGGAGGGGGAGGCGGCGGGGGCTCGGCGGGGT TCCTGGAGCCTCCCGCCGCGCTCCCTCCGCCGCCGCGCAACGGTTTCTGTCAGGATGA ATTGGCAGAGCTTGACCCAGGCACTAATGATCGGGCTGAACAACGAACCTGTCTCATT TGTGGGGACCGCGCTACAGGCTTGCACTATGGGATCATCTCCTGTGAGGGCTGCAAAG GGTTTTTCAAGCGGAGCATTTGCAACAAACGGGTATATCGATGCAGTCGTGACAAGAA CTGTGTCATGTCTCGGAAGCAGAGGAACAGGTGCCAGTACTGCCGCCTGCTCAAATGC CTCCAGATGGGGATGAACCGGAAGGCTATCAGAGAAGATGGCATGCCTGGAGGCCGGA ATAAGAGCATTGGGCCAGTCCAGATATCGGAAGAAGAAATCGAAAGGATCATGTCTGG GCAGGAGTTTGAGGAAGAGGCCAATCACTGGAGCAACCATGGTGATAGTGACCACAGT TCCCCTGGGAACAGGGCTTCGGAGAGCAACCAGCCCTCACCAGGCTCCACACTGTCTT CCAGTAGGTCTGTGGAACTGAATGGATTCATGGCCTTCAGGGAACAGTACATGGGAAT GTCTGTGCCTCCACATTACCAATATATACCGCACCTTTTTAGCTATTCTGGCCACTCA CCACTTCTGCCCCAACAAGCTCGCAGCCTGGATCCCCAGTCATACAGTCTGATTCACC AGCTGTTATCAGCCGAGGACCTGGAACCATTGGGCACGCCCATGTTGATTGAAGATGG ATACGCTGTGACACAGGCAGAACTATTTGCCCTGCTTTGCCGCCTGGCCGACGAGCTG CTCTTTAGGCAGATTGCCTGGATCAAGAAACTGCCTTTCTTCTGCGAGCTCTCAATCA AGGATTACACGTGCCTCTTGAGCTCTACGTGGCAGGAGCTAATCCTGCTGTCTTCCCT CACCGTTTACAGCAAGCAGATCTTTGGGGAACTGGCTGATGTCACTGCCAAGTACTCG CCCTCCGATGAAGAACTACACAGATTTAGTGATGAAGGGATGGAGGTGATCGAGCGGC TCATCTACCTCTATCACAAGTTCCATCAGCTAAAGGTCAGCAACGAGGAGTATGCTTG CATGAAAGCAATTAACTTCCTAAATCAAGATATCAGGGGTCTGACCAGTGCCTCACAG CTGGAACAATTGAATAAACGATACTGGTACATTTGCCAGGATTTTACTGAATATAAAT ACACACATCAGCCGAACCGCTTTCCTGATCTCATGATGTGCTTACCTGAGATTCGATA TATTGCAGGAAAGATGGTGAATGTGCCCCTGGAGCAGCTGCCCCTCCTCTTTAAGGTG
GTGCTGCATTCCTGCAAGACCAGTGTGGGCAAGGAATGA
(SEQ IDNO: 92) Mouse polypeptide sequence:
MERDERPPSGGGGGGGSAGFLEPPAALPPPPRNGFCQDELAELDPGTNGETDSLTLGQ GHIPVSVPDDRAEQRTCLICGDRATGLHYGIISCEGCKGFFKRSICNKRVYRCSRDKN CVMSRKQRNRCQYCRLLKCLQMGMNRKAIREDGMPGGRNKSIGPVQISEEEIERIMSG QEFEEEANHWSNHGDSDHSSPGNRASESNQPSPGSTLSSSRSVELNGFMAFRDQYMGM SVPPHYQYIPHLFSYSGHSPLLPPQARSLDPQSYSLIHQLMSAEDLEPLGTPMLIEDG YAVTQAELFALLCRLADELLFRQIAWIKKLPFFCELSIKDYTCLLSST QELILLSSL TVYSKQIFGELADVTAKYSPSDEELHRFSDEGMEVIERLIYLYHKFHQLKVSNEEYAC MKAINFLNQDIRGLTSASQLEQLNKRYWYICQDFTEYKYTHQPNRFPDLMMCLPEIRY IAGKMVNVPLEQLPLLFKWLHSCKTSTVKE (SEQ IDNO: 93)
Mouse polynucleotide sequence: ATGGAGCGGGACGAACGGCCACCTAGCGGAGGGGGAGGCGGCGGGGGCTCGGCGGGGT TCCTGGAGCCGCCCGCCGCGCTCCCTCCGCCGCCGCGCAACGGTTTCTGTCAGGATGA ATTGGCAGAGCTTGATCCAGGCACTAATGGAGAGACTGACAGTTTAACACTTGGCCAA GGCCATATACCTGTTTCCGTCCCAGATGATCGAGCTGAACAACGAACCTGTCTCATCT GTGGGGACCGCGCTACGGGCTTGCACTATGGGATCATCTCCTGCGAGGGCTGCAAGGG GTTTTTCAAGAGGAGCATTTGCAACAAACGGGTGTATCGGTGCAGTCGTGACAAGAAC TGTGTCATGTCCCGGAAGCAGAGGAACAGATGTCAGTACTGCCGCCTGCTCAAGTGTC TCCAGATGGGCATGAACAGGAAGGCTATCAGAGAAGATGGCATGCCTGGAGGCCGGAA CAAGAGCATTGGACCAGTCCAGATATCAGAAGAAGAAATTGAAAGAATCATGTCTGGA CAGGAGTTTGAGGAAGAAGCCAATCACTGGAGCAACCATGGTGACAGCGACCACAGTT CCCCTGGGAACAGGGCTTCAGAGAGCAACCAGCCCTCACCAGGCTCCACACTATCATC CAGTAGGTCTGTGGAACTAAATGGATTCATGGCATTCAGGGATCAGTACATGGGGATG TCAGTGCCTCCACATTATCAATACATACCACACCTTTTTAGCTATTCTGGCCACTCAC CACTTTTGCCCCCACAAGCTCGAAGCCTGGACCCTCAGTCCTACAGTCTGATTCATCA GCTGATGTCAGCCGAAGACCTGGAGCCATTGGGCACACCTATGTTGATTGAAGATGGG TATGCTGTGACACAGGCAGAACTGTTTGCTCTGCTTTGCCGCCTGGCCGACGAGTTGC TCTTTAGGCAGATTGCCTGGATCAAGAAGCTGCCTTTCTTCTGCGAGCTCTCAATCAA GGATTACACGTGCCTCTTGAGCTCTACGTGGCAGGAGTTAATCCTGCTCTCCTCCCTC ACAGTGTACAGCAAGCAGATCTTTGGGGAGCTGGCTGATGTCACAGCCAAGTACTCAC CCTCTGATGAAGAACTCCACAGATTTAGTGATGAAGGGATGGAGGTGATTGAACGACT CATCTACCTATATCACAAGTTCCATCAGCTGAAGGTCAGCAACGAGGAGTACGCATGC ATGAAAGCAATTAACTTCCTGAATCAAGATATCAGGGGTCTGACCAGTGCCTCACAGC TGGAACAACTGAACAAGCGGTATTGGTACATTTGTCAGGATTTCACTGAATATAAATA CACACATCAGCCAAACCGCTTTCCTGATCTTATGATGTGCTTGCCAGAGATCCGATAC ATCGCAGGCAAGATGGTGAATGTGCCCCTGGAGCAGCTGCCCCTCCTCTTTAAGGTGG TGCTGCACTCCTGCAAGACAAGTACGGTGAAGGAGTGA (SEQ IDNO: 94) NRD1
Human polypeptide sequence:
MTTLDSNNNTGGVITYIGSSGSSPSRTSPESLYSDNSNGSFQSLTQGCPTYFPPSPTG SLTQDPARSFGSIPPSLSDDGSPSSSSSSSSSSSSFYNGSPPGSLQVAMEDSSRVSPS KSTSNITKLNGMVLLCKVCGDVASGFHYGVHACEGCKGFFRRSIQQNIQYKRCLKNEN CSIVRINRNRCQQCRFKKCLSVGMSRDAVRFGRIPKREKQRMLAEMQSAMNLANNQLS SQCPLETSPTQHPTPGPMGPSPPPAPVPSPLVGFSQFPQQLTPPRSPSPEPTVEDVIS QVARAHREIFTYAHDKLGSSPGNFNANHASGSPPATTPHRWENQGCPPAPNDNNTLAA QRHNEALNGLRQAPSSYPPT PPGPAHHSCHQSNSNGHRLCPTHVYAAPEGKAPANSP RQGNSKNVLLACPMNMYPHGRSGRTVQEIWEDFSMSFTPAVREWEFAKHIPGFRDLS QHDQVTLLKAGTFEVLMVRFASLFNVKDQTVMFLSRTTYSLQELGAMGMGDLLSAMFD FSEKLNSLALTEEELGLFTAWLVSADRSGMENSASVEQLQETLLRALRALVLKNRPL ETSRFTKLLLKLPDLRTLNNMHSEKLLSFRVDAQ
(SEQ ID NO: 95)
Human polynucleotide sequence:
ATGACGACCCTGGACTCCAACAACAACACAGGTGGCGTCATCACCTACATTGGCTCCA GTGGCTCCTCCCCAAGCCGCACCAGCCCTGAATCCCTCTATAGTGACAACTCCAATGG CAGCTTCCAGTCCCTGACCCAAGGCTGTCCCACCTACTTCCCACCATCCCCCACTGGC TCCCTCACCCAAGACCCGGCTCGCTCCTTTGGGAGCATTCCACCCAGCCTGAGTGATG ACGGCTCCCCTTCTTCCTCATCTTCCTCGTCGTCATCCTCCTCCTCCTTCTATAATGG GAGCCCCCCTGGGAGTCTACAAGTGGCCATGGAGGACAGCAGCCGAGTGTCCCCCAGC AAGAGCACCAGCAACATCACCAAGCTGAATGGCATGGTGTTACTGTGTAAAGTGTGTG GGGACGTTGCCTCGGGCTTCCACTACGGTGTGCACGCCTGCGAGGGCTGCAAGGGCTT TTTCCGTCGGAGCATCCAGCAGAACATCCAGTACAAAAGGTGTCTGAAGAATGAGAAT TGCTCCATCGTCCGCATCAATCGCAACCGCTGCCAGCAATGTCGCTTCAAGAAGTGTC TCTCTGTGGGCATGTCTCGAGACGCTGTGCGTTTTGGGCGCATCCCCAAACGAGAGAA GCAGCGGATGCTTGCTGAGATGCAGAGTGCCATGAACCTGGCCAACAACCAGTTGAGC AGCCAGTGCCCGCTGGAGACTTCACCCACCCAGCACCCCACCCCAGGCCCCATGGGCC CCTCGCCACCCCCTGCTCCGGTCCCCTCACCCCTGGTGGGCTTCTCCCAGTTTCCACA ACAGCTGACGCCTCCCAGATCCCCAAGCCCTGAGCCCACAGTGGAGGATGTGATATCC CAGGTGGCCCGGGCCCATCGAGAGATCTTCACCTACGCCCATGACAAGCTGGGCAGCT CACCTGGCAACTTCAATGCCAACCATGCATCAGGTAGCCCTCCAGCCACCACCCCACA TCGCTGGGAAAATCAGGGCTGCCCACCTGCCCCCAATGACAACAACACCTTGGCTGCC CAGCGTCATAACGAGGCCCTAAATGGTCTGCGCCAGGCTCCCTCCTCCTACCCTCCCA • CCTGGCCTCCTGGCCCTGCACACCACAGCTGCCACCAGTCCAACAGCAACGGGCACCG TCTATGCCCCACCCACGTGTATGCAGCCCCAGAAGGCAAGGCACCTGCCAACAGTCCC CGGCAGGGCAACTCAAAGAATGTTCTGCTGGCATGTCCTATGAACATGTACCCGCATG GACGCAGTGGGCGAACGGTGCAGGAGATCTGGGAGGATTTCTCCATGAGCTTCACGCC CGCTGTGCGGGAGGTGGTAGAGTTTGCCAAACACATCCCGGGCTTCCGTGACCTTTCT CAGCATGACCAAGTCACCCTGCTTAAGGCTGGCACCTTTGAGGTGCTGATGGTGCGCT TTGCTTCGTTGTTCAACGTGAAGGACCAGACAGTGATGTTCCTAAGCCGCACCACCTA CAGCCTGCAGGAGCTTGGTGCCATGGGCATGGGAGACCTGCTCAGTGCCATGTTCGAC TTCAGCGAGAAGCTCAACTCCCTGGCGCTTACCGAGGAGGAGCTGGGCCTCTTCACCG CGGTGGTGCTTGTCTCTGCAGACCGCTCGGGCATGGAGAATTCCGCTTCGGTGGAGCA GCTCCAGGAGACGCTGCTGCGGGCTCTTCGGGCTCTGGTGCTGAAGAACCGGCCCTTG GAGACTTCCCGCTTCACCAAGCTGCTGCTCAAGCTGCCGGACCTGCGGACCCTGAACA ACATGCATTCCGAGAAGCTGCTGTCCTTCCGGGTGGACGCCCAGTGA (SEQ ID NO: 96) Mouse. polypeptide sequence:
MTTLDSNNNTXXGVITYIGSSGSSPSRTSPESLYSDSSNGSFQSLTQGCPTYFPPSPT GSLTQDPARSFGSAPPSLSDDSSPSSASSSSSSSSSSFYNGSPPGSLQVAMEDSSRVS PSKGTSNITKLNGMVLLCKVCGDVASGFHYGVHACEGCKGFFRRSIQQNIQYKRCLKN ENCSIVRINRNRCQQCRFKKCLSVGMSRDAVRFGRIPKREKQRMLAEMQSAMNLANNQ LSSLCPLETSPTPHPTSGSMGPSPPPAPAPTPLVGFSQFPQQLTPPRSPSPEPTMEDV ISQVARAHREIFTYAHDKLGTSPGNFNANHASGSPSATTPHR ESQGCPSAPNDNNLL AAQRHNEALNGLRQGPSSYPPTWPSGPTHHSCHQPNSNGHRLCPTHVYSAPEGEAPAN SLRQGNTKNVLLACPMNMYPHGRSGRTVQEI EDFSMSFTPAVREWEFAKHIPGFRD LSQHDQVTLLKAGTFEVLMVRFASLFNVKDQTVMFLSRTTYSLQELGAMGMGDLLNAM FDFSEKLNSLALTEEELGLFTAWLVSADRSGMENSASVEQLQETLLRALRALVLKNR PSETSRFTKLLLKLPDLRTLNNMHSEKLLSFRVDAQ (SEQ ID NO: 97)
Mouse polynucleotide sequence: ' '
GGCGAGAGAGGCCATCACAACCTCCAGTTTGTGTCAAGGTCCAGTTTGAATGACCGCT TTCAGCTGGTGAAGACATGACGACCCTGGACTCCAATAACAACACAGGTGGTGTTATC ACCTACATTGGCTCTAGTGGCTCCTCCCCGAGCCGGACCAGCCCGGAGTCCCTCTACA GTGACAGCTCCAATGGCAGCTTCCAGTCCCTGACTCAAGGTTGTCCCACATACTTCCC ACCATCACCTACTGGCTCCCTCACCCAGGACCCTGCCCGCTCTTTTGGCAGTGCGCCA CCCAGTCTCAGTGATGATAGCTCCCCTTCTTCTGCATCATCGTCATCCTCTTCATCCT CCTCCTCCTTCTATAACGGGAGCCCCCCAGGAAGTCTACAAGTGGCCATGGAAGACAG CAGCCGAGTGTCCCCCAGCAAGGGCACAAGCAACATTACCAAGCTGAATGGCATGGTG CTACTGTGTAAGGTGTGTGGGGACGTGGCCTCAGGCTTCCACTATGGAGTGCACGCCT GTGAGGGCTGCAAGGGCTTTTTTCGCCGGAGCATCCAACAGAATATCCAGTACAAACG GTGTCTGAAAAACGAAAACTGCTCCATCGTTCGCATCAATCGCAACCGCTGCCAGCAG TGTCGCTTCAAGAAGTGTCTCTCCGTTGGCATGTCTAGAGATGCTGTGCGTTTTGGGC GCATCCCCAAGAGAGAGAAGCAACGGATGCTTGCCGAGATGCAGAGCGCCATGAACTT GGCCAACAACCAACTGAGCAGCCTGTGCCCTCTAGAGACCTCACCTACTCCACATCCC ACCTCTGGCTCCATGGGCCCCTCACCTCCTCCTGCACCAGCCCCCACACCTTTGGTGG GCTTCTCTCAGTTCCCACAACAGCTGACACCACCCAGGTCTCCCAGCCCTGAGCCCAC CATGGAGGATGTGATATCCCAGGTCGCCCGGGCCCATCGAGAAATCTTCACCTATGCC CATGACAAGTTAGGCACCTCACCTGGTAACTTCAATGCCAATCATGCATCAGGTAGCC CTTCAGCTACAACTCCACACCGCTGGGAGAGTCAGGGATGCCCGTCTGCCCCCAACGA CAACAACCTTTTGGCGGCTCAGCGTCATAATGAAGCGCTGAATGGTCTACGCCAGGGC CCTTCCTCCTACCCGCCTACCTGGCCTTCTGGCCCCACCCACCACAGCTGCCACCAAC CTAACAGCAATGGGCACCGTCTGTGCCCCACCCACGTATATTCGGCCCCAGAAGGGGA GGCACCTGCCAACAGTCTACGGCAAGGCAACACCAAGAATGTTCTGCTGGCATGTCCC ATGAACATGTATCCCCATGGACGCAGCGGCCGGACTGTGCAGGAGATCTGGGAAGACT TCTCTATGAGCTTCACGCCTGCCGTTCGGGAGGTGGTAGAGTTTGCCAAACACATCCC AGGCTTCCGTGACCTTTCTCAGCACGACCAGGTGACCCTGCTTAAGGCTGGCACCTTT GAGGTGCTGATGGTGCGCTTTGCATCGTTGTTCAACGTGAAGGACCAGACAGTGATGT TCCTGAGCCGCACAACCTACAGTCTGCAGGAGCTCGGTGCCATGGGCATGGGCGACCT GCTCAATGCCATGTTTGACTTCAGCGAGAAGCTCAACTCCCTGGCACTTACCGAGGAG GAGCTGGGCCTATTCACCGCGGTGGTGCTTGTCTCTGCAGACCGCTCGGGAATGGAGA ATTCCGCTTCGGTGGAGCAGCTCCAGGAGACGCTGCTGCGGGCTCTTCGGGCTCTGGT GCTGAAGAACCGGCCCTCGGAGACTTCCCGCTTCACCAAGCTGCTGCTCAAGCTGCCG GACCTGCGGACCCTGAACAACATGCATTCCGAGAAGCTGCTGTCCTTCCGGGTGGACG CCCAGTGACCCGCCCGGCCGGCCTTCTGCCGCTGCCCCCTTGTACAGAATCGAACTCT GCACTTCTCTCTCCTTTACGAGACGAAAAGGAAAAGCAAACCAGAATCTTATTTATAT TGTTATAAAATATTCCAAGATGAGCCTCTGGCCCCCTGAGCCTTCTTGTAAATAACTC TTCCCCCACCCCCACCGCCATGCTCCCATCCTCCCCTATTTAAACCACTCTTGCTCTC TCCACCCTCCTCTGGCCCCTCGATTTGTTCTGTTCCTGTCTCAAATCCAATAGTTCAC AGCTGA (SEQ ID NO: 98)
NRD2
Human polypeptide sequence:
MEVNAGGVIAYISSSSSASSPASCHSEGSENSFQSSSSSVPSSPNSSNSDTNGNPKNG DLANIEGILKNDRIDCSMKTSKSSAPGMTKSHSGVTKFSGMVLLCKVCGDVASGFHYG VHACEGCKGFFRRSIQQNIQYKKCLKNENCSIMRMNRNRCQQCRFKKCLSVGMSRDAV RFGRIPKREKQRMLIEMQSAMKTMMNSQFSGHLQNDTLVEHHEQTALPAQEQLRPKPQ LEQENIKSSSPPSSDFAKEEVIGMVTRAHKDTFMYNQEQQENSAESMQPQRGERIPKN MEQYNLNHDHCGNGLSSHFPCSESQQHLNGQFKGRNIMHYPNGHAICIANGHCMNFSN AYTQRVCDRVPIDGFSQNENKNSYLCNTGGRMHLVCPMSKSPYVDPHKSGHEI EEFS MSFTPAVKEWEFAKRIPGFRDLSQHDQVNLLKAGTFEVLMVRFASLFDAKERTVTFL SGKKYSVDDLHSMGAGDLLNSMFEFSEKLNALQLSDEEMSLFTAWLVSADRSGIENV NSVEALQETLIRALRTLIMKNHPNEASIFTKLLLKLPDLRSLNNMHSEELLAFKVHP (SEQ ID NO: 99)
Human polynucleotide sequence:
GGAGGTGAATGCAGGAGGTGTGATTGCCTATATCAGTTCTTCCAGCTCAGCCTCAAGC CCTGCCTCTTGTCACAGTGAGGGTTCTGAGAATAGTTTCCAGTCCTCCTCCTCTTCTG TTCCATCTTCTCCAAATAGCTCTAATTCTGATACCAATGGTAATCCCAAGAATGGTGA TCTCGCCAATATTGAAGGCATCTTGAAGAATGATCGAATAGATTGTTCTATGAAAACA AGCAAATCGAGTGCACCTGGGATGACAAAAAGTCATAGTGGTGTGACAAAATTTAGTG GCATGGTTCTACTGTGTAAAGTCTGTGGGGATGTGGCGTCAGGATTCCACTATGGAGT TCATGCTTGCGAAGGCTGTAAGGGTTTCTTTCGGAGAAGTATTCAACAAAACATCCAG TACAAGAAGTGCCTGAAGAATGAAAACTGTTCTATAATGAGAATGAATAGGAACAGAT GTCAGCAATGTCGCTTCAAAAAGTGCCTGTCTGTTGGAATGTCAAGAGATGCTGTTCG GTTTGGTCGTATTCCTAAGCGTGAAAAACAGAGGATGCTAATTGAAATGCAAAGTGCA ATGAAGACCATGATGAACAGCCAGTTCAGTGGTCACTTGCAAAATGACACATTAGTAG AACATCATGAACAGACAGCCTTGCCAGCCCAGGAACAGCTGCGACCCAAGCCCCAACT GGAGCAAGAAAACATCAAAAGCTCTTCTCCTCCATCTTCTGATTTTGCAAAGGAAGAA GTGATTGGCATGGTGACCAGAGCTCACAAGGATACCTTTATGTATAATCAAGAGCAGC AAGAAAACTCAGCTGAGAGCATGCAGCCCCAGAGAGGAGAACGGATTCCCAAGAACAT GGAGCAATATAATTTAAATCATGATCATTGCGGCAATGGGCTTAGCAGCCATTTTCCC TGTAGTGAGAGCCAGCAGCATCTCAATGGACAGTTCAAAGGGAGGAATATAATGCATT ACCCAAATGGTCATGCCATTTGTATTGCAAATGGACATTGTATGAACTTCTCCAATGC TTATACTCAAAGAGTATGTGATAGAGTTCCGATAGATGGATTTTCTCAGAATGAGAAC AAGAATAGTTACCTGTGCAACACTGGAGGAAGAATGCATCTGGTTTGTCCAATGAGTA AGTCTCCATATGTGGATCCTCATAAATCAGGACATGAAATCTGGGAAGAATTTTCGAT GAGCTTCACTCCAGCAGTGAAAGAAGTGGTGGAATTTGCAAAGCGTATTCCTGGGTTC AGAGATCTCTCTCAGCATGACCAGGTCAACCTTTTAAAGGCTGGGACTTTTGAGGTTT TAATGGTACGGTTCGCATCATTATTTGATGCAAAGGAACGAACTGTCACCTTTTTAAG TGGAAAGAAATATAGTGTGGATGATTTACACTCAATGGGAGCAGGGGATCTGCTAAAC TCTATGTTTGAATTTAGTGAGAAGCTAAATGCCCTCCAACTTAGTGATGAAGAGATGA GTTTGTTTACAGCTGTTGTCCTGGTATCTGCAGATCGATCTGGAAATAGAAAAAACGT CAACTCTGTGGAGGCTTTGCAGGAAACTCTCATTCGTGCACTAAGGACCTTAATAATG AAAAACCATCCAAATGAGGCCTCTATTTTTACAAAACTGCTTCTAAAGTTGCCAGATC TTCGATCTTTAAACAACATGCACTCTGAGGAGCTCTTGGCCTTTAAAGTTCACCCTTA A (SEQ IDNO: 100)
Mouse polypeptide sequence:
MELNAGGVIAYISSSSSASSPASCHSEGSENSFQSSSSSVPSSPNSSNCDANGNPKNA DISSIDGVLKSDRTDCPVKTGKTSAPGMTKSHSGMTKFSGMVLLCKVCGDVASGFHYG VHACEGCKGFFRRSIQQNIQYKKCLKNENCSIMRMNRNRCQQCRFKKCLSVGMSRDAV RFGRIPKREKQRMLIEMQSAMKTMMNTQFSGHLQNDTLAEQHDQSALPAQEQLRPKSQ LEQENIKNTPSDFAKEEVIGMVTRAHKDTFLYNQEHRENSSESMPPQRGERIPRNMEQ YNLNQDHRGSGIHNHFPCSERQQHLSGQYKGRNIMHYPNGHAVCIANGHCMNFSSAYT QRVCDRIPVGGCSQTENRNSYLCNTGGRMHLVCPMSKSPYVDPQKSGHEIWEEFSMSF TPAVKEWEFAKRIPGFRDLSQHDQVNLLKAGTFEVLMVRFASLFDAKERTVTFLSGK KYSVDDLHSMGAGDLLSSMFEFSEKLNALQLSDEEMSLFTAWLVSADRSGIENVNSV EALQETLIRALRTLIMKNHPNEASIFTKLLLKLPDLRSLNNMHSEELLAFKVHP (SEQ IDNO: 101) Mouse polynucleotide sequence:
ATGGAGCTGAACGCAGGAGGTGTGATTGCCTACATCAGTTCCTCTAGCTCTGCCTCCA GCCCTGCCTCTTGTCACAGTGAGGGTTCTGAGAATAGCTTCCAGTCCTCGTCCTCGTC TGTTCCATCTTCTCCAAATAGCTCTAACTGTGATGCCAACGGCAATCCCAAGAACGCT GATATCTCTAGCATCGATGGTGTTCTGAAGAGTGACCGCACAGATTGTCCTGTGAAAA CAGGCAAAACCAGTGCTCCTGGCATGACTAAGAGTCACAGTGGAATGACAAAATTTAG TGGCATGGTTCTACTGTGTAAAGTCTGTGGGGATGTGGCATCAGGATTCCACTATGGA GTTCATGCTTGTGAAGGCTGTAAGGGTTTCTTTCGGAGGAGCATTCAGCAAAACATCC AGTATAAGAAGTGCCTGAAGAATGAGAACTGTTCCATCATGAGGATGAACAGGAACCG GTGCCAGCAGTGCCGCTTTAAGAAGTGTCTGTCTGTGGGGATGTCACGAGATGCTGTT CGATTTGGCCGAATTCCTAAGCGTGAAAAACAGAGAATGCTAATTGAAATGCAAAGTG CAATGAAGACCATGATGAACACCCAGTTCAGTGGCCACCTGCAGAATGACACCTTAGC AGAACAGCATGATCAGTCAGCACTACCAGCTCAGGAACAGCTGCGGCCCAAGTCCCAG CTGGAGCAAGAAAACATCAAAAACACTCCTTCTGATTTTGCAAAGGAGGAAGTGATTG GTATGGTGACCAGAGCCCACAΆGGATACCTTTCTGTATAΆTCAGGAACATCGAGAAAA CTCATCTGAGAGCATGCCACCTCAGAGAGGAGAACGGATTCCCAGGAACATGGAGCAA TATAATTTAAATCAAGACCATCGTGGCAGTGGGATTCACAΆCCACTTCCCCTGTAGTG AGAGGCAGCAACATCTCAGTGGACAGTACAAAGGGAGGAACATAATGCATTACCCAAA CGGCCATGCCGTTTGTATTGCAAATGGACACTGTATGAACTTCTCCAGTGCTTATACT CAAAGAGTCTGTGATAGAΆTTCCAGTAGGTGGATGTTCTCAGACTGAGAΆCAGAAATA GTTACCTGTGCAACACTGGAGGGAGGATGCATCTGGTGTGTCCTATGAGCAAGTCTCC ATATGTGGACCCTCAGAAGTCTGGACATGAAATCTGGGAAGAATTTTCAATGAGTTTT ACCCCAGCAGTAAAAGAGGTGGTGGAATTTGCAAAGAGGATTCCTGGCTTCCGAGATC TGTCTCAGCATGATCAGGTCAATCTGTTAAAAGCTGGGACTTTTGAGGTTTTAATGGT ACGATTTGCTTCATTATTTGATGCAAAGGAACGGACTGTCACCTTTCTAAGTGGTAAG AAGTACAGTGTGGATGACCTGCACTCAATGGGAGCAGGGGATCTGCTCAGCTCTATGT TTGAGTTCAGTGAGAAGCTGAATGCCCTCCAGCTCAGTGATGAGGAAATGAGCTTGTT CACAGCAGTTGTTCTGGTATCTGCAGATCGATCTGGAATTGAAAATGTCAACTCAGTG GAGGCTTTGCAGGAAACACTCATCCGTGCACTAAGGACCTTAATAATGAAAAACCATC CAAATGAGGCCTCCATTTTTACAAAATTACTTCTAAAGTTGCCAGATCTTCGATCTTT AAACAACATGCACTCTGAGGAACTCTTGGCCTTTAAAGTTCATCCTTAA (SEQ ID NO: 102) NRH2
Human polypeptide sequence:
MSSPTTSSLDTPLPGNGPPQPGAPSSSPTVKEEGPEPWPGGPDPDVPGTDEASSACST DWVIPDPEEEPERKRKKGPAPKMLGHELCRVCGDKASGFHYNVLSCEGCKGFFRRSW RGGARRYACRGGGTCQMDAFMRRKCQQCRLRKCKEAGMREQCVLSEEQIRKKKIRKQQ QQESQSQSQSPVGPQGSSSSASGPGASPGGSEAGSQGSGEGEGVQLTAAQELMIQQLV AAQLQCNKRSFSDQPKVTPWPLGADPQSRDARQQRFAHFTELAIISVQEIVDFAKQVP GFLQLGREDQIALLKASTIEIMLLETARRYNHETECITFLKDFTYSKDDFHRAGLQVE FINPIFEFSRAMRRLGLDDAEYALLIAINIFSADRPNVQEPGRVEALQQPYVEALLSY TRIKRPQDQLRFPRMLMKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEI DVHE (SEQ IDNO: 103)
Human polynucleotide sequence:
ATGTCCTCTCCTACCACGAGTTCCCTGGATACCCCCCTGCCTGGAAATGGCCCCCCTC AGCCTGGCGCCCCTTCTTCTTCACCCACTGTAAAGGAGGAGGGTCCGGAGCCGTGGCC CGGGGGTCCGGACCCTGATGTCCCAGGCACTGATGAGGCCAGCTCAGCCTGCAGCACA GACTGGGTCATCCCAGATCCCGAAGAGGAACCAGAGCGCAAGCGAAAGAAGGGCCCAG CCCCGAAGATGCTGGGCCACGAGCTTTGCCGTGTCTGTGGGGACAAGGCCTCCGGCTT CCACTACAACGTGCTCAGCTGCGAAGGCTGCAAGGGCTTCTTCCGGCGCAGTGTGGTC CGTGGTGGGGCCAGGCGCTATGCCTGCCGGGGTGGCGGAACCTGCCAGATGGACGCTT TCATGCGGCGCAAGTGCCAGCAGTGCCGGCTGCGCAAGTGCAAGGAGGCAGGGATGAG GGAGCAGTGCGTCCTTTCTGAAGAACAGATCCGGAAGAAGAAGATTCGGAAACAGCAG CAGCAGGAGTCACAGTCACAGTCGCAGTCACCTGTGGGGCCGCAGGGCAGCAGCAGCT CAGCCTCTGGGCCTGGGGCTTCCCCTGGTGGATCTGAGGCAGGCAGCCAGGGCTCCGG GGAAGGCGAGGGTGTCCAGCTAACAGCGGCTCAAGAACTAATGATCCAGCAGTTGGTG GCGGCCCAACTGCAGTGCAACAAACGCTCCTTCTCCGACCAGCCCAAAGTCACGCCCT GGCCCCTGGGCGCAGACCCCCAGTCCCGAGATGCCCGCCAGCAACGCTTTGCCCACTT CACGGAGCTGGCCATCATCTCAGTCCAGGAGATCGTGGACTTCGCTAAGCAAGTGCCT GGTTTCCTGCAGCTGGGCCGGGAGGACCAGATCGCCCTCCTGAAGGCATCCACTATCG AGATCATGCTGCTAGAGACAGCCAGGCGCTACAACCACGAGACAGAGTGTATCACCTT CTTGAAGGACTTCACCTACAGCAAGGACGACTTCCACCGTGCAGGCCTGCAGGTGGAG TTCATCAACCCCATCTTCGAGTTCTCGCGGGCCATGCGGCGGCTGGGCCTGGACGACG CTGAGTACGCCCTGCTCATCGCCATCAACATCTTCTCGGCCGACCGGCCCAACGTGCA GGAGCCGGGCCGCGTGGAGGCGTTGCAGCAGCCCTACGTGGAGGCGCTGCTGTCCTAC ACGCGCATCAAGAGGCCGCAGGACCAGCTGCGCTTCCCGCGCATGCTCATGAAGCTGG TGAGCCTGCGCACGCTGAGCTCTGTGCACTCGGAGCAGGTCTTCGCCTTGCGGCTCCA GGACAAGAAGCTGCCGCCTCTGCTGTCGGAGATCTGGGACGTCCACGAGTGA (SEQ ID NO: 104)
Mouse polypeptide sequence:
MSSPTSSLDTPVPGNGSPQPSTSATSPTIKEEGQETDPPPGSEGSSSAYIWILEPED EPERKRKKGPAPKMLGHELCRVCGDKASGFHYNVLSCEGCKGFFRRSWHGGAGRYAC RGSGTCQMDAFMRRKCQLCRLRKCKEAGMREQCVLSEEQIRKKRIQKQQQQQPPPPSE PAASSSGRPAASPGTSEASSQGSGEGEGIQLTAAQELMIQQLVAAQLQCNKRSFSDQP KVTPWPLGADPQSRDARQQRFAHFTELAIISVQEIVDFAKQVPGFLQLGREDQIALLK ASTIEIMLLETARRYNHETECITFLKDFTYSKDDFHRAGLQVEFINPIFEFSRAMRRL GLDDAEYALLIAINIFSADRPNVQEPSRVEALQQPYVEALLSYTRIKRPQDQLRFPRM LMKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEIWDVHE (SEQ ID NO: 105)
Mouse polynucleotide sequence: ATGTCTTCCCCCACAAGTTCTCTGGACACTCCCGTGCCTGGGAATGGTTCTCCTCAGC CCAGTACCTCCGCCACGTCACCCACTATTAAGGAAGAGGGGCAGGAGACTGATCCTCC TCCAGGCTCTGAAGGGTCCAGCTCTGCCTACATCGTGGTCATCTTAGAGCCAGAGGAT GAGCCTGAGCGCAAGCGGAAGAAGGGGCCGGCCCCGAAGATGCTGGGCCATGAGCTGT GCCGCGTGTGCGGAGACAAGGCCTCGGGCTTCCACTACAACGTGCTCAGCTGTGAAGG CTGCAAAGGCTTCTTCCGGCGCAGTGTGGTCCACGGTGGGGCCGGGCGCTATGCCTGT CGGGGCAGCGGAACCTGCCAGATGGATGCCTTCATGCGGCGCAAGTGCCAGCTCTGCC GGCTGCGCAAGTGCAAGGAGGCTGGCATGCGGGAGCAGTGCGTGCTCTCTGAGGAGCA GATTCGGAAGAAAAGGATTCAGAAGCAGCAACAGCAGCAGCCACCACCCCCATCTGAG CCAGCAGCCAGCAGCTCAGGCCGGCCAGCGGCCTCCCCTGGCACTTCGGAAGCAAGCA GCCAGGGCTCCGGGGAAGGAGAGGGCATCCAGCTGACCGCGGCTCAGGAGCTGATGAT CCAGCAGTTAGTTGCCGCGCAGCTGCAGTGCAACAAACGATCTTTCTCCGACCAGCCC AAAGTCACGCCCTGGCCCCTGGGTGCAGACCCTCAGTCCCGAGATGCCCGTCAGCAAC GCTTTGCCCACTTCACCGAGCTAGCCATCATCTCGGTCCAGGAGATTGTGGACTTTGC CAAGCAGGTGCCAGGGTTCTTGCAGTTGGGCCGGGAGGACCAGATCGCCCTCCTGAAG GCGTCCACCATTGAGATCATGTTGCTAGAAACAGCCAGACGCTACAACCACGAGACAG AATGCATCACGTTCCTGAAGGACTTCACCTACAGCAAGGACGACTTCCACCGTGCAGG CTTGCAGGTGGAATTCATCAATCCCATCTTCGAGTTCTCGCGGGCCATGCGGCGGCTG GGCCTGGACGATGCAGAGTATGCCTTGCTTATCGCCATCAACATCTTCTCAGCCGATC GGCCTAATGTGCAGGAGCCCAGCCGTGTGGAGGCCCTGCAGCAGCCATACGTGGAGGC GCTCCTCTCCTACACGAGGATCAAGCGCCCACAGGACCAGCTCCGCTTCCCACGCATG CTCATGAAGCTGGTGAGCCTGCGCACCCTCAGCTCCGTGCACTCGGAGCAGGTCTTTG CATTGCGACTCCAGGACAAGAAGCTGCCGCCCTTGCTGTCCGAGATCTGGGATGTGCA
CGAGTAG
(SEQ ID NO: 106) NRH3
Human polypeptide sequence:
MSLWLGAPVPDIPPDSAVELWKPGAQDASSQAQGGSSCILREEARMPHSAGGTAGVGL EAAEPTALLTRAEPPSEPTEIRPQKRKKGPAPKMLGNELCSVCGDKASGFHYNVLSCE GCKGFFRRSVIKGAHYICHSGGHCPMDTYMRRKCQECRLRKCRQAGMREECVLSEEQI RLKKLKRQEEEQAHATSLPPRRSSPPQILPQLSPEQLGMIEKLVAAQQQCNRRSFSDR LRVTPWPMAPDPHSREARQQRFAHFTELAIVSVQEIVDFAKQLPGFLQLSREDQIALL KTSAIEVMLLETSRRYNPGSESITFLKDFSYNREDFAKAGLQVEFINPIFEFSRAMNE LQLNDAEFALLIAISIFSADRPNVQDQLQVERLQHTYVEALHAYVSIHHPHDRLMFPR MLMKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEIWDVHE (SEQ IDNO: 107)
Human polynucleotide sequence:
ATGTCCTTGTGGCTGGGGGCCCCTGTGCCTGACATTCCTCCTGACTCTGCGGTGGAGC TGTGGAAGCCAGGCGCACAGGATGCAAGCAGCCAGGCCCAGGGAGGCAGCAGCTGCAT CCTCAGAGAGGAAGCCAGGATGCCCCACTCTGCTGGGGGTACTGCAGGGGTGGGGCTG GAGGCTGCAGAGCCCACAGCCCTGCTCACCAGGGCAGAGCCCCCTTCAGAACCCACAG AGATCCGTCCACAAAAGCGGAAAAAGGGGCCAGCCCCCAAAATGCTGGGGAACGAGCT ATGCAGCGTGTGTGGGGACAAGGCCTCGGGCTTCCACTACAATGTTCTGAGCTGCGAG GGCTGCAAGGGATTCTTCCGCCGCAGCGTCATCAAGGGAGCGCACTACATCTGCCACA GTGGCGGCCACTGCCCCATGGACACCTACATGCGTCGCAAGTGCCAGGAGTGTCGGCT TCGCAAATGCCGTCAGGCTGGCATGCGGGAGGAGTGTGTCCTGTCAGAAGAACAGATC CGCCTGAAGAAACTGAAGCGGCAAGAGGAGGAACAGGCTCATGCCACATCCTTGCCCC CCAGGCGTTCCTCACCCCCCCAAATCCTGCCCCAGCTCAGCCCGGAACAACTGGGCAT GATCGAGAAGCTCGTCGCTGCCCAGCAACAGTGTAACCGGCGCTCCTTTTCTGACCGG CTTCGAGTCACGCCTTGGCCCATGGCACCAGATCCCCATAGCCGGGAGGCCCGTCAGC AGCGCTTTGCCCACTTCACTGAGCTGGCCATCGTCTCTGTGCAGGAGATAGTTGACTT TGCTAAACAGCTACCCGGCTTCCTGCAGCTCAGCCGGGAGGACCAGATTGCCCTGCTG AAGACCTCTGCGATCGAGGTGATGCTTCTGGAGACATCTCGGAGGTACAACCCTGGGA GTGAGAGTATCACCTTCCTCAAGGATTTCAGTTATAACCGGGAAGACTTTGCCAAAGC AGGGCTGCAAGTGGAATTCATCAACCCCATCTTCGAGTTCTCCAGGGCCATGAATGAG CTGCAACTCAATGATGCCGAGTTTGCCTTGCTCATTGCTATCAGCATCTTCTCTGCAG ACCGGCCCAACGTGCAGGACCAGCTCCAGGTGGAGAGGCTGCAGCACACATATGTGGA AGCCCTGCATGCCTACGTCTCCATCCACCATCCCCATGACCGACTGATGTTCCCACGG ATGCTAATGAAACTGGTGAGCCTCCGGACCCTGAGCAGCGTCCACTCAGAGCAAGTGT TTGCACTGCGTCTGCAGGACAAAAAGCTCCCACCGCTGCTCTCTGAGATCTGGGATGT GCACGAATGA (SEQ ID NO: 108)
Mouse polypeptide sequence:
MSL LEASMPDVSPDSATELWKTEPQDAGDQGGNTCILREEARMPQSTGVALGIGLES AEPTALLPRAETLPEPTELRPQKRKKGPAPKMLGNELCSVCGDKASGFHYNVLSCEGC KGFFRRSVIKGARYVCHSGGHCPMDTYMRRKCQECRLRKCRQAGMREECVLSEEQIRL KKLKRQEEEQAQATSVSPRVSSPPQVLPQLSPEQLGMIEKLVAAQQQCNRRSFSDRLR VTPWPIAPDPQSREARQQRFAHFTELAIVSVQEIVDFAKQLPGFLQLSREDQIALLKT SAIEVMLLETSRRYNPGSESITFLKDFSYNREDFAKAGLQVEFINPIFEFSRAMNELQ LNDAEFALLIAISIFSADRPNVQDQLQVERLQHTYVEALHAYVSI HPHDRLMFPRML MKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEIWDVHE
(SEQ ID NO: 109)
Mouse polynucleotide sequence:
ATGTCCTTGTGGCTGGAGGCCTCAATGCCTGATGTTTCTCCTGATTCTGCAACGGAGT TGTGGAAGACAGAACCTCAAGATGCAGGAGACCAGGGAGGCAACACTTGCATCCTCAG GGAGGAAGCCAGGATGCCCCAGTCAACTGGGGTTGCTTTAGGGATAGGGTTGGAGTCA GCAGAGCCTACAGCCCTGCTCCCCAGGGCAGAGACCCTCCCAGAGCCGACAGAGCTTC GTCCACAAAAGCGGAAAAAGGGCCCAGCCCCCAAAATGCTGGGGAACGAGCTGTGCAG TGTCTGTGGGGACAAAGCCTCTGGCTTCCATTACAACGTGCTGAGCTGCGAGGGCTGC AAGGGATTCTTCCGCCGCAGTGTCATCAAGGGAGCACGCTATGTCTGCCACAGCGGTG GCCACTGCCCCATGGACACCTACATGCGGCGGAAATGCCAGGAGTGTCGACTTCGCAA ATGCCGCCAGGCAGGCATGAGGGAGGAGTGTGTGCTGTCAGAAGAACAGATCCGCTTG AAGAAACTGAAGCGGCAAGAAGAGGAACAGGCTCAAGCCACTTCGGTGTCCCCAAGGG TGTCCTCACCTCCTCAAGTCCTGCCACAGCTCAGCCCAGAGCAGCTGGGCATGATCGA GAAGCTGGTGGCTGCCCAGCAACAGTGTAACAGGCGCTCCTTTTCAGACCGCCTGCGC GTCACGCCTTGGCCCATTGCACCCGACCCTCAGAGCCGGGAAGCCCGACAACAGCGCT TTGCCCACTTTACTGAGCTGGCCATCGTGTCCGTGCAGGAGATTGTTGACTTTGCCAA ACAGCTCCCTGGCTTCCTACAGCTCAGCAGGGAGGACCAGATCGCCTTGCTGAAGACC TCTGCAATTGAGGTCATGCTTCTGGAGACGTCACGGAGGTACAACCCCGGCAGTGAGA GCATCACCTTCCTCAAGGACTTCAGTTACAACCGGGAAGACTTTGCCAAAGCAGGGCT GCAGGTGGAGTTCATCAACCCCATCTTTGAGTTCTCCAGAGCCATGAATGAGCTGCAA CTCAATGATGCTGAGTTTGCTCTGCTCATTGCCATCAGCATCTTCTCTGCAGACCGGC CCAACGTGCAGGACCAGCTCCAAGTAGAGAGGCTGCAACACACATATGTGGAGGCCCT GCACGCCTACGTCTCCATCAACCACCCCCACGACCCACTGATGTTCCCACGGATGCTA ATGAAGCTGGTGAGCCTCCGTACTTTGAGCAGCGTCCATTCAGAGCAAGTGTTTGCCC TTCGCCTGCAGGACAAAAAGCTTCCCCCTCTGCTGTCTGAGATCTGGGATGTCCACGA GTGA (SEQIDNO: 110)
NRI3
Human polypeptide sequence:
MASREDELRNCWCGDQATGYHFNALTCEGCKGFFRRTVSKSIGPTCPFAGSCEVSKT QRRHCPACRLQKCLDAGMRKDMILSAEALALRRAKQAQRRAQQTPVQLSKEQEELIRT LLGAHTRHMGTMFEQFVQFRPPAHLFIHHQPLPTLAPVLPLVTHFADINTFMVLQVIK FTKDLPVFRSLPIEDQISLLKGAAVEICHIVLNTTFCLQTQNFLCGPLRYTIEDGARV GFQVEFLELLFHFHGTLRKLQLQEPEYVLLAAMALFSPDRPGVTQRDEIDQLQEEMAL TLQSYIKGQQRRPRDRFLYAKLLGLLAELRSINEAYGYQIQHIQGLSAMMPLLQEICS
(SEQ ID NO: 111) Human polynucleotide sequence:
ATGGCCAGTAGGGAAGATGAGCTGAGGAACTGTGTGGTATGTGGGGACCAAGCCACAG GCTACCACTTTAATGCGCTGACTTGTGAGGGCTGCAAGGGTTTCTTCAGGAGAACAGT CAGCAAAAGCATTGGTCCCACCTGCCCCTTTGCTGGAAGCTGTGAAGTCAGCAAGACT CAGAGGCGCCACTGCCCAGCCTGCAGGTTGCAGAAGTGCTTAGATGCTGGCATGAGGA AAGACATGATACTGTCGGCAGAAGCCCTGGCATTGCGGCGAGCAAAGCAGGCCCAGCG GCGGGCACAGCAAACACCTGTGCAACTGAGTAAGGAGCAAGAAGAGCTGATCCGGACA CTCCTGGGGGCCCACACCCGCCACATGGGCACCATGTTTGAACAGTTTGTGCAGTTTA GGCCTCCAGCTCATCTGTTCATCCATCACCAGCCCTTGCCCACCCTGGCCCCTGTGCT GCCTCTGGTCACACACTTCGCAGACATCAACACTTTCATGGTACTGCAAGTCATCAAG TTTACTAAGGACCTGCCCGTCTTCCGTTCCCTGCCCATTGAAGACCAGATCTCCCTTC TCAAGGGAGCAGCTGTGGAAATCTGTCACATCGTACTCAATACCACTTTCTGTCTCCA AACACAAAACTTCCTCTGCGGGCCTCTTCGCTACACAATTGAAGATGGAGCCCGTGTG GGGTTCCAGGTAGAGTTTTTGGAGTTGCTCTTTCACTTCCATGGAACACTACGAAAAC TGCAGCTCCAAGAGCCTGAGTATGTGCTCTTGGCTGCCATGGCCCTCTTCTCTCCTGA CCGACCTGGAGTTACCCAGAGAGATGAGATTGATCAGCTGCAAGAGGAGATGGCACTG ACTCTGCAAAGCTACATCAAGGGCCAGCAGCGAAGGCCCCGGGATCGGTTTCTGTATG CGAAGTTGCTAGGCCTGCTGGCTGAGCTCCGGAGCATTAATGAGGCCTACGGGTACCA AATCCAGCACATCCAGGGCCTGTCTGCCATGATGCCGCTGCTCCAGGAGATCTGCAGC TGA
(SEQ IDNO: 112)
Mouse polypeptide sequence: MTAMLTLETMASEEEYGPRNCWCGDRATGYHFHALTCEGCKGFFRRTVSKTIGPICP FAGRCEVSKAQRRHCPACRLQKCLNVGMRKDMILSAEALALRRARQAQRRAEKASLQL NQQQKELVQILLGAHTRHVGPLFDQFVQFKPPAYLFMHHRPFQPRGPVLPLLTHFADI NTFMVQQIIKFTKDLPLFRSLTMEDQISLLKGAAVEILHISLNTTFCLQTENFFCGPL CYKMEDAVHAGFQYEFLESILHFHKNLKGLHLQEPEYVLMAATALFSPDRPGVTQREE IDQLQEEMALILNNHIMEQQSRLQSRFLYAKLMGLLADLRSINNAYSYELQRLEELSA MTPLLGEICS (SEQ ID NO: 113)
Mouse polynucleotide sequence:
ATGACAGCTATGCTAACACTAGAAACCATGGCCAGTGAAGAAGAATATGGGCCGAGGA ACTGTGTGGTGTGTGGAGACCGGGCCACAGGCTATCATTTCCACGCCCTGACTTGTGA GGGCTGCAAGGGCTTCTTCAGACGAACAGTCAGCAAAACCATTGGTCCCATCTGTCCG TTTGCTGGAAGGTGTGAGGTCAGCAAGGCCCAGAGACGCCACTGTCCAGCCTGCAGGT TGCAGAAGTGTCTAAATGTTGGCATGAGGAAAGACATGATACTGTCAGCAGAAGCCCT GGCATTGCGGCGAGCCAGACAGGCACAGCGGCGGGCAGAGAAAGCATCTTTGCAACTG AATCAGCAGCAGAAAGAACTGGTCCAGATCCTCCTGGGGGCCCACACTCGCCATGTGG GCCCATTGTTTGACCAGTTTGTGCAGTTCAAGCCTCCAGCCTATCTGTTCATGCATCA CCGGCCTTTCCAGCCTCGGGGCCCCGTGTTGCCTCTGCTCACACACTTTGCAGATATC AACACGTTTATGGTGCAACAGATCATCAAGTTCACCAAGGATCTGCCGCTCTTCCGGT CCCTAACCATGGAGGACCAGATCTCCCTTCTCAAGGGAGCGGCTGTGGAAATATTGCA TATCTCACTCAACACTACGTTCTGTCTTCAAACAGAGAATTTCTTCTGTGGGCCTCTT TGCTACAAGATGGAGGACGCAGTCCATGCAGGGTTCCAGTACGAGTTTTTGGAGTCGA TCCTCCACTTCCATAAAAACCTGAAAGGACTGCATCTCCAGGAGCCTGAGTATGTGCT CATGGCTGCCACGGCCCTCTTCTCCCCTGGTTTCTGTATGCAAAGCTGA (SEQ ID NO: 114)
P65 Human polypeptide sequence:
MGPENESPVGGEMWGRVCVFSARQKRPRCSTLNSLLVARTCYNMLALVDWIEQDFKST RKAHVSLRGFLDFELGRRKEVAGAFLGGDTRPDPKKPRGGSKKNVEVYDDDVGSQAA DSPGKRMAPKGTFRDKDKFEGLFKLGALVAKKALTPAFSCSPNRGSPLHAHYGDEILY KVESGPVNICEGGKRGVGIHPPDNYGDTLDENLGLPQKIVIKVKPQTEEANTWLRQDL KNHNSAKEAGGSDEIKTFVTGCKKDGHSGRKNMTTHDRNSKK QRVNLSLMASLQLDS RGGRAGPRRGARRLCLVCEDYASCSNTCVWSCEAYKVFFRRSQSFTDPACFTNDCNIS KNRSKSCPACLLRCLHPSINEIRKDKRAALKVRDNVGEEVDMTGPSWTCLKLLFSDGE KVIPRLGHELPGIKGGRQAKQQSHRGSPIPKNRKG PPGHVLSNDGGAGGRVWKKKSC KPIRREGPKW DRLNESTPLF GSRANKSLGKGGTRGRIFIKHPHLFKFAADPQDKHW LAEQHHMRATGGKMAYLLIEEDIGQHHGQGFPVMLLKISHIRHMVGGVAHCLYDMKEK KFVLPSWKVEKLGKYVETLRTEKEHRAAEASPQT
(SEQ IDNO: 115) Human polynucleotide sequence:
ATGGGACCCGAAAACGAGAGCCCCGTGGGGGGGGAGATGTGGGGGAGAGTGTGTGTGT TCAGCGCTAGACAAAAGAGACCGCGATGCAGCACTTTAAATAGTCTTCTCGTTGCTAG AACATGCTATAACATGCTGGCGCTGGTGGATTGGATCGAGCAGGATTTCAAGAGCACT TGGCGAAAGGCTCACGTTTCCCTCCGCGGGTTCCTCGATTTCGAGCTGGGGAGACGAA AAGAGGTTGCCGGGGCTTTTCTGGGTGGGGATACCAGACCTGACCCCAAAAAGCCGCG GGGGGGGTCCAAAAAGAACGTGGAGGTGTATGATGATGACGTAGGCTCTCAGGCTGCG GACAGCCCCGGGAAACGCATGGCCCCGAAAGGGACATTTAGAGATAAGGACAAATTTG AAGGGCTGTTTAAGCTCGGGGCGCTGGTGGCAAAAAAAGCCTTGACCCCAGCATTTTC TTGTTCCCCCAACAGGGGGTCGCCTCTACACGCCCATTATGGGGATGAAATCCTCTAC AAGGTTGAATCCGGGCCCGTCAACATTTGCGAGGGGGGCAAAAGAGGCGTGGGGATCC ACCCCCCAGATAACTACGGCGATACCCTTGATGAAAATCTTGGCCTTCCCCAAAAAAT TGTGATTAAGGTGAAGCCCCAAACCGAGGAAGCCAACACTTGGTTAAGGCAGGATCTG AAAAATCATAACAGTGCAAAGGAGGCCGGGGGCTCCGACGAGATTAAAACCTTTGTGA CAGGATGTAAAAAAGATGGGCATAGTGGGCGTAAAAATATGACCACACATGACAGAAA TTCAAAAAAGTGGCAACGGGTAAACTTGTCCCTTATGGCCTCCCTCCAGCTAGATTCT AGGGGCGGACGCGCGGGGCCCCGGCGCGGAGCGCGGCGCCTGTGCCTGGTGTGTGAGG ACTATGCCAGCTGTTCAAACACCTGTGTCTGGTCCTGTGAAGCCTACAAGGTCTTCTT TCGCCGAAGTCAAAGTTTCACAGATCCAGCCTGTTTCACAAACGATTGCAACATCTCT AAGAATAGGTCTAAGTCTTGCCCAGCTTGCCTCCTCCGTTGCCTGCACCCTAGCATTA ATGAGATCCGAAAAGACAAGCGAGCAGCGCTGAAAGTGCGAGACAACGTTGGTGAAGA GGTGGATATGACCGGTCCTAGCTGGACCTGCCTGAAGCTACTTTTTTCAGATGGGGAA AAAGTGATACCCAGATTGGGCCATGAACTCCCAGGGATCAAGGGGGGCCGGCAGGCAA AACAGCAGTCCCACCGAGGAAGCCCCATCCCCAAAAACAGGAAAGGTTGGCCCCCCGG ACATGTCCTGTCAAATGACGGCGGAGCTGGTGGCAGGGTATGGAAAAAAAAATCCTGT AAACCAATTCGCCGAGAAGGCCCCAAGTGGTGGGATCGGCTGAATGAATCTACACCTT TGTTTTGGGGGTCTCGAGCCAACAAGAGTTTAGGGAAGGGAGGCACCAGGGGGAGGAT TTTCATCAAGCACCCACACCTCTTTAAGTTTGCAGCAGATCCTCAGGACAAGCACTGG CTGGCTGAGCAGCATCATATGCGGGCAACAGGAGGAAAGATGGCGTACCTTCTCATTG AGGAAGACATCGGGCAGCATCATGGCCAGGGGTTCCCAGTTATGCTTCTCAAGATTAG CCATATTAGGCACATGGTTGGGGGAGTGGCTCATTGCTTGTACGACATGAAAGAAAAG AAGTTTGTTCTGCCATCCTGGAAGGTTGAGAAGTTGGGGAAATACGTGGAGACACTAC GGACAGAAAAAGAGCATCGTGCTGCTGAAGCAAGTCCCCAGACCTGA (SEQIDNO: 116)
Mouse polypeptide sequence:
MGATGDTEQPRGPGGAERGGLELGDAGAAGQPVLTNPWNIMIKHRQVQRRGRRSQMTT SFTDPAISMDLLRAVLQPSINEEIQGVFNKYMKFFQKAALNVRDNVGEEVDAEQLIQE ACRSCLEQAKLLFSDGEKVIPRLAHELPGIKRGRQAEEESHRGSPIPKKRKGRPPGHV LSNDRAAAGMVWKQKSCEPIRREGPKWDPARLNESTTFVLGSRANKALGMGGTRGRIY IKHPHLFKYAADPQDKHWLAEQHHMRATGGKMAYLLIEEDIRDLAASDDYRGCLDLKL EELKSFVLPSWMVEKMRKYMETLRTENEHRAAEAPPQT (SEQ IDNO: 117)
Mouse polynucleotide sequence:
GCTGAGTCGAGCTGAGGTTGTTGTGGGCCGGGGGGCGCCATGGGGGCGACTGGCGACA CCGAGCAGCCGCGGGGCCCCGGCGGGGCGGAGCGAGGTGGCCTGGAGCTGGGCGACGC GGGCGCGGCGGGCCAGCCGGTTCTCACGAACCCTTGGAACATAATGATAAAACATCGG CAGGTGCAGCGAAGGGGCCGCCGATCTCAGATGACCACAAGTTTCACAGACCCAGCCA TCTCTATGGATCTCCTCCGTGCTGTCCTGCAGCCTAGCATCAATGAGGAGATCCAGGG TGTCTTCAACAAGTACATGAAGTTCTTCCAGAAGGCAGCGCTGAATGTGCGAGACAAT GTTGGGGAAGAAGTGGACGCAGAGCAGTTGATTCAGGAGGCCTGCCGqAGCTGCCTGG AGCAGGCAAAGCTGCTCTTTTCTGATGGAGAGAAAGTGATACCCAGATTGGCCCATGA GCTTCCAGGGATCAAGCGGGGCCGGCAAGCAGAAGAGGAGTCCCACCGAGGAAGCCCC ATTCCCAAAAAGAGGAAAGGTCGGCCTCCTGGACACGTCCTGTCAAATGACCGCGCAG CTGCTGGCATGGTATGGAAACAAAAATCCTGTGAACCAATTCGCCGAGAAGGCCCCAA GTGGGACCCAGCTCGGCTGAATGAATCTACCACCTTTGTTTTGGGGTCTCGAGCCAAC AAGGCCTTGGGGATGGGAGGCACCAGAGGGAGAATCTACATCAAGCACCCACACCTCT TTAAGTATGCAGCAGATCCTCAGGACAAGCACTGGCTGGCTGAGCAGCATCACATGCG GGCAACAGGCGGAAAGATGGCGTACCTTCTCATTGAAGAAGACATCCGGGACTTGGCT GCCAGCGATGACTACAGAGGATGCTTGGACCTGAAGTTGGAGGAGCTGAAATCCTTTG TTCTGCCATCCTGGATGGTTGAGAAGATGCGGAAATACATGGAGACACTGCGGACAGA AAATGAGCACCGCGCTGCGGAAGCGCCTCCCCAGACCTGAGCCGGGTGTCCTGGCTAC TACACTTGGCGGCCTGCCTCCAAGACCCTCTTTCCCCACCCGGCTGAGGCCATCATGG GGATTTGGTCTAGTTGACTCTTAACAGCATTAAGCTGTACATGAGCTAGTTTGTAGTG ACTCACTGCAGAGCACCCCAGACTGGCATGTGGTTCTGTTTCTAAAGTTATTGGAATA AGAAGCAATTAAACAGTTTGTAATAAAAAAAAAAAAAAA (SEQ ID NO: 118)
PPAR Human polypeptide sequence:
MVDTESPLCPLSPLEAGDLESPLSEEFLQEMGNIQEISQSIGEDSSGSFGFTEYQYLG SCPGSDGSVITDTLSPASSPSSVTYPWPGSVDESPSGALNIECRICGDKASGYHYGV HACEGCKGFFRRTIRLKLVYDKCDRSCKIQKKNRNKCQYCRFHKCLSVGMSHNAIRFG RMPRSEKAKLKAEILTCEHDIEDSETADLKSLAKRIYEAYLKNFNMNKVKARVILSGK ASNNPPFVIHDMETLCMAEKTLVAKLVANGIQNKEAEVRIFHCCQCTSVETVTELTEF AKAIPGFANLDLNDQVTLLKYGVYEAIFAMLSSVMNKDGMLVAYGNGFITREFLKSLR KPFCDIMEPKFDFAMKFNALELDDSDISLFVAAIICCGDRPGLLNVGHIEKMQEGIVH VLRLHLQSNHPDDIFLFPKLLQKMADLRQLVTEHAQLVQIIKKTESDAALHPLLQEIY RDMY
(SEQ IDNO: 119)
Human polynucleotide sequence: ATGGTGGACACGGAAAGCCCACTCTGCCCCCTCTCCCCACTCGAGGCCGGCGATCTAG AGAGCCCGTTATCTGAAGAGTTCCTGCAAGAAATGGGAAACATCCAAGAGATTTCGCA ATCCATCGGCGAGGATAGTTCTGGAAGCTTTGGCTTTACGGAATACCAGTATTTAGGA AGCTGTCCTGGCTCAGATGGCTCGGTCATCACGGACACGCTTTCACCAGCTTCGAGCC CCTCCTCGGTGACTTATCCTGTGGTCCCCGGCAGCGTGGACGAGTCTCCCAGTGGAGC ATTGAACATCGAATGTAGAATCTGCGGGGACAAGGCCTCAGGCTATCATTACGGAGTC CACGCGTGTGAAGGCTGCAAGGGCTTCTTTCGGCGAACGATTCGACTCAAGCTGGTGT ATGACAAGTGCGACCGCAGCTGCAAGATCCAGAAAAAGAACAGAAACAAATGCCAGTA TTGTCGATTTCACAAGTGCCTTTCTGTCGGGATGTCACACAACGCGATTCGTTTTGGA CGAATGCCAAGATCTGAGAAAGCAAAACTGAAAGCAGAAATTCTTACCTGTGAACATG ACATAGAAGATTCTGAAACTGCAGATCTCAAATCTCTGGCCAAGAGAATCTACGAGGC CTACTTGAAGAACTTCAACATGAACAAGGTCAAAGCCCGGGTCATCCTCTCAGGAAAG GCCAGTAACAATCCACCTTTTGTCATACATGATATGGAGACACTGTGTATGGCTGAGA AGACGCTGGTGGCCAAGCTGGTGGCCAATGGCATCCAGAACAAGGAGGCGGAGGTCCG CATCTTTCACTGCTGCCAGTGCACGTCAGTGGAGACCGTCACGGAGCTCACGGAATTC GCCAAGGCCATCCCAGGCTTCGCAAACTTGGACCTGAACGATCAAGTGACATTGCTAA AATACGGAGTTTATGAGGCCATATTCGCCATGCTGTCTTCTGTGATGAACAAAGACGG GATGCTGGTAGCGTATGGAAATGGGTTTATAACTCGTGAATTCCTAAAAAGCCTAAGG AAACCGTTCTGTGATATCATGGAACCCAAGTTTGATTTTGCCATGAAGTTCAATGCAC TGGAACTGGATGACAGTGATATCTCCCTTTTTGTGGCTGCTATCATTTGCTGTGGAGA TCGTCCTGGCCTTCTAAACGTAGGACACATTGAAAAAATGCAGGAGGGTATTGTACAT GTGCTCAGACTCCACCTGCAGAGCAACCACCCGGACGATATCTTTCTCTTCCCAAAAC TTCTTCAAAAAATGGCAGACCTCCGGCAGCTGGTGACGGAGCATGCGCAGCTGGTGCA GATCATCAAGAAGACGGAGTCGGATGCTGCGCTGCACCCGCTACTGCAGGAGATCTAC AGGGACATGTACTGA (SEQ IDNO: 120)
Mouse polypeptide sequence:
MVDTESPICPLSPLEADDLESPLSEEFLQEMGNIQEISQSIGEESSGSFGFADYQYLG SCPGSEGSVITDTLSPASSPSSVSCPVIPASTDESPGSALNIECRICGDKASGYHYGV HACEGCKGFFRRTIRLKLVYDKCDRSCKIQKKNRNKCQYCRFHKCLSVGMSHNAIRFG RMPRSEKAKLKAEILTCEHDLKDSETADLKSLGKRIHEAYLKNFNMNKVKARVILAGK TSNNPPFVIHDMETLCMAEKTLVAKMVANGVEDKEAEVRFFHCCQCMSVETVTELTEF AKAIPGFANLDLNDQVTLLKYGVYEAIFTMLSSLMNKDGMLIAYGNGFITREFLKNLR KPFCDIMEPKFDFAMKFNALELDDSDISLFVAAIICCGDRPGLLNIGYIEKLQEGIVH VLKLHLQSNHPDDTFLFPKLLQKMVDLRQLVTEHAQLVQVIKKTESDAALHPLLQEIY RDMY (SEQ IDNO: 121)
Mouse polynucleotide sequence:
GTCACAGCCTAGGCTTTGCTGGGGACCTGAGAAACGCTGCCGCCAAGTTGAAGTTCAA GGCCCTGCCTTCCCTGTGAACTGACGTTTGTGGCTGGTCAAGTTCGGGAACAAGACGT TGTCATCACAGCTTAGCGCTCTGTGGCCTGCCTGGCCACATCCATCCAACATGGTGGA CACAGAGAGCCCCATCTGTCCTCTCTCCCCACTGGAGGCAGATGACCTGGAAAGTCCC TTATCTGAAGAATTCTTACAAGAAATGGGAAACATTCAAGAGATTTCTCAGTCCATCG GTGAGGAGAGCTCTGGAAGCTTTGGTTTTGCAGACTACCAGTACTTAGGAAGCTGTCC GGGCTCCGAGGGCTCTGTCATCACAGACACCCTCTCTCCACGTTCCAGCCCTTCCTCA GTCAGCTGCCCCGTGATCCCCGCCAGCACGGACGAGTCCCCCGGCAGTGCCCTGAACA TCGAGTGTCGAATATGTGGGGACAAGGCCTCAGGGTACCACTACGGAGTTCACGCATG TGAAGGCTGTAAGGGCTTCTTTCGGCGAACTATTCGGCTGAAGCTGGTGTACGACAAG TGTGATCGGAGCTGCAAGATTCAGAAGAAGAACCGGAACAAATGCCAGTACTGCCGTT TTCACAAGTGCCTGTCTGTCGGGATGTCACACAATGCAATTCGCTTTGGAAGAATGCC AAGATCTGAAAAAGCAAAACTGAAAGCAGAAATTCTTACCTGTGAACACGACCTGAAA GATTCGGAAACTGCAGACCTCAAATCTCTGGGCAAGAGAATCCACGAAGCCTACCTGA AGAACTTCAACATGAACAAGGTCAAGGCCCGGGTCATACTCGCGGGAAAGACCAGCAA CAACCCGCCTTTTGTCATACATGACATGGAGACCTTGTGTATGGCCGAGAAGACGCTT GTGGCCAAGATGGTGGCCAACGGCGTCGAAGACAAAGAGGCAGAGGTCCGATTCTTCC ACTGCTGCCAGTGCATGTCCGTGGAGACCGTCACGGAGCTCACAGAATTTGCCAAGGC TATCCCAGGCTTTGCAAACTTGGACTTGAACGACCAAGTCACCTTGCTAAAGTACGGT GTGTATGAAGCCATCTTCACGATGCTGTCCTCCTTGATGAACAAAGACGGGATGCTGA TCGCGTACGGCAATGGCTTTATCACACGCGAGTTCCTTAAGAACCTGAGGAAGCCGTT CTGTGACATCATGGAACCCAAGTTTGACTTCGCTATGAAGTTCAATGCCTTAGAACTG GATGACAGTGACATTTCCCTGTTTGTGGCTGCTATAATTTGCTGTGGAGATCGGCCTG GCCTTCTAAACATAGGCTACATTGAGAAGTTGCAGGAGGGGATTGTGCACGTGCTTAA GCTCCACCTGCAGAGCAACCATCCAGATGACACCTTCCTCTTCCCAAAGCTCCTTCAA AAAATGGTGGACCTTCGGCAGCTGGTCACGGAGCATGCGCAGCTCGTACAGGTCATCA AGAAGACCGAGTCCGACGCAGCGCTGCACCCACTGTTGCAAGAGATCTACAGAGACAT GTACTGATCTTTCCTGAGATGGCAGGCCATTACCACTGTTCAGGGACCTCCGAGGCCT GCGGCCCCATACAGGAGAGCAGGGATTTGCACAGAGGGCCTCCCTCCTACGCTTGGGG ATGAAGAGGGCTGAGCGTAGGTAATGCGGGCTCTCCCCACATCCTTTCTGAATGGGCA CTTCTAAGACTACCTGCTACCGAAATGGGGGTGATCGGAGGCTAATAGGATTCAGACA GTGACAGACAACGGCAGTCCCCAGTCTGGTCTTAACCGGCCCAATGTTAATCAATGCA
CAGCACTCTACGTTGCGTTTATAATTCGCCATTAATTAACGGGTAACCTCGAAGTCTG
AGCGGTCTGTTCCCTTCCTGCCACCCTTCTGGCTATGTGCACTCTCTTAAATCCCTGA
AAACTAATCTGCACTTTTTAACCTTTGAAAACCTACAAGTCAAGGTGTGGCCCAAGGT
TAGCCATTTAAATGTGGCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
(SEQ IDNO: 122)
PPARG
Human polypeptide sequence:
MGETLGDSPIDPESDSFTDTLSANISQEMTMVDTEMPFWPTNFGISSVDLSVMEDHSH SFDIKPFTTVDFSSISTPHYEDIPFTRTDPWADYKYDLKLQEYQSAIKVEPASPPYY SEKTQLYNKPHEEPSNSLMAIECRVCGDKASGFHYGVHACEGCKGFFRRTIRLKLIYD RCDLNCRIHKKSRNKCQYCRFQKCLAVGMSHNAIRFGRMPQAEKE.KLLAEISSDIDQL NPESADLRALAKHLYDSYIKSFPLTKAKARAILTGKTTDKSPFVIYDMNSLMMGEDKI KFKHITPLQEQSKEVAIRlFQGCQFRSVEAVQEITEYAKSIPGFVNLDLNDQVTLLKY GVHEIIYTMLASLMNKDGVLISEGQGFMTREFLKSLRKPFGDFMEPKFEFAVKFNALE LDDSDLAIFIAVIILSGDRPGLLNVKPIEDIQDNLLQALELQLKLNHPESSQLFAKLL QKMTDLRQIVTEHVQLLQVIKKTETDMSLHPLLQEIYKDLY (SEQ ID NO: 123)
Human polynucleotide sequence:
ATGGTTGACACAGAGATGCCATTCTGGCCCACCAACTTTGGGATCAGCTCCGTGGATC TCTCCGTAATGGAAGACCACTCCCACTCCTTTGATATCAAGCCCTTCACTACTGTTGA CTTCTCCAGCATTTCTACTCCACATTACGAAGACATTCCATTCACAAGAACAGATCCA GTGGTTGCAGATTACAAGTATGACCTGAAACTTCAAGAGTACCAAAGTGCAATCAAAG TGGAGCCTGCATCTCCACCTTATTATTCTGAGAAGACTCAGCTCTACAATAAGCCTCA TGAAGAGCCTTCCAACTCCCTCATGGCAATTGAATGTCGTGTCTGTGGAGATAAAGCT TCTGGATTTCACTATGGAGTTCATGCTTGTGAAGGATGCAAGGGTTTCTTCCGGAGAA CAATCAGATTGAAGCTTATCTATGACAGATGTGATCTTAACTGTCGGATCCACAAAAA AAGTAGAAATAAATGTCAGTACTGTCGGTTTCAGAAATGCCTTGCAGTGGGGATGTCT CATAATGCCATCAGGTTTGGGCGGATGCCACAGGCCGAGAAGGAGAAGCTGTTGGCGG AGATCTCCAGTGATATCGACCAGCTGAATCCAGAGTCCGCTGACCTCCGGGCCCTGGC AAAACATTTGTATGACTCATACATAAAGTCCTTCCCGCTGACCAAAGCAAAGGCGAGG GCGATCTTGACAGGAAAGACAACAGACAAATCACCATTCGTTATCTATGACATGAATT CCTTAATGATGGGAGAAGATAAAATCAAGTTCAAACACATCACCCCCCTGCAGGAGCA GAGCAAAGAGGTGGCCATCCGCATCTTTCAGGGCTGCCAGTTTCGCTCCGTGGAGGCT GTGCAGGAGATCACAGAGTATGCCAAAAGCATTCCTGGTTTTGTAAATCTTGACTTGA ACGACCAAGTAACTCTCCTCAAATATGGAGTCCACGAGATCATTTACACAATGCTGGC CTCCTTGATGAATAAAGATGGGGTTCTCATATCCGAGGGCCAAGGCTTCATGACAAGG GAGTTTCTAAAGAGCCTGCGAAAGCCTTTTGGTGACTTTATGGAGCCCAAGTTTGAGT TTGCTGTGAAGTTCAATGCACTGGAATTAGATGACAGCGACTTGGCAATATTTATTGC TGTCATTATTCTCAGTGGAGACCGCCCAGGTTTGCTGAATGTGAAGCCCATTGAAGAC ATTCAAGACAACCTGCTACAAGCCCTGGAGCTCCAGCTGAAGCTGAACCACCCTGAGT CCTCACAGCTGTTTGCCAAGCTGCTCCAGAAAATGACAGACCTCAGACAGATTGTCAC GGAACACGTGCAGCTACTGCAGGTGATCAAGAAGACGGAGACAGACATGAGTCTTCAC CCGCTCCTGCAGGAGATCTACAAGGACTTGTACTAG (SEQ ID NO: 124) Mouse polypeptide sequence:
MGETLGDSPVDPEHGAFADALPMSTSQEITMVDTEMPF PTNFGISSVDLSVMEDHSH SFDIKPFTTVDFSSISAPHYEDIPFTRADPMVADYKYDLKLQEYQSAIKVEPASPPYY 5 SEKTQLYNRPHEEPSNSLMAIECRVCGDKASGFHYGVHACEGCKGFFRRTIRLKLIYD RCDLNCRIHKKSRNKCQYCRFQKCLAVGMSHNAIRFGRMPQAEKEKLLAEISSDIDQL NPESADLRALAKHLYDSYIKSFPLTKAKARAILTGKTTDKSPFVIYDMNSLMMGEDKI KFKHITPLQEQSKEVAIRIFQGCQFRSVEAVQEITEYAKNIPGFINLDLNDQVTLLKY GVHEIIYTMLASLMNKDGVLISEGQGFMTREFLKNLRKPFGDFMEPKFEFAVKFNALE 10 LDDSDLAIFIAVIILSGDRPGLLNVKPIEDIQDNLLQALELQLKLNHPESSQLFAKVL QKMTDLRQIVTEHVQLLHVIKKTETDMSLHPLLQEIYKDLY (SEQ IDNO: 125)
Mouse polynucleotide sequence:
15
ATGGTTGACACAGAGATGCCATTCTGGCCCACCAACTTCGGAATCAGCTCTGTGGACC TCTCCGTGATGGAAGACCACTCGCATTCCTTTGACATCAAGCCCTTTACCACAGTTGA TTTCTCCAGCATTTCTGCTCCACACTATGAAGACATTCCATTCACAAGAGCTGACCCA ATGGTTGCTGATTACAAATATGACCTGAAGCTCCAAGAATACCAAAGTGCGATCAAAG
20 TAGAACCTGCATCTCCACCTTATTATTCTGAAAAGACCCAGCTCTACAACAGGCCTCA TGAAGAACCTTCTAACTCCCTCATGGCCATTGAGTGCCGAGTCTGTGGGGATAAAGCA TCAGGCTTCCACTATGGAGTTCATGCTTGTGAAGGATGCAAGGGTTTTTTCCGAAGAA CCATCCGATTGAAGCTTATTTATGATAGGTGTGATCTTAACTGCCGGATCCACAAAAA AAGTAGAAATAAATGTCAGTACTGTCGGTTTCAGAAGTGCCTTGCTGTGGGGATGTCT
25 CACAATGCCATCAGGTTTGGGCGGGATCGACAGGCCGAGAAGGAGAAGCTGTTGGCGG AGATCTCCAGTGATATCGACCAGCTGAACCCAGAGTCTGCTGATCTGCGAGCCCTGGC AAAGCATTTGTATGACTCATACATAAAGTCCTTCCCGCTGACCAAAGCCAAGGCGAGG GCGATCTTGACAGGAAAGACAACGGACAAATCACCATTTGTCATCTACGACATGAGTT CCTTTATGATGGGAGAAGATAAAATCAAGTTCAAACATATCACCCCCCTGCAGGAGCA
30 GAGCAAAGAGGTGGCCATCCGAATTTTTCAAGGGTGCCAGTTTCGATCCGTAGAAGCC GTGCAAGAGATCACAGAGTATGCCAAAAATATCCCTGGTTTCATTAACCTTGATTTGA ATGACCAAGTGACTCTGCTCAAGTATGGTGTCCATGAGATCATCTACACGATGCTGGC CTCCCTGATGAATAAAGATGGAGTCCTCATCTCAGAGGGCCAAGGATTCATGACCAGG GAGTTCCTCAAAAGCCTGCGGAAGCCCTTTGGTGACTTTATGGAGCCTAAGTTTGAGT
35. TTGCTGTGAAGTTCAATGCACTGGAATTAGATGACAGTGACTTGGCTATATTTATAGC TGTCATTATTCTCAGTGGAGACCGCCCAGGCTTGCTGAACGTGAAGCCCATCGAGGAC ATCCAAGACAACCTGCTGCAGGCCCTGGAACTGCAGCTCAAGCTGAATCACCCAGAGT CCTCTCAGCTGTTCGCCAAGGTGCTCCAGAAGATGACAGACCTCAGGCAGATCGTCAC AGAGCACGTGCAGCTACTGCATGTGATCAAGAAGACAGAGACAGACATGAGCCTTCAC
40 CCCCTGTTCCAGGAGATCTACAAGGACTTGTATTAG (SEQ IDNO: 126)
PPAS
45
Human polypeptide sequence:
MEQPQEEAPEVREEEEKEEVAEAEGAPELNGGPQHALPSSSYTDLSRSSSPPSLLDQL QMGCDGASCGSLNMECRVCGDKASGFHYGVHACEGCKGFFRRTIRMKLEYEKCERSCK 50 IQKKNRNKCQYCRFQKCLALGMSHNAIRFGRMPEAEKRKLVAGLTANEGSQYNPQVAD LKAFSKHIYNAYLKNFNMTKKKARSILTGKASHTAPFVIHDIETLWQAEKGLV KQLV NGLPPYKEISVHVFYRCQCTTVETVRELTEFAKSIPSFSSLFLNDQVTLLKYGVHEAI FAMLASIVNKDGLLVANGSGFVTREFLRSLRKPFSDIIEPKFEFAVKFNALELDDSDL ALFIAAIILCGDRPGLMNVPRVEAIQDTILRALEFHLQANHPDAQYLFPKLLQKMADL
RQLVTEHAQMMQRIKKTETETSLHPLLQEIYKDMY
(SEQ ID NO: 127) Human polynucleotide sequence:
ATGGAGCAGCCACAGGAGGAAGCCCCTGAGGTCCGGGAAGAGGAGGAGAAAGAGGAAG TGGCAGAGGCAGAAGGAGCCCCAGAGCTCAATGGGGGACCACAGCATGCACTTCCTTC CAGCAGCTACACAGACCTCTCCCGGAGCTCCTCGCCACCCTCACTGCTGGACCAACTG CAGATGGGCTGTGACGGGGCCTCATGCGGCAGCCTCAACATGGAGTGCCGGGTGTGCG GGGACAAGGCATCGGGCTTCCACTACGGTGTTCATGCATGTGAGGGGTGCAAGGGCTT CTTCCGTCGTACGATCCGCATGAAGCTGGAGTACGAGAAGTGTGAGCGCAGCTGCAAG ATTCAGAAGAAGAACCGCAACAAGTGCCAGTACTGCCGCTTCCAGAAGTGCCTGGCAC TGGGCATGTCACACAACGCTATCCGTTTTGGTCGGATGCCGGAGGCTGAGAAGAGGAA GCTGGTGGCAGGGCTGACTGCAAACGAGGGGAGCCAGTACAACCCACAGGTGGCCGAC CTGAAGGCCTTCTCCAAGCACATCTACAATGCCTACCTGAAAAACTTCAACATGACCA AAAAGAAGGCCCGCAGCATCCTCACCGGCAAAGCCAGCCACACGGCGCCCTTTGTGAT CCACGACATCGAGACATTGTGGCAGGCAGAGAAGGGGCTGGTGTGGAAGCAGTTGGTG AATGGCCTGCCTCCCTACAAGGAGATCAGCGTGCACGTCTTCTACCGCTGCCAGTGCA CCACAGTGGAGACCGTGCGGGAGCTCACTGAGTTCGCCAAGAGCATCCCCAGCTTCAG CAGCCTCTTCCTCAACGACCAGGTTACCCTTCTCAAGTATGGCGTGCACGAGGCCATC TTCGCCATGCTGGCCTCTATCGTCAACAAGGACGGGCTGCTGGTAGCCAACGGCAGTG GCTTTGTCACCCGTGAGTTCCTGCGCAGCCTCCGCAAACCCTTCAGTGATATCATTGA GCCTAAGTTTGAATTTGCTGTCAAGTTCAACGCCCTGGAACTTGATGACAGTGACCTG GCCCTATTCATTGCGGCCATCATTCTGTGTGGAGACCGGCCAGGCCTCATGAACGTTC CACGGGTGGAGGCTATCCAGGACACCATCCTGCGTGCCCTCGAATTCCACCTGCAGGC CAACCACCCTGATGCCCAGTACCTCTTCCCCAAGCTGCTGCAGAAGATGGCTGACCTG CGGCAACTGGTCACCGAGCACGCCCAGATGATGCAGCGGATCAAGAAGACCGAAACCG AGACCTCGCTGCACCCTCTGCTCCAGGAGATCTACAAGGACATGTACTAA (SEQ ID NO: 128)
Mouse polypeptide sequence:
MEQPQEETPEAREEEKEEVAMGDGAPELNGGPEHTLPSSSCADLSQNSSPSSLLDQLQ MGCDGASGGSLNMECRVCGDKASGFHYGVHACEGCKGFFRRTIRMKLEYEKCDRICKI QKKNRNKCQYCRFQKCLALGMSHNAIRFGRMPEAEKRKLVAGLTASEGCQHNPQLADL KAFSKHIYNAYLKNFNMTKKKARSILTGKSSHNAPFVIHDIETL QAEKGLVWKQLVN GLPPYNEISVHVFYRCQSTTVETVRELTEFAKNIPNFSSLFLNDQVTLLKYGVHEAIF AMLASIVNKDGLLVANGSGFVTHEFLRSLRKPFSDIIEPKFEFAVKFNALELDDSDLA LFIAAIILCGDRPGLMNVPQVEAIQDTILRALEFHLQVNHPDSQYLFPKLLQKMADLR QLVTEHAQMMQWLKKTESETLLHPLLQEIYKDMY (SEQ IDNO: 129)
Mouse polynucleotide sequence:
ATGGAACAGCCACAGGAGGAGACCCCTGAGGCCCGGGAAGAGGAGAAAGAGGAAGTGG CCATGGGTGACGGAGCCCCGGAGCTCAATGGGGGACCAGAACACACGCTTCCTTCCAG CAGCTGTGCAGACCTCTCCCAGAATTCCTCCCCTTCCTCCCTGCTGGACCAGCTGCAG ATGGGCTGTGATGGGGCCTCAGGCGGCAGCCTCAACATGGAATGTCGGGTGTGCGGGG ACAAGGCCTCGGGCTTCCACTACGGGGTCCACGCGTGCGAGGGGTGCAAGGGCTTCTT CCGCCGGACAATCCGCATGAAGCTCGAGTATGAGAAGTGCGATCGGATCTGCAAGATC CAGAAGAAGAACCGCAACAAGTGTCAGTACTGCCGCTTCCAGAAGTGCCTGGCACTCG GCATGTCGCACAACGCTATCCGCTTTGGACGGATGCCGGAGGCCGAGAAGAGGAAGCT GGTGGCGGGGCTGACTGCCAGCGAGGGGTGCCAGCACAACCCCCAGCTGGCCGACCTG AAGGCCTTCTCTAAGCACATCTACAACGCCTACCTGAAAAACTTCAACATGACCAAAA AGAAGGCCCGGAGCATCCTCACCGGCAAGTCCAGCCACAACGCACCCTTTGTCATCCA CGACATCGAGACACTGTGGCAGGCAGAGAAGGGCCTGGTGTGGAAACAGCTGGTGAAC GGGCTGCCGCCCTACAACGAGATCAGTGTGCACGTGTTCTACCGCTGCCAGTCCACCA CAGTGGAGACAGTCCGAGAGCTCACCGAGTTCGCCAAGAACATCCCCAACTTCAGCAG CCTCTTCCTCAATGACCAGGTGACCCTCCTCAAGTATGGCGTGCACGAGGCCATCTTT GCCATGCTGGCCTCCATCGTCAACAAAGACGGGCTGCTGGTGGCCAACGGCAGTGGCT TCGTCACCCACGAGTTCTTGCGAAGTCTCCGCAAGCCCTTCAGTGACATCATTGAGCC CAAGTTCGAGTTTGCTGTCAAGTTCAATGCGCTGGAGCTCGATGACAGTGACCTGGCG CTCTTCATCGCGGCCATCATTCTGTGTGGAGACCGGCCAGGCCTCATGAATGTGCCCC AGGTAGAAGCCATCCAGGACACCATTCTGCGGGCTCTAGAATTCCATCTGCAGGTCAA CCACCCTGACAGCCAGTACCTCTTCCCCAAGCTGCTGCAGAAGATGGCAGACCTGCGG CAGCTGGTCACTGAGCATGCCCAGATGATGCAGTGGCTAAAGAAGACGGAGAGTGAGA CCTTGCTGCACCCCCTGCTCCAGGAAATCTACAAGGACATGTACTAA (SEQ IDNO: 130) PRGR
Human polypeptide sequence:
MTELKAKGPRAPHVAGGPPSPEVGSPLLCRPAAGPFPGSQTSDTLPEVSAIPISLDGL LFPRPCQGQDPSDEKTQDQQSLSDVEGAYSRAEATRGAGGSSSSPPEKDSGLLDSVLD TLLAPSGPGQSQPSPPACEVTSSWCLFGPELPEDPPAAPATQRVLSPLMSRSGCKVGD SSGTAAAHKVLPRGLSPARQLLLPASESPH SGAPVKPSPQAAAVEVEEEDGSESEES AGPLLKGKPRALGGAAAGGGAAAVPPGAAAGGVALVPKEDSRFSAPRVALVEQDAPMA PGRSPLATTVMDFIHVPILPLNHALLAARTRQLLEDESYDGGAGAASAFAPPRSSPCA SSTPVAVGDFPDCAYPPDAEPKDDAYPLYSDFQPPALKIKEEEEGAEASARSPRSYLV AGANPAAFPDFPLGPPPPLPPRATPSRPGEAAVTAAPASASVSSASSSGSTLECILYK AEGAPPQQGPFAPPPCKAPGASGCLLPRDGLPSTSASAAAAGAAPALYPALGLNGLPQ LGYQAAVLKEGLPQVYPPYLNYLRPDSEASQSPQYSFESLPQKICLICGDEASGCHYG VLTCGSCKVFFKRAMEGQHNYLCAGRNDCIVDKIRRKNCPACRLRKCCQAGMVLGGRK FKKFNKVRWRALDAVALPQPLGVPNESQALSQRFTFSPGQDIQLIPPLINLLMSIEP DVIYAGHDNTKPDTSSSLLTSLNQLGERQLLSWKWSKSLPGFRNLHIDDQITLIQYS WMSLMVFGLG RSYKHVSGQMLYFAPDLILNEQRMKESSFYSLCLTM QIPQEFVKLQ VSQEEFLCMKVLLLLNTIPLEGLRSQTQFEEMRSSYIRELIKAIGLRQKGWSSSQRF YQLTKLLDNLHDLVKQLHLYCLNTFIQSRALSVEFPEMMSEVIAAQLPKILAGMVKPL LFHKK
(SEQ ID NO: 131)
Human polynucleotide sequence: ATGACTGAGCTGAAGGCAAAGGGTCCCCGGGCTCCCCACGTGGCGGGCGGCCCGCCCT CCCCCGAGGTCGGATCCCCACTGCTGTGTCGCCCAGCCGCAGGTCCGTTCCCGGGGAG CCAGACCTCGGACACCTTGCCTGAAGTTTCGGCCATACCTATCTCCCTGGACGGGCTA CTCTTCCCTCGGCCCTGCCAGGGACAGGACCCCTCCGACGAAAAGACGCAGGACCAGC AGTCGCTGTCGGACGTGGAGGGCGCATATTCCAGAGCTGAAGCTACAAGGGGTGCTGG AGGCAGCAGTTCTAGTCCCCCAGAAAAGGACAGCGGACTGCTGGACAGTGTCTTGGAC ACTCTGTTGGCGCCCTCAGGTCCCGGGCAGAGCCAACCCAGCCCTCCCGCCTGCGAGG TCACCAGCTCTTGGTGCCTGTTTGGCCCCGAACTTCCCGAAGATCCACCGGCTGCCCC CGCCACCCAGCGGGTGTTGTCCCCGCTCATGAGCCGGTCCGGGTGCAAGGTTGGAGAC AGCTCCGGGACGGCAGCTGCCCATAAAGTGCTGCCCCGGGGCCTGTCACCAGCCCGGC AGCTGCTGCTCCCGGCCTCTGAGAGCCCTCACTGGTCCGGGGCCCCAGTGAAGCCGTC TCCGCAGGCCGCTGCGGTGGAGGTTGAGGAGGAGGATAGCTCTGAGTCCGAGGAGTCT GCGGGTCCGCTTCTGAAGGGCAAACCTCGGGCTCTGGGTGGCGCGGCGGCTGGAGGAG GAGCCGCGGCTTGTCCGCCGGGGGCGGCAGCAGGAGGCGTCGCCCTGGTCCCCAAGGA AGATTCCCGCTTCTCAGCGCCCAGGGTCGCCCTGGTGGAGCAGGACGCGCCGATGGCG CCCGGGCGCTCCCCGCTGGCCACCACGGTGATGGATTTCATCCACGTGCCTATCCTGC CTCTCAATCACGCCTTATTGGCAGCCCGCACTCGGCAGCTGCTGGAAGACGAAAGTTA CGACGGCGGGGCCGGGGCTGCCAGCGCCTTTGCCCCGCCGCGGACTTCACCCTGTGCC TCGTCCACCCCGGTCGCTGTAGGCGACTTCCCCGACTGCGCGTACCCGCCCGACGCCG AGCCCAAGGACGACGCGTACCCTCTCTATAGCGACTTCCAGCCGCCCGCTCTAAAGAT AAAGGAGGAGGAGGAAGGCGCGGAGGCCTCCGCGCGCTCCCCGCGTTCCTACCTTGTG GCCGGTGCCAACCCCGCAGCCTTCCCGGATTTCCCGTTGGGGCCACCGCCCCCGCTGC CGCCGCGAGCGACCCCATCCAGACCCGGGGAAGCGGCGGTGACGGCCGCACCCGCCAG TGCCTCAGTCTCGTCTGCGTCCTCCTCGGGGTCGACCCTGGAGTGCATCCTGTACAAA GCGGAGGGCGCGCCGCCCCAGCAGGGCCCGTTCGCGCCGCCGCCCTGCAAGGCGCCGG GCGCGAGCGGCTGCCTGCTCCCGCGGGACGGCCTGCCCTCCACCTCCGCCTCTGCCGC CGCCGCCGGGGCGGCCCCCGCGCTCTACCCTGCACTCGGCCTCAACGGGCTCCCGCAG CTCGGCTACCAGGCCGCCGTGCTCAAGGAGGGCCTGCCGCAGGTCTACCCGCCCTATC TCAACTACCTGAGGCCGGATTCAGAAGCCAGCCAGAGCCCACAATACAGCTTCGAGTC ATTACCTCAGAAGATTTGTTTAATCTGTGGGGATGAAGCATCAGGCTGTCATTATGGT GTCCTTACCTGTGGGAGCTGTAAGGTCTTCTTTAAGAGGGCAATGGAAGGGCAGCACA ACTACTTATGTGCTGGAAGAAATGACTGCATCGTTGATAAAATCCGCAGAAAAAACTG CCCAGCATGTCGCCTTAGAAAGTGCTGTCAGGCTGGCATGGTCCTTGGAGGTCGAAAA TTTAAAAAGTTCAATAAAGTCAGAGTTGTGAGAGCACTGGATGCTGTTGCTCTCCCAC AGCCATTGGGCGTTCCAAATGAAAGCCAAGCCCTAAGCCAGAGATTCACTTTTTCACC AGGTCAAGACATACAGTTGATTCCACCACTGATCAACCTGTTAATGAGCATTGAACCA GATGTGATCTATGCAGGACATGACAACACAAAACCTGACACCTCCAGTTCTTTGCTGA CAAGTCTTAATCAACTAGGCGAGAGGCAACTTCTTTCAGTAGTCAAGTGGTCTAAATC ATTGCCAGGTTTTCGAAACTTACATATTGATGACCAGATAACTCTCATTCAGTATTCT TGGATGAGCTTAATGGTGTTTGGTCTAGGATGGAGATCCTACAAACATGTCAGTGGGC AGATGCTGTATTTTGCACCTGATCTAATACTAAATGAACAGCGGATGAAAGAATCATC ATTCTATTCATTATGCCTTACCATGTGGCAGATCCCACAGGAGTTTGTCAAGCTTCAA GTTAGCCAAGAAGAGTTCCTCTGTATGAAAGTATTGTTACTTCTTAATACAATTCCTT TGGAAGGGCTACGAAGTCAAACCCAGTTTGAGGAGATGAGGTCAAGCTACATTAGAGA GCTCATCAAGGCAATTGGTTTGAGGCAAAAAGGAGTTGTGTCGAGCTCACAGCGTTTC TATCAACTTACAAAACTTCTTGATAACTTGCATGATCTTGTCAAACAGCTTCATCTGT ACTGCTTGAATACATTTATCCAGTCCCGGGCACTGAGTGTTGAATTTCCAGAAATGAT GTCTGAAGTTATTGCTGCACAATTACCCAAGATATTGGCAGGGATGGTGAAACCCCTT CTCTTTCATAAAAAGTGA (SEQ ID NO: 132) Mouse polypeptide sequence:
MTELQAKDPQVLHTSGASPSPPHIGSPLLARLDSGPFQGSQHSDVSSWSPIPISLDG LLFPRSCRGPELPDGKTGDQQSLSDVEGAFSGVEATHREGGRNSRPPEKDSRLLDSVL DSLLTPSGPEQSHASPPACEAITS CLFGPELPEDPRSVPATKGLLSPLMSRPEIKVG DQSGTGRGQKVLPKGLSPPRQLLLPTSGSAHWPGAGVKPSPQPAAGEVEEDSGLETEG SASPLLKSKPRALEGTGQGGGVAANAPSAAPGGVTLVPKEDSRFSAPRVSLEQDSPIA PGRSPLATTWDFIHVPILPLNHALLAARTRQLLEGESYDGGATAGPFCPPRSPSAPS TPVPRGDFPDCTYPLEGDPKEDVFPLYGDFQTPGLKIKEEEEGADAAVRSPRPYLSAG ASSSTFPDFPLAPAPQAAPSSRPGEAAVAGGPSSAAVSPASSSGSALECILYKAEAPP TQGSFAPLPCKPPAAASCLLPRDSLPAAPGTAAAPAIYQPLGLNGLPQLGYQAAVLKD SLPQVYPPYLNYLRPDSEASQSPQYGFDSLPQKICLICGDEASGCHYGVLTCGSCKVF FKRAMEGQHNYLCAGRNDCIVDKIRRKNCPACRLRKCCQAGMVLGGRKFKKFNKVRVM RTLDGVALPQSVGLPNESQALSQRITFSPNQEIQLVPPLINLLMSIEPDVIYAGHDNT KPDTSSSLLTSLNQLGERQLLSWK SKSLPGFRNLHIDDQITLIQYS MSLMVFGLG WRSYKHVSGQMLYFAPDLILNEQRMKELSFYSLCLTMWQIPQEFVKLQVTHEEFLCMK VLLLLNTIPLEGLRSQSQFEEMRSSYIRELIKAIGLRQKGWPTSQRFYQLTKLLDSL HDLVKQLHLYCLNTFIQSRTLAVEFPEMMSEVIAAQLPKILAGMVKPLLFHKK (SEQ IDNO: 133) Mouse polynucleotide sequence:
ATGACTGAGCTGCAGGCAAAGGATCCGCAGGTTCTCCACACGTCTGGCGCTTCGCCCT CCCCCCCACACATCGGGTCCCCCTTGCTTGCACGCTTGGACTCAGGTCCCTTCCAAGG GAGCCAGCACTCGGACGTGTCGTCTGTAGTCTCGCCTATACCGATCTCCCTGGACGGG CTGCTTTTTCCTCGGTCCTGCCGGGGTCCCGAGCTCCCAGACGGAAAGACAGGGGACC AGCAGTCGCTGTCCGACGTGGAGGGCGCTTTCTCTGGGGTAGAAGCCACTCATAGGGA GGGAGGCAGAAATTCCAGACCCCCGGAGAAGGACAGCAGACTCTTAGACAGTGTCTTA GACTCGTTGTTGACTCCCTCCGGACCGGAACAGAGTCACGCCAGCCCTCCAGCCTGCG AGGCCATCACTTCCTGGTGTCTCTTTGGGCCAGAGCTTCCAGAAGACCCCCGCAGTGT CCCTGCTACCAAAGGGTTGTTGTCCCCGCTCATGAGTCGGCCAGAGATCAAGGTCGGC 'GACCAGTCCGGGACAGGACGAGGACAGAAGGTGCTGCCCAAAGGACTGTCACCACCCA GGCAGCTGTTGCTCCCTACCTCGGGGAGTGCTCACTGGCCCGGGGCAGGGGTGAAGCC GTCCCCGCAGCCAGCTGCAGGGGAGGTGGAAGAGGACAGTGGCCTGGAGACCGAGGGC TCTGCCAGTCCGCTTCTAAAGAGCAAACCTCGAGCACTGGAAGGCACCGGCCAGGGAG GAGGAGTCGCAGCCAACGCGCCGTCAGCGGCCCCAGGCGGTGTCACTCTGGTCCCAAA GGAAGATTCACGGTTTTCTGCTCCTAGGGTCTCCTTGGAGCAAGACTCTCCCATTGCC CCCGGGCGCTCCCCACTGGCCACCACAGTGGTGGATTTCATCCATGTGCCCATCCTGC CTCTGAACCACGCACTCCTGGCCGCCCGCACCCGGCAGCTGCTGGAGGGGGAGAGCTA CGACGGCGGGGCCACAGCAGGGCCCTTTTGCCCGCCTAGGTCGCCCTCCGCGCCATCC ACCCCGGTGCCCCGCGGTGACTTCCCAGACTGCACCTACCCTCTGGAAGGCGACCCCA AAGAGGACGTGTTCCCTCTTTACGGCGACTTCCAGACGCCTGGCTTGAAGATCAAGGA GGAGGAGGAAGGCGCGGATGCTGCTGTGCGCTCGCCGCGCCCCTACCTGTCGGCTGGA GCCAGCTCCTCCACCTTCCCAGACTTCCCGCTGGCACCCGCGCCGCAGGCAGCGCCAT CCTCCAGGCCCGGAGAAGCGGCGGTGGCCGGCGGACCCAGCAGCGCCGCGGTGTCGCC AGCGTCCTCCTCCGGCTCCGCGCTGGAGTGCATCCTGTACAAAGCGGAAGCGCCGCCC ACGCAGGGTTCGTTCGCGCCACTGCCGTGCAAGCCCCCAGCCGCCGCGTCCTGCCTAC TACCCCGGGACAGCCTGCCGGCCGCCCCCGGCACCGCCGCAGCACCCGCCATCTACCA GCCGCTCGGCCTCAATGGGCTCCCGCAGCTGGGCTACCAGGCCGCGGTGCTCAAGGAC AGCCTGCCCCAGGTCTACCCGCCATACCTCAACTACCTGAGGCCAGATTCAGAAGCCA GCCAGAGCCCACAGTATGGCTTTGATTCCTTACCTCAGAAGATCTGCTTAATCTGCGG GGATGAAGCATCTGGCTGTCACTATGGCGTGCTTACCTGTGGGAGCTGCAAGGTCTTC TTTAAGAGGGCAATGGAAGGGCAGCATAACTATTTATGTGCTGGAAGAAATGACTGCA TTGTTGATAAAATTCGCAGAAAAAACTGCCCAGCATGTCGTCTGAGAAAGTGTTGTCA GGCTGGCATGGTCCTTGGAGGTCGTAAGTTTAAGAAGTTTAATAAAGTCCGAGTTATG AGAACCCTTGACGGTGTTGCTCTCCCCCAGTCGGTGGGCCTTCCTAACGAGAGCCAGG CCCTGAGCCAGAGAATCACCTTTTCACCAAATCAAGAAATTCAACTGGTCCCGCCACT CATCAACCTGCTCATGAGCATTGAGCCTGATGTGATCTATGCAGGGCATGACAACACA AAGCCTGACACTTCCAGCTCTTTGCTGACCAGTCTCAACCAACTAGGCGAGAGACAAC TGCTTTCAGTAGTCAAATGGTCTAAATCTCTGCCAGGTTTCCGGAACTTACACATTGA TGACCAGATAACCCTGATTCAGTACTCCTGGATGAGCCTGATGGTGTTTGGCCTGGGG TGGAGGTCGTACAAGCATGTCAGTGGACAGATGCTATATTTTGCACCTGATCTAATCC TAAATGAGCAGAGGATGAAGGAGCTGTCATTCTACTCGCTGTGCCTTACCATGTGGCA AATCCCACAGGAGTTTGTCAAACTCCAGGTGACCCATGAGGAATTCCTCTGTATGAAA GTCTTACTACTTCTTAACACAATTCCTTTGGAAGGACTGAGGAGTCAAAGCCAGTTTG AAGAGATGAGATCAAGCTATATCCGCGAATTGATCAAGGCAATTGGTTTAAGACAGAA AGGGGTTGTCCCCACGTCACAGCGCTTCTACCAACTCACAAAACTTCTCGACAGCTTG CATGATCTTGTGAAACAGCTCCACCTGTACTGCTTGAATACATTCATCCAATCCCGGA CACTGGCTGTGGAATTTCCGGAAATGATGTCTGAAGTTATTGCTGCCCAGTTGCCCAA GATCCTGGCGGGCATGGTGAAGCCGCTCCTCTTTCACAAAAAGTGA (SEQ IDNO: 134) PXR
Human polypeptide sequence: MEVRPKESWNHADFVHCEDTESVPGKPSVNADEEVGGPQICRVCGDKATGYHFNVMTC EGCKGFFRRAMKRNARLRCPFRKGACEITRKTRRQCQACRLRKCLESGMKKEMIMSDE AVEERRALIKRKKSERTGTQPLGVQGLTEEQRMMIRELMDAQMKTFDTTFSHFKNFRL PGVLSSGCELPESLQAPSREEAAKWSQVRKDLCSLKVSLQLRGEDGSV NYKPPADSG GKEIFSLLPHMADMSTYMFKGIISFAKVISYFRDLPIEDQISLLKGAAFELCQLRFNT VFNAETGT ECGRLSYCLEDTAGGFQQLLLEPMLKFHYMLKKLQLHEEEYVLMQAISL FSPDRPGVLQHRWDQLQEQFAITLKSYIECNRPQPAHRFLFLKIMAMLTELRSINAQ HTQRLLRIQDIHPFATPLMQELFGITGS (SEQ IDNO: 135) Human polynucleotide sequence:
CTGGAGGTGAGACCCAAAGAAAGCTGGAACCATGCTGACTTTGTACACTGTGAGGACA CAGAGTCTGTTCCTGGAAAGCCCAGTGTCAACGCAGATGAGGAAGTCGGAGGTCCCCA AATCTGCCGTGTATGTGGGGACAAGGCCACTGGCTATCACTTCAATGTCATGACATGT GAAGGATGCAAGGGCTTTTTCAGGAGGGCCATGAAACGCAACGCCCGGCTGAGGTGCC CCTTCCGGAAGGGCGCCTGCGAGATCACCCGGAAGACCCGGCGACAGTGCCAGGCCTG CCGCCTGCGCAAGTGCCTGGAGAGCGGCATGAAGAAGGAGATGATCATGTCCGACGAG GCCGTGGAGGAGAGGCGGGCCTTGATCAAGCGGAAGAAAAGTGAACGGACAGGGACTC AGCCACTGGGAGTGCAGGGGCTGACAGAGGAGCAGCGGATGATGATCAGGGAGCTGAT GGACGCTCAGATGAAAACCTTTGACACTACCTTCTCCCATTTCAAGAATTTCCGGCTG CCAGGGGTGCTTAGCAGTGGCTGCGAGTTGCCAGAGTCTCTGCAGGCCCCATCGAGGG AAGAAGCTGCCAAGTGGAGCCAGGTCCGGAAAGATCTGTGCTCTTTGAAGGTCTCTCT GCAGCTGCGGGGGGAGGATGGCAGTGTCTGGAACTACAAACCCCCAGCCGACAGTGGC GGGAAAGAGATCTTCTCCCTGCTGCCCCACATGGCTGACATGTCAACCTACATGTTCA AAGGCATCATCAGCTTTGCCAAAGTCATCTCCTACTTCAGGGACTTGCCCATCGAGGA CCAGATCTCCCTGCTGAAGGGGGCCGCTTTCGAGCTGTGTCAACTGAGATTCAACACA GTGTTCAACGCGGAGACTGGAACCTGGGAGTGTGGCCGGCTGTCCTACTGCTTGGAAG ACACTGCAGGTGGCTTCCAGCAACTTCTACTGGAGCCCATGCTGAAATTCCACTACAT GCTGAAGAAGCTGCAGCTGCATGAGGAGGAGTATGTGCTGATGCAGGCCATCTCCCTC TTCTCCCCAGACCGCCCAGGTGTGCTGCAGCACCGCGTGGTGGACCAGCTGCAGGAGC AATTCGCCATTACTCTGAAGTCCTACATTGAATGCAATCGGCCCCAGCCTGCTCATAG GTTCTTGTTCCTGAAGATCATGGCTATGCTCACCGAGCTCCGCAGCATCAATGCTCAG CACACCCAGCGGCTGCTGCGCATCCAGGACATACACCCCTTTGCTACGCCCCTCATGC AGGAGTTGTTCGGCATCACAGGTAGCTGA (SEQ IDNO: 136)
Mouse polypeptide sequence: MRPEES SRVGLVQCEEADSALEEPINVEEEDGGLQICRVCGDKANGYHFNVMTCEGC KGFFRRAMKRNVRLRCPFRKGTCEITRKTRRQCQACRLRKCLESGMKKEMIMSDAAVE QRRALIKRKKREKIEAPPPGGQGLTEEQQALIQELMDAQMQTFDTTFSHFKDFRLPAV FHSGCELPEFLQASLLEDPATWSQIMKDRVPMKISLQLRGEDGSI NYQPPSKSDGKE IIPLLPHLADVSTYMFKGVINFAKVISYFRDLPIEDQISLLKGATFEMCILRFNTMFD TETGTWECGRLAYCFEDPNGGFQKLLLDPLMKFHCMLKKLQLHKEEYVLMQAISLFSP DRPGWQRSWDQLQERFALTLKAYIECSRPYPAHRFLFLKIMAVLTELRSINAQQTQ QLLRIQDSHPFATPLMQELFSSTDG (SEQ ID NO: 137) Mouse polynucleotide sequence:
ATGAGACCTGAGGAGAGCTGGAGCCGAGTTGGCCTTGTACAGTGTGAAGAAGCAGACT CTGCCTTGGAAGAGCCCATCAACGTAGAGGAGGAAGATGGAGGTCTTCAAATCTGCCG TGTATGTGGGGACAAGGCCAATGGCTACCACTTCAATGTCATGACGTGTGAAGGATGC AAGGGGTTTTTCAGAAGGGCCATGAAACGCAATGTCCGGCTGAGGTGCCCCTTCCGCA AGGGAACCTGCGAGATCACCCGGAAGACACGACGGCAGTGCCAGGCCTGCCGTTTGCG CAAGTGCCTGGAGAGTGGCATGAAGAAAGAGATGATCATGTCCGATGCCGCTGTGGAG CAGAGGCGGGCCTTGATCAAGAGGAAGAAGAGGGAAAAGATTGAGGCTCCACCGCCTG GAGGGCAGGGGCTGACGGAAGAACAGCAGGCGCTGATCCAGGAGCTGATGGACGCTCA GATGCAAACCTTTGACACAACTTTCTCCCACTTCAAGGATTTCCGGCTGCCTGCAGTG TTCCACAGTGGCTGTGAGCTTCCAGAGTTTCTGCAGGCCTCACTGTTGGAAGACCCTG CCACATGGAGTCAAATCATGAAAGACAGGGTTCCAATGAAGATCTCTCTGCAGCTGCG CGGAGAAGACGGCAGCATCTGGAACTACCAACCCCCTTCCAAGAGCGACGGGAAAGAG ATCATCCCTCTTCTGCCACACCTGGCCGATGTGTCAACCTACATGTTCAAGGGCGTCA TCAACTTCGCCAAAGTCATATCCTACTTTAGGGACCTGCCTATTGAGGACCAGATCTC CCTGCTGAAGGGGGCCACTTTTGAGATGTGCATCCTGAGGTTCAACACGATGTTCGAC ACGGAAACGGGAACCTGGGAGTGCGGCCGGCTGGCTTACTGCTTCGAAGACCCTAATG GTGGCTTCCAGAAACTTCTGTTGGATCCATTGATGAAATTCCACTGCATGCTGAAGAA GCTACAGCTGCATAAGGAGGAGTATGTGCTGATGCAGGCCATCTCCCTCTTCTCCCCA GATCGTCCTGGTGTGGTCCAGCGCAGCGTGGTAGACCAACTGCAGGAGAGGTTTGCCC TCACCCTGAAGGCCTACATTGAGTGTAGTCGGCCATATCCTGCTCACAGGTTCCTGTT CCTGAAGATCATGGCCGTCCTCACTGAGCTGCGAAGCATCAACGCCCAGCAAACCCAG CAGTTGCTGCGCATCCAAGACTCGCACCCCTTTGCCACCCCACTCATGCAAGAGTTAT TTAGCAGCACAGATGGCTGA (SEQ IDNO: 138)
RORA Human polypeptide sequence:
MNEGAPGDSDLETEARVPWSIMGHCLRTGQARMSATPTPAGEGARRDELFGILQILHQ CILSSGDAFVLTGVCCSWRQNGKPPYSQKEDKEVQTGYMNAQIEIIPCKICGDKSSGI HYGVITCEGCKGFFRRSQQSNATYSCPRQKNCLIDRTSRNRCQHCRLQKCLAVGMSRD AVKFGRMSKKQRDSLYAEVQKHRMQQQQRDHQQQPGEAEPLTPTYNISANGLTELHDD LSNYIDGHTPEGSKADSAVSSFYLDIQPSPDQSGLDINGIKPEPICDYTPASGFFPYC SFTNGETSPTVSMAELEHLAQNISKSHLETCQYLREELQQITWQTFLQEEIENYQNKQ REVMWQLCAIKITEAIQYWEFAKRIDGFMELCQNDQIVLLKAGSLEWFIRMCRAFD SQNNTVYFDGKYASPDVFKSLGCEDFISFVFEFGKSLCSMHLTEDEIALFSAFVLMSA DRSWLQEKVKIEKLQQKIQLALQHVLQKNHREDGILTKLICKVSTLRALCGRHTEKLM AFKAIYPDIVRLHFPPLYKELFTSEFEPAMQIDG (SEQ IDNO: 139)
Human polynucleotide sequence:
ATGAATGAGGGGGCCCCAGGAGACAGTGACTTAGAGACTGAGGCAAGAGTGCCGTGGT CAATCATGGGTCATTGTCTTCGAACTGGACAGGCCAGAATGTCTGCCACACCCACACC TGCAGGTGAAGGAGCCAGAAGGGATGAACTTTTTGGGATTCTCCAAATACTCCATCAG TGTATCCTGTCTTCAGGTGATGCTTTTGTTCTTACTGGCGTCTGTTGTTCCTGGAGGC AGAATGGCAAGCCACCATATTCACAAAAGGAAGATAAGGAAGTACAAACTGGATACAT GAATGCTCAAATTGAAATTATTCCATGCAAGATCTGTGGAGACAAATCATCAGGAATC CATTATGGTGTCATTACATGTGAAGGCTGCAAGGGCTTTTTCAGGAGAAGTCAGCAAA GCAATGCCACCTACTCCTGTCCTCGTCAGAAGAACTGTTTGATTGATCGAACCAGTAG AAACCGCTGCCAACACTGTCGATTACAGAAATGCCTTGCCGTAGGGATGTCTCGAGAT GCTGTAAAATTTGGCCGAATGTCAAAAAAGCAGAGAGACAGCTTGTATGCAGAAGTAC AGAAACACCGGATGCAGCAGCAGCAGCGCGACCACCAGCAGCAGCCTGGAGAGGCTGA GCCGCTGACGCCCACCTACAACATCTCGGCCAACGGGCTGACGGAACTTCACGACGAC CTCAGTAACTACATTGACGGGCACACCCCTGAGGGGAGTAAGGCAGACTCCGCCGTCA GCAGCTTCTACCTGGACATACAGCCTTCCCCAGACCAGTCAGGTCTTGATATCAATGG AATCAAACCAGAACCAATATGTGACTACACACCAGCATCAGGCTTCTTTCCCTACTGT TCGTTCACCAACGGCGAGACTTCCCCAACTGTGTCCATGGCAGAATTAGAACACCTTG CACAGAATATATCTAAATCGCATCTGGAAACCTGCCAATACTTGAGAGAAGAGCTCCA GCAGATAACGTGGCAGACCTTTTTACAGGAAGAAATTGAGAACTATCAAAACAAGCAG CGGGAGGTGATGTGGCAATTGTGTGCCATCAAAATTACAGAAGCTATACAGTATGTGG TGGAGTTTGCCAAACGCATTGATGGATTTATGGAACTGTGTCAAAATGATCAAATTGT GCTTCTAAAAGCAGGTTCTCTAGAGGTGGTGTTTATCAGAATGTGCCGTGCCTTTGAC TCTCAGAACAACACCGTGTACTTTGATGGGAAGTATGCCAGCCCCGACGTCTTCAAAT CCTTAGGTTGTGAAGACTTTATTAGCTTTGTGTTTGAATTTGGAAAGAGTTTATGTTC TATGCACCTGACTGAAGATGAAATTGCATTATTTTCTGCATTTGTACTGATGTCAGCA GATCGCTCATGGCTGCAAGAAAAGGTAAAAATTGAAAAACTGCAACAGAAAATTCAGC TAGCTCTTCAACACGTCCTACAGAAGAATCACCGAGAAGATGGAATACTAACAAAGTT AATATGCAAGGTGTCTACATTAAGAGCCTTATGTGGACGACATACAGAAAAGCTAATG GCATTTAAAGCAATATACCCAGACATTGTGCGACTTCATTTTCCTCCATTATACAAGG AGTTGTTCACTTCAGAATTTGAGCCAGCAATGCAAATTGATGGGTAA (SEQ ID NO: 140)
Mouse polypeptide sequence:
MESAPAAPDPAASEPGSSGSEAAAGSRETPLTQDTGRKSEAPGAGRRQSYASSSRGIS VTKKTHTSQIEIIPCKICGDKSSGIHYGVITCEGCKGFFRRSQQSNATYSCPRQKNCL IDRTSRNRCQHCRLQKCLAVGMSRDAVKFGRMSKKQRDSLYAEVQKHRMQQQQRDHQQ QPGEAEPLTPTYNISANGLTELHDDLSTYMDGHTPEGSKADSAVSSFYLDIQPSPDQS GLDINGIKPEPICDYTPASGFFPYCSFTNGETSPTVSMAELEHLAQNISKSHLETCQY LREELQQITWQTFLQEEIENYQNKQREVMWQLCAIKITEAIQYWEFAKRIDGFMELC QNDQIVLLKAGSLEWFIRMCRAFDSQNNTVYFDGKYASPDVFKSLGCEDFISFVFEF GKSLCSMHLTEDEIALFSAFVLMSADRSWLQEKVKIEKLQQKIQLALQHVLQKNHRED GILTKLICKVSTLRALCGRHTEKLMAFKAIYPDIVRLHFPPLYKELFTSEFEPAMQID G (SEQ ID NO: 141)
Mouse polynucleotide sequence:
ATGGAGTCAGCTCCGGCAGCCCCCGACCCCGCCGCCAGCGAACCGGGCAGCAGCGGCT CGGAGGCGGCCGCGGGCTCCAGGGAGACCCCGCTGACCCAGGACACGGGCCGCAAGAG CGAGGCACCGGGCGCGGGGCGCAGGCAGAGCTATGCGAGCTCCAGCCGAGGTATCTCA GTCACGAAGAAGACACACACATCTCAAATTGAAATTATTCCATGCAAGATCTGTGGAG ACAAATCGTCAGGAATCCATTATGGTGTCATTACGTGTGAAGGCTGCAAGGGCTTTTT CAGGAGAAGTCAGCAGAGCAATGCCACCTACTCCTGTCCTCGTCAGAAGAACTGTTTG ATTGATCGGACCAGCAGAAACCGCTGCCAGCATTGTCGGCTGCAGAAATGCCTGGCCG TGGGGATGTCTCGAGATGCTGTCAAGTTTGGTCGGATGTCCAAGAAGCAGAGAGACAG CTTGTACGCCGAGGTGCAGAAGCACCGGATGCAGCAGCAGCAGCGAGACCACCAGCAG CAGCCTGGGGAGGCGGAGCCGCTGACGCCCACCTACAACATCTCAGCCAATGGGCTGA CGGAACTGCATGATGACCTCAGCACCTATATGGATGGGCACACCCCCGAGGGCAGCAA GGCCGACTCAGCCGTCAGCAGCTTCTACCTGGACATCCAGCCCTCCCCAGACCAGTCG GGATTGGACATCAATGGGATCAAACCCGAACCCATATGTGACTACACACCAGCATCTG GCTTCTTCCCCTACTGTTCCTTCACCAACGGAGAGACTTCCCCAACCGTGTCCATGGC AGAACTAGAACACCTTGCCCAGAACATATCCAAATCCCACCTGGAAACCTGCCAGTAC TTGCGGGAAGAGCTCCAGCAGATAACGTGGCAGACCTTCCTGCAGGAGGAGATTGAAA ACTACCAGAACAAGCAGAGAGAGGTGATGTGGCAGCTGTGTGCCATCAAGATTACAGA AGCTATCCAGTATGTGGTGGAGTTTGCCAAACGCATTGATGGATTTATGGAGCTGTGT CAAAATGATCAAATTGTGCTTCTAAAAGCAGGCTCGCTAGAGGTGGTGTTTATTAGGA TGTGCCGTGCCTTTGACTCTCAGAACAACACCGTGTACTTTGACGGGAAGTATGCGAG CCCCGATGTCTTCAAGTCCCTAGGTTGTGAAGACTTCATCAGCTTTGTGTTTGAATTT GGGAAGAGTTTGTGTTCTATGCACCTGACCGAAGACGAAATCGCGTTATTTTCTGCAT TCGTACTGATGTCAGCGGATCGCTCGTGGCTTCAGGAAAAGGTAAAAATAGAAAAGCT GCAACAGAAAATTCAGCTGGCCCTTCAGCACGTCCTACAGAAGAACCACCGAGAAGAT GGAATTCTAACCAAGCTAATATGCAAGGTGTCTACGTTAAGAGCCCTATGTGGACGAC ATACGGAAAAGCTAATGGCATTTAAAGCAATATACCCAGACATTGTGCGACTCCATTT TCCTCCATTATACAAGGAATTGTTCACTTCAGAATTTGAGCCAGCCATGCAAATCGAT GGGTAA (SEQ IDNO: 142)
RORB
Human polypeptide sequence:
MRAQIEVIPCKICGDKSSGIHYGVITCEGCKGFFRRSQQNNASYSCPRQRNCLIDRTN RNRCQHCRLQKCLALGMSRDAVKFGRMSKKQRDSLYAEVQKHQQRLQEQRQEQSGEAE RLARVYSSSISNGLSNLNNETSGTYANGSVIDLPKSEGYYNWSGQPSPDQSGLDMTG IKQIKQEPIYDLTSVPNLFTYSSFNNGQLAPGITMTEIDRIAQNIIKSHLETCQYTME ELHQLA QTHTYEEIKAYQSKSREALWQQCAIQITHAIQYWEFAKRITGFMELCQND QILLLKSGCLEWLVRMCRAFNPLNNTVLFEGKYGGMQMFKALGSDDLVNEAFDFAKN LCSLQLTEEEIALFSSAVLISPDRA LIEPRKVQKLQEKIYFALQHVIQKNHLDDETL AKLIAKIPTITAVCNLHGEKLQVFKQSHPEIVNTLFPPLYKELFNPDCATACK (SEQ ID NO: 143)
Human polynucleotide sequence:
ATGCGAGCACAAATTGAAGTGATACCATGCAAAATTTGTGGCGATAAGTCCTCTGGGA TCCACTACGGAGTCATCACATGTGAAGGCTGCAAGGGATTCTTTAGGAGGAGCCAGCA GAACAATGCTTCTTATTCCTGCCCAAGGCAGAGAAACTGTTTAATTGACAGAACGAAC AGAAACCGTTGCCAACACTGCCGACTGCAGAAGTGTCTTGCCCTAGGAATGTCAAGAG ATGCTGTGAAGTTTGGGAGGATGTCCAAGAAGCAAAGGGACAGCCTGTATGCTGAGGT GCAGAAGCACCAGCAGCGGCTGCAGGAACAGCGGCAGGAGCAGAGTGGGGAGGCAGAA CGCCTTGCCAGGGTGTACAGCAGCAGCATTAGCAACGGCCTGAGCAACCTGAACAACG AGACCAGCGGCACTTATGCCAACGGCAGCGTCATTGACCTGCCCAAGTCTGAGGGTTA TTACAACGTCGTTTCCGGTCAGCCGTCCCCTGATCAGTCAGGACTTGACATGACTGGA ATCAAACAGATAAAGCAAGAACCTATCTATGACCTCACATCCGTACCCAACTTGTTTA CCTATAGCTCTTTCAACAATGGGCAGTTAGCACCAGGGATAACCATGACTGAAATCGA CCGAATTGCACAGAACATCATTAAGTCCCATTTGGAGACATGTCAATACACCATGGAA GAGCTGCACCAGCTGGCGTGGCAGACCCACACCTATGAAGAAATTAAAGCATATCAAA GCAAGTCCAGGGAAGCACTGTGGCAACAATGTGCCATCCAGATCACTCACGCCATCCA ATACGTGGTGGAGTTTGCAAAGCGGATAACAGGCTTCATGGAGCTCTGTCAAAATGAT CAAATTCTACTTCTGAAGTCAGGTTGCTTGGAAGTGGTTTTAGTGAGAATGTGCCGTG CCTTCAACCCATTAAACAACACTGTTCTGTTTGAAGGAAAATATGGAGGAATGCAAAT GTTCAAAGCCTTAGGTTCTGATGACCTAGTGAATGAAGCATTTGACTTTGCAAAGAAT TTGTGTTCCTTGCAGCTGACCGAGGAGGAGATCGCTTTGTTCTCATCTGCTGTTCTGA TATCTCCAGACCGAGCCTGGCTTATAGAACCAAGGAAAGTCCAGAAGCTTCAGGAAAA AATTTATTTTGCACTTCAACATGTGATTCAGAAGAATCACCTGGATGATGAGACCTTG GCAAAGTTAATAGCCAAGATACCAACCATCACGGCAGTTTGCAACTTGCACGGGGAGA AGCTGCAGGTATTTAAGCAATCTCATCCAGAGATAGTGAATACACTGTTTCCTCCGTT ATACAAGGAGCTCTTTAATCCTGACTGTGCCACCGCGTGCAAATGA (SEQ IDNO: 144) Mouse polypeptide sequence:
MSKKQRDSLYAEVQKHQQRLQEQRQQQSGEAEALARVYSSSISNGLSNLNTETGGTYA NGHVIDLPKSEGYYSIDSGQPSPDQSGLDMTGIKQIKQEPIYDLTSVPNLFTYSSFNN GQLAPGITMSEIDRIAQNIIKSHLETCQYTMEELHQLA QTHTYEEIKAYQSKSREAL WQQCAIQITHAIQYWEFAKRITGFMELCQNDQILLLKSGCLEWLVRMCRAFNPLNN TVLFEGKYGGMQMFKALGSDDLVNEAFDFAKNLCSLQLTEEEIALFSSAVLISPDRAW 'LIEPRKVQKLQEKIYFALQHVIQKNHLDDETLAKLIAKIPTITAVCNLHGEKLQVFKQ SHPDIVNTLFPPLYKELFNPDCAAVCK (SEQ ID NO: 145)
Mouse polynucleotide sequence:
AGGGGCAGTCCTCAGACCTCAAGTGAAACGGGGAGATATTTTTCAGTCAGGCTTTTCA CTGCTCCGTCAGAATGTGTGAGAACCAGCCCAAAACTAAAGCTGACGGCACTGAGCAA GCATAGCACGCAGCACTCTGTGGGCAATTACACGAAGATCCATCAAAGCACAAATTGA AGTGATACCATGCAAAATTTGTGGCGATAAATCCTCCGGGATCCACTACGGAGTCATC ACGTGTGAAGGCTGCAAGGGATTCTTCAGGAGGAGCCAGCAGAACAATGCCTCTTACT CCTGCCCAAGGCAGAGAAACTGTTTAATTGACAGAACCAACAGGAACCGTTGCCAACA CTGCCGCCTGCAGAAGTGTCTTGCCCTAGGAATGTCAAGAGATGCTGTAAAGTTCGGG AGGATGTCCAAGAAGCAGCGGGACAGCCTGTATGCTGAGGTGCAGAAGCATCAGCAAA GGCTGCAGGAGCAGCGGCAGCAGCAGAGTGGGGAGGCGGAGGCCCTCGCCAGGGTGTA CAGCAGCAGCATTAGCAATGGCCTCAGCAACCTGAACACCGAGACCGGCGGCACATAC GCCAACGGGCACGTCATTGACCTGCCCAAGTCCGAAGGTTATTACAGCATAGATTCCG GTCAGCCGTCTCCCGATCAGTCAGGACTGGACATGACTGGGATCAAACAGATAAAGCA AGAACCTATCTATGACCTCACATCTGTACCCAACTTGTTTACCTATAGCTCTTTCAAC AACGGGCAGTTAGCTCCCGGGATAACAATGTCTGAGATCGATCGAATTGCACAGAACA TCATTAAGTCCCATTTGGAGACATGTCAGTACACCATGGAAGAACTCCATCAGCTGGC ATGGCAGACCCACACCTACGAGGAAATCAAGGCGTATCAAAGCAAGTCCAGGGAGGCT CTGTGGCAGCAGTGTGCCATCCAGATCACCCATGCTATCCAGTACGTGGTGGAGTTCG CCAAGCGGATAACAGGCTTCATGGAGCTGTGTCAGAACGATCAGATCTTACTTCTGAA GTCAGGTTGCTTGGAAGTGGTTTTAGTGAGAATGTGTCGTGCCTTCAACCCATTAAAC AACACTGTTCTGTTTGAAGGAAAATATGGAGGAATGCAAATGTTCAAAGCCTTAGGTT CGGATGACCTAGTGAATGAAGCATTTGACTTTGCGAAGAATCTGTGTTCCTTGCAGCT GACTGAGGAAGAGATTGCTCTGTTCTCCTCTGCTGTTCTGATATCCCCAGACCGAGCC TGGCTGATCGAACCAAGAAAAGTCCAGAAGCTTCAGGAAAAGATTTATTTTGCACTGC AACATGTGATTCAGAAGAACCACCTGGATGATGAGACCCTGGCAAAGTTAATAGCCAA GATACCAACTATCACGGCAGTCTGCAACTTGCATGGGGAGAAGCTGCAGGTATTTAAG CAGTCTCATCCAGACATAGTGAATACACTGTTTCCTCCATTGTACAAGGAGCTCTTTA ATCCTGACTGTGCTGCGGTCTGCAAATGAAGGGGACGAGAACTCTCAGAGTCATGGAA TGCATCGCCGTTAAGACAAAAGCAATGTGTTCATGGGGACTTAAGGAAAATGTCACTA CTGCAACATTAGGAATGTCCTGCACTTAATAGAAATATTTTTCACCGCTACAGTTTGA AGAATGTAAATATGCACCTGAGTGGGGCTCTTTTGTTTGTTCGTTTGTTGTTTGTTTG TTTTTGAAATGATCATAAATATACAAATATAGGACAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ IDNO: 146)
RRA Human polypeptide sequence:
MASNSSSCPTPGGGHLNGYPVPPYAFFFPPMLGGLSPPGALTTLQHQLPVSGYSTPSP ATIETQSSSSEEIVPSPPSPPPLPRIYKPCFVCQDKSSGYHYGVSACEGCKGFFRRSI QKNMVYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKESVRNDRNKKKKEVPKPEC SESYTLTPEVGELIEKVRKAHQETFPALCQLGKYTTNNSSEQRVSLDIDL DKFSELS TKCIIKTVEFAKQLPGFTTLTIADQITLLKAACLDILILRICTRYTPEQDTMTFSDGL TLNRTQMHNAGFGPLTDLVFAFANQLLPLEMDDAETGLLSAICLICGDRQDLEQPDRV DMLQEPLLEALKVYVRKRRPSRPHMFPKMLMKITDLRSISAKGAERVITLKMEIPGSM PPLIQEMLENSEGLDTLSGQPGGGGRDGGGLAPPPGSCSPSLSPSSNRSSPATHSP (SEQ IDNO: 147)
Human polynucleotide sequence:
ATGGCCAGCAACAGCAGCTCCTGCCCGACACCTGGGGGCGGGCACCTCAATGGGTACC CGGTGCCTCCCTACGCCTTCTTCTTCCCCCCTATGCTGGGTGGACTCTCCCCGCCAGG CGCTCTGACCACTCTCCAGCACCAGCTTCCAGTTAGTGGATATAGCACACCATCCCCA GCCACCATTGAGACCCAGAGCAGCAGTTCTGAAGAGATAGTGCCCAGCCCTCCCTCGC CACCCCCTCTACCCCGCATCTACAAGCCTTGCTTTGTCTGTCAGGACAAGTCCTCAGG CTACCACTATGGGGTCAGCGCCTGTGAGGGCTGCAAGGGCTTCTTCCGCCGCAGCATC CAGAAGAACATGGTGTACACGTGTCACCGGGACAAGAACTGCATCATCAACAAGGTGA CCCGGAACCGCTGCCAGTACTGCCGACTGCAGAAGTGCTTTGAAGTGGGCATGTCCAA GGAGTCTGTGAGAAACGACCGAAACAAGAAGAAGAAGGAGGTGCCCAAGCCCGAGTGC TCTGAGAGCTACACGCTGACGCCGGAGGTGGGGGAGCTCATTGAGAAGGTGCGCAAAG CGCACCAGGAAACCTTCCCTGCCCTCTGCCAGCTGGGCAAATACACTACGAACAACAG CTCAGAACAACGTGTCTCTCTGGACATTGACCTCTGGGACAAGTTCAGTGAACTCTCC ACCAAGTGCATCATTAAGACTGTGGAGTTCGCCAAGCAGCTGCCCGGCTTCACCACCC TCACCATCGCCGACCAGATCACCCTCCTCAAGGCTGCCTGCCTGGACATCCTGATCCT GCGGATCTGCACGCGGTACACGCCCGAGCAGGACACCATGACCTTCTCGGACGGGCTG ACCCTGAACCGGACCCAGATGCACAACGCTGGCTTCGGCCCCCTCACCGACCTGGTCT TTGCCTTCGCCAACCAGCTGCTGCCCCTGGAGATGGATGATGCGGAGACGGGGCTGCT CAGCGCCATCTGCCTCATCTGCGGAGACCGCCAGGACCTGGAGCAGCCGGACCGGGTG GACATGCTGCAGGAGCCGCTGCTGGAGGCGCTAAAGGTCTACGTGCGGAAGCGGAGGC CCAGCCGCCCCCACATGTTCCCCAAGATGCTAATGAAGATTACTGACCTGCGAAGCAT CAGCGCCAAGGGGGCTGAGCGGGTGATCACGCTGAAGATGGAGATCCCGGGCTCCATG CCGCCTCTCATCCAGGAAATGTTGGAGAACTCAGAGGGCCTGGACACTCTGAGCGGAC AGCCGGGGGGTGGGGGGCGGGACGGGGGTGGCCTGGCCCCCCCGCCAGGCAGCTGTAG CCCCAGCCTCAGCCCCAGCTCCAACAGAAGCAGCCCGGCCACCCACTCCCCGTGA (SEQ IDNO: 148)
Mouse polypeptide sequence:
MASNSSSCPTPGGGHLNGYPVPPYAFFFPPMLGGLSPPGALTSLQHQLPVSGYSTPSP ATIETQSSSSEEIVPSPPSPPPLPRIYKPCFVCQDKSSGYHYGVSACEGCKGFFRRSI QKNMVYTCHRDKNCIINKVTRNRCQYCRLQKCFDVGMSKESVRNDRNKKKKEAPKPEC SESYTLTPEVGELIEKVRKAHQETFPALCQLGKYTTNNSSEQRVSLDIDL DKFSELS TKCIIKTVEFAKQLPGFTTLTIADQITLLKAACLDILILRICTRYTPEQDTMTFSDGL TLNRTQMHNAGFGPLTDLVFAFANQLLPLEMDDAETGLLSAICLICGDRQDLEQPDKV DMLQEPLLEALKVYVRKRRPSRPHMFPKMLMKITDLRSISAKGAERVITLKMEIPGSM PPLIQEMLENSEGLDTLSGQSGGGTRDGGGLAPPPGSCSPSLSPSSHRSSPATQSP (SEQ ID NO: 149)
Mouse polynucleotide sequence:
ATGGCCAGCAATAGCAGTTCCTGCCCAACACCTGGGGGCGGGCACCTCAATGGGTACC CAGTACCCCCCTACGCCTTCTTCTTTCCCCCTATGCTGGGTGGACTCTCCCCACCCGG CGCTCTCACCAGCCTCCAGCACCAGCTTCCAGTCAGTGGTTACAGCACACCGTCCCCA GCCACCATCGAGACCCAGAGCAGCAGTTCCGAAGAGATAGTACCCAGCCCTCCCTCAC CACCGCCCCTGCCCCGCATCTACAAGCCTTGCTTTGTTTGTCAAGACAAATCATCCGG CTACCACTATGGGGTCAGCGCCTGTGAGGGCTGTAAGGGCTTCTTCCGACGAAGCATC CAGAAGAACATGGTGTATACGTGTCACCGGGACAAGAACTGCATCATCAACAAGGTGA CCCGGAACCGCTGCCAGTACTGCCGGCTGCAGAAATGTTTCGACGTGGGCATGTCCAA GGAGTCGGTGCGAAACGATCGAAACAAAAAGAAGAAAGAGGCACCCAAGCCCGAGTGC TCAGAGAGCTACACGCTGACGCCTGAGGTGGGCGAGCTCATTGAGAAGGTTCGCAAAG CGCACCAGGAGACCTTCCCGGCCCTCTGCCAGCTGGGCAAGTACACTACGAACAACAG CTCAGAACAACGAGTCTCCCTGGACATTGACCTCTGGGACAAGTTCAGTGAACTCTCC ACCAAGTGCATCATTAAGACTGTGGAGTTCGCCAAGCAGCTTCCCGGCTTCACCACCC TCACCATCGCCGACCAGATCACCCTCCTCAAGGCTGCCTGCCTGGATATCCTGATTCT GCGAATCTGCACGCGGTACACGCCTGAGCAAGACACAATGACCTTCTCAGATGGACTG ACCCTGAACCGGACTCAGATGCACAACGCTGGCTTTGGCCCCCTCACCGACTTGGTCT TTGCCTTCGCCAACCAGCTGCTGCCCCTGGAGATGGACGATGCTGAGACTGGACTGCT CAGTGCCATCTGCCTCATCTGTGGAGACCGACAGGACCTGGAGCAGCCAGACAAGGTG GACATGCTGCAAGAGCCGCTGCTGGAAGCACTGAAAGTCTACGTCCGGAAACGGAGGC CCAGCCGACCCCACATGTTCCCCAAGATGCTGATGAAGATCACAGACCTTCGGAGCAT CAGCGCCAAGGGAGCTGAACGGGTGATCACATTGAAGATGGAGATCCCAGGCTCCATG CCACCGCTGATCCAGGAAATGCTGGAGAACTCTGAGGGCTTGGACACTCTAAGCGGAC AGTCGGGGGGCGGAACACGAGATGGGGGTGGCCTGGCCCCCCCTCCGGGTAGCTGTAG CCCCAGCCTCAGTCCCAGCTCCCACAGAAGCAGCCCAGCCACCCAATCCCCATGA (SEQ ID NO: 150) RRB
Human polypeptide sequence:
MFDCMDVLSVSPGQILDFYTASPSSCMLQEKALKACFSGLTQTEWQHRHTAQSIETQS TSSEELVPSPPSPLPPPRVYKPCFVCQDKSSGYHYGVSACEGCKGFFRRSIQKNMIYT CHRDKNCVINKVTRNRCQYCRLQKCFEVGMSKESVRNDRNKKKKETSKQECTESYEMT AELDDLTEKIRKAHQETFPSLCQLGKYTTNSSADHRVRLDLGLWDKFSELATKCIIKI VEFAKRLPGFTGLTIADQITLLKAACLDILILRICTRYTPEQDTMTFSDGLTLNRTQM HNAGFGPLTDLVFTFANQLLPLEMDDTETGLLSAICLICGDRQDLEEPTKVDKLQEPL LEALKIYIRKRRPSKPHMFPKILMKITDLRSISAKGAERVITLKMEIPGSMPPLIQEM LENSEGHEPLTPSSSGNTAEHSPSISPSSVENSGVSQSPLVQ (SEQ ID NO: 151)
Human polynucleotide sequence:
ATGTTTGACTGTATGGATGTTCTGTCAGTGAGTCCTGGGCAAATCCTGGATTTCTACA CTGCGAGTCCGTCTTCCTGCATGCTCCAGGAGAAAGCTCTCAAAGCATGCTTCAGTGG ATTGACCCAAACCGAATGGCAGCATCGGCACACTGCTCAATCAATTGAAACACAGAGC ACCAGCTCTGAGGAACTCGTCCCAAGCCCCCCATCTCCACTTCCTCCCCCTCGAGTGT ACAAACCCTGCTTCGTCTGCCAGGACAAATCATCAGGGTACCACTATGGGGTCAGCGC CTGTGAGGGATGTAAGGGCTTTTTCCGCAGAAGTATTCAGAAGAATATGATTTACACT TGTCACCGAGATAAGAACTGTGTTATTAATAAAGTCACCAGGAATCGATGCCAATACT GTCGACTCCAGAAGTGCTTTGAAGTGGGAATGTCCAAAGAATCTGTCAGGAATGACAG GAACAAGAAAAAAAAGGAGACTTCGAAGCAAGAATGCACAGAGAGCTATGAAATGACA GCTGAGTTGGACGATCTCACAGAGAAGATCCGAAAAGCTCACCAGGAAACTTTCCCTT CACTCTGCCAGCTGGGTAAATACACCACGAATTCCAGTGCTGACCATCGAGTCCGACT GGACCTGGGCCTCTGGGACAAATTCAGTGAACTGGCCACCAAGTGCATTATTAAGATC GTGGAGTTTGCTAAACGTCTGCCTGGTTTCACTGGCTTGACCATCGCAGACCAAATTA CCCTGCTGAAGGCCGCCTGCCTGGACATCCTGATTCTTAGAATTTGCACCAGGTATAC CCCAGAACAAGACACCATGACTTTCTCAGACGGCCTTACCCTAAATCGAACTCAGATG CACAATGCTGGATTTGGTCCTCTGACTGACCTTGTGTTCACCTTTGCCAACCAGCTCC AGCCTTTGGAAATGGATGACACAGAAACAGGCCTTCTCAGTGCCATCTGCTTAATCTG TGGAGACCGCCAGGACCTTGAGGAACCGACAAAAGTAGATAAGCTACAAGAACCATTG CTGGAAGCACTAAAAATTTATATCAGAAAAAGACGACCCAGCAAGCCTCACATGTTTC CAAAGATCTTAATGAAAATCACAGATCTCCGTAGCATCAGTGCTAAAGGTGCAGAGCG TGTAATTACCTTGAAAATGGAAATTCCTGGATCAATGCCACCTCTCATTCAAGAAATG CTGGAGAATTCTGAAGGACATGAACCCTTGACCCCAAGTTCAAGTGGGAACACAGCAG AGCACAGTCCTAGCATCTCACCCAGCTCAGTGGAAAACAGTGGGGTCAGTCAGTCACC ACTCCTGCAATAA (SEQ ID NO: 152)
Mouse polypeptide sequence:
MSTSSHACPVPAVRGHMTHYPAAPYPLLFPPVIRGLSLPPLHGLHGHPPPSGCSTPSP ASVGQACQRTTGGSQFAASTKWTPSLNAAIETQSTSSEELVPSPPSPLPPPRVYKPCF VCQDKSSGYHYGVSACEGCKGFFRRSIQKNMIYTCHRDKNCVINKVTRNRCQYCRLQK CFEVGMSKESVRNDRNKKKKEPSKQECTESYEMTAELDDLTEKIRKAHQETFPSLCQL GKYTTNSSADHRVRLDLGL DKFSELATKCIIKIVEFAKRLPGFTGLTIADQITLLKA ACLDILILRICTRYTPEQDTMTFSDGLTLNRTQMHNAGFGPLTDLVFTFANQLLPLEM DDTETGLLSAICLICGDRQDLEEPTKVDKLQEPLLEALKIYIRKRRPSKPHMFPKILM KITDLRSISAKGAERVITLKMEIPGSMPPLIQEMLENSEGHEPLTPSSSGNIAEHSPS VSPSSVENSGVSQSPLLQ (SEQ ID NO: 153)
Mouse polynucleotide sequence:
GAATTCCACGCGAGCCACCCGGGCAGGGAGCGTCTGGGCACCGGCGGGGTAGGACCCG CGCGCTCCCGGAGGCCTGCGCGGGCGTCGCCTGGAAGGGAGAACTTGGGATCGGTGCG GGAACCCCCGCCCTGGCTGGATCGGCCGAGCGAGCCTGGAAAATGGTAAATGATCATT TGGATCAATTACAGGCTTTTAGCTGGCTTGTCTGTCATAATTCATGATTCGGGGCTGG GAAAAAGACCAACAGCCTACGTGCCAAAAAAGGGGCAGAGTTTGATGGAGTTCGTGGA CTTTTCTGTGCGGCTCGCCTCCACACCTAGAGGATAAGCACTTTTGCAGAGCGCGGTG CGGAGAGATCATGTTTGACTGTATGGATGTTCTGTCAGTGAGTCCCGGGCAGATCCTG GATTTCTACACCGCGAGCCCTTCCTCCTGCATGCTGCAGGAAAAGGCTCTCAAAGCCT GCCTCAGTGGATTCACCCAGGCCGAATGGCAGCACCGGCATACTGCTCAATCCATCGA GACACAGAGTACCAGCTCTGAGGAGCTCGTCCCGAGCCCACCATCTCCACTTCCTCCT CCTCGGGTGTACAAGCCCTGCTTCGTTTGCCAGGACAAGTCATCGGGCTACCACTATG GCGTCAGTGCCTGCGAGGGGTGCAAGGGCTTTTTCCGCAGAAGTATTCAGAAGAACAT GATCTACACTTGCCATCGAGATAAGAACTGCGTCATTAACAAGGTCACTAGGAACCGA TGCCAGTACTGCCGCCTGCAGAAGTGCTTTGAAGTGGGCATGTCCAAAGAGTCTGTTA GGAATGACAGGAACAAGAAAAAGAAGGAGCCTTCAAAGCAGGAATGCACAGAGAGCTA TGAGATGACAGCGGAGCTAGACGACCTCACTGAGAAGATCCGGAAAGCCCACCAGGAA ACCTTTCCCTCACTCTGCCAGCTGGGTAAATACACCACGAATTCCAGCGCTGACCACC GGGTCCGATTGGACTTGGGCCTCTGGGACAAATTCAGTGAGCTGGCCACCAAGTGCAT TATTAAGATCGTGGAGTTCGCCAAGCGTCTGCCGGGCTTCACAGGTCTGACCATCGCA GACCAGATCACCCTGCTCAAAGCCGCCTGCTTGGATATCTTGATTCTCAGAATTTGTA CCAGGTATACCCCAGAGCAAGACACCATGACTTTCTCTGATGGCCTTACACTAAATCG
AACTCAGATGCACAATGCTGGCTTCGGTCCTCTGACTGACCTTGTGTTCACCTTTGCC AΆCCAGCTCCTGCCTTTGGAAATGGATGACACAGAAACAGGCCTTCTCAGTGCCATCT GTTTAATCTGTGGAGACCGCCAGGACCTTGAGGAACCAACAAAAGTAGACAAGCTCCA AGAACCACTGCTGGAAGCACTAAAGATTTACATTAGAAAACGACGACCCAGCAAGCCT CACATGTTTCCAAAGATCTTAATGAAAATCACAGATCTCCGCAGCATCAGCGCGAAAG GTGCCGAACGTGTAATTACCTTGAAAATGGAAATTCCTGGATCAATGCCACCTCTCAT TCAGGAAATGCTGGAGAATTCTGAAGGACATGAACCCTTGACCCCAAGTTCAAGTGGG AATATAGCAGAGCACAGTCCCAGCGTGTCCCCCAGCTCAGTGGAGAACAGTGGAGTCA GTCAGTCACCACTGCTGCAGTGAGACATTTCCAGCTGTTGCAGACATTCCCCAGGACC TTCAGTTCCAGATTGAAAATGCAAGGAAAACATTTTTACTGCTGCTTAGTTTTTGAAC TGAAATATGTTAAACTCAAAAAGGACCAAGAAGTTTTCATATGTATCAATATATATTC CTTACTGTATAACTTCCCTAGAAATACAAACTTTTCAAATTCTGAAAATCAGCCATTT CATGCCACCAGAATCTAGTTTAAAGCTTCTACTTTCCTCTCTGAATAGTCAAGATGCA TGGCAAAGACCCAGTTGAGATGATTTAGCCCTGGTTAAGTTTCTGAAGACTTTGTACA TATAGAAGTACGGCTCTGTTCTTTCTATACTGTATGTTGGTGCTTTCTTTTTGTCTTG CATACTCAATAACCAAGACACCGAGGTTGTGGAGTAAACCACTGTACATCCACTGTAC GTCCTGCTTTCATGAATAACCAGGCTCACGGTAAGGAACCAGGGCCTCTGTACAGTAC AAGATGACACTAAAGACACTCTGGTTTAAGTAGTGTGGAAGCTTCTCCTTGCTTTTTG ATGCTCTCAAGCTTCATTCTTTCCCTTATGTTGCCCAGATAGAGTACACCACTTGACT GCACTAGCAGAATTCTGTATCACTGAAACTGCCAGTTCAGTTAAGCCAACATCATTGT TCAATTGTTAATGATGTCACGGGAAAGGAAAAGTGGTTTGTTCCTTAATGACACAACT ACCGAATGAAAAAAAAAATGAAGCATTTTTACAGTCATGATAGCCTCCAAGGCAAAAA CACTGTCCAGTGTTAATAAGTTTGTTTACCTGTTCACAAGCCATTGGAGAAATATCAC AGGATAATCAGCAAGTTAGTCTGCCGTCTGGACTCTAGTAGCCCAGTGTCCTTGCTGA CTCAGGCCTGATCCTGGGATTTCCCCCAGTCTTGATGCTTGAAGGTATGGGCAAGTGG CCTCCTCTGGCCTTGTTCAATCACCATGATGCAGACTGACAGCTCTGGGAGAATGAGT GGTTGACAGACTCAAGTGTCGGCTTCTGAGTTCTCATGTAAGCACTAGTGGAATTTTT GTTTGTTCGTTTTTGATATATTAGCAAAAGTCTGTGATGTACCACTAGCTCTGTTTGT ACATTGAGATGGTTTAACAGTGCTTTCTATGTTCATATACTGTTTACCTTTTTCCATG GAGTCTCCTGGCAAAGAATAAATATATTTATTTTAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAGGAATTC (SEQ IDNO: 154)
RRG1
Human polypeptide sequence:
MATNKERLFAAGALGPGSGYPGAGFPFAFPGALRGSPPFEMLSPSFRGLGQPDLPKEM ASLSVETQSTSSEEMVPSSPSPPPPPRVYKPCFVCNDKSSGYHYGVSSCEGCKGFFRR SIQKNMVYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKEAVRNDRNKKKKEVKEE GSPDSYELSPQLEELITKVSKAHQETFPSLCQLGKYTTNSSADHRVQLDLGLWDKFSE LATKCIIKIVEFAKRLPGFTGLSIADQITLLKAACLDILMLRICTRYTPEQDTMTFSD GLTLNRTQMHNAGFGPLTDLVFAFAGQLLPLEMDDTETGLLSAICLICGDRMDLEEPE KVDKLQEPLLEALRLYARRRRPSQPYMFPRMLMKITDLRGISTKGAERAITLKMEIPG PMPPLIREMLENPEMFEDDSSQPGPHPNASSEDEVPGGQGKGGLKSPA (SEQ IDNO: 155)
Human polynucleotide sequence: ATGGCCACCAATAAGGAGCGACTCTTTGCGGCTGGTGCCCTGGGGCCTGGATCTGGCT ACCCAGGGGCAGGTTTCCCCTTCGCCTTCCCAGGGGCACTCAGGGGGTCTCCGCCTTT CGAGATGCTGAGCCCTAGCTTCCGGGGCCTGGGCCAGCCTGACCTCCCCAAGGAGATG GCCTCTCTGTCGGTGGAGACACAGAGCACCAGCTCAGAGGAGATGGTGCCCAGCTCGC CCTCGCCCCCTCCGCCTCCTCGGGTCTACAAGCCATGCTTCGTGTGCAATGACAAGTC CTCTGGCTACCACTATGGGGTCAGCTCTTGTGAAGGCTGCAAGGGCTTCTTTCGCCGA AGCATCCAGAAGAACATGGTGTACACGTGTCACCGCGACAAAAACTGTATCATCAACA AGGTGACCAGGAATCGCTGCCAGTACTGCCGGCTACAGAAGTGCTTCGAAGTGGGCAT GTCCAAGGAAGCTGTGCGAAATGACCGGAACAAGAAGAAGAAAGAGGTGAAGGAAGAA GGGTCACCTGACAGCTATGAGCTGAGCCCTCAGTTAGAAGAGCTCATCACCAAGGTCA GCAAAGCCCATCAGGAGACTTTCCCCTCGCTCTGCCAGCTGGGCAAGTATACCACGAA CTCCAGTGCAGACCACCGCGTGCAGCTGGATCTGGGGCTGTGGGACAAGTTCAGTGAG CTGGCTACCAAGTGCATCATCAAGATCGTGGAGTTTGCCAAGCGGTTGCCTGGCTTTA CAGGGCTCAGCATTGCTGACCAGATCACTCTGCTCAAAGCTGCCTGCCTAGATATCCT GATGCTGCGTATCTGCACAAGGTACACCCCAGAGCAGGACACCATGACCTTCTCCGAC GGGCTGACCCTGAACCGGACCCAGATGCACAATGCCGGCTTCGGGCCCCTCACAGACC TTGTCTTTGCCTTTGCTGGGCAGCTCCTGCCCCTGGAGATGGATGACACCGAGACAGG GCTGCTCAGCGCCATCTGCCTCATCTGCGGAGACCGCATGGACCTGGAGGAGCCCGAA AAAGTGGACAAGCTGCAGGAGCCACTGCTGGAAGCCCTGAGGCTGTACGCCCGGCGCC GGCGGCCCAGCCAGCCCTACATGTTCCCAAGGATGCTAATGAAAATCACCGACCTCCG GGGCATCAGCACTAAGGGAGCTGAAAGGGCCATTACTCTGAAGATGGAGATTCCAGGC CCGATGCCTCCCTTAATCCGAGAGATGCTGGAGAACCCTGAAATGTTTGAGGATGACT CCTCGCAGCCTGGTCCCCACCCCAATGCCTCTAGCGAGGATGAGGTTCCTGGGGGCCA
GGGCAAAGGGGGCCTGAAGTCCCCAGCCTGA
(SEQ ID NO: 156) Mouse polypeptide sequence:
MATNKERLFAPGALGPGSGYPGAGFPFAFPGALRGSPPFEMLSPSFRGLGQPDLPKEM ASLSVETQSTSSEEMVPSSPSPPPPPRVYKPCFVCNDKSSGYHYGVSSCEGCKGFFRR SIQKNMVYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKEAVRNDRNKKKKEVKEE GSPDSYELSPQLEELITKVSKAHQETFPSLCQLGKYTTNSSADHRVQLDLGLWDKFSE LATKCIIKIVEFAKRLPGFTGLSIADQITLLKAACLDILMLRICTRYTPEQDTMTFSD GLTLNRTQMHNAGFGPLTDLVFAFAGQLLPLEMDDTETGLLSAICLICGDRMDLEEPE KVDKLQEPLLEALRLYARRRDPAKPYMFPRMLMKITDLRGISTKGAERAITLKMEIPG PMPPLIREMLENPEMFEDDSSKPGPHPKASSEDEAPGGQGKRGQSPQPDQGP (SEQ IDNO: 157)
Mouse polynucleotide sequence:
ATGGCCACCAATAAGGAGAGACTCTTTGCGCCCGGTGCCCTGGGGCCTGGATCTGGTT ACCCAGGAGCAGGCTTCCCATTCGCCTTCCCAGGTGCACTCAGAGGGTCGCCACCATT TGAGATGCTGAGCCCTAGCTTCCGGGGCCTGGGCCAGCCTGACCTCCCCAAGGAGATG GCTTCTCTCTCGGTGGAGACACAGAGCACCAGCTCGGAGGAGATGGTACCCAGCTCTC CCTCACCCCCACCACCTCCTCGGGTCTATAAGCCATGCTTTGTATGCAATGACAAGTC TTCTGGCTACCACTATGGGGTCAGCTCCTGTGAAGGCTGCAAGGGCTTCTTCAGACGC AGCATTCAGAAAAACATGGTGTATACATGTCACCGTGACAAAAACTGTATCATCAACA AGGTCACCAGAAATCGATGCCAGTACTGCAGGCTACAAAAGTGTTTCGAAGTGGGCAT GTCCAAGGAAGCTGTAAGGAACGATCGAAACAAGAAGAAAAAGGAGGTAAAAGAGGAG GGCTCGCCCGACAGCTATGAACTGAGTCCACAGTTAGAGGAACTCATCACCAAGGTCA GCAAAGCCCACCAGGAGACTTTTCCCTCACTCTGCCAGCTGGGCAAGTACACCACGAA CTCCAGTGCAGATCACCGGGTGCAGCTGGACCTGGGGCTGTGGGACAAGTTCAGCGAG CTGGCCACCAAATGCATCATCAAGATTGTGGAGTTTGCGAAGCGGCTGCCTGGTTTTA CAGGGCTCAGCATTGCCGACCAGATCACGCTGCTCAAGGCTGCTTGTCTGGACATCCT AATGCTGCGGATCTGTACAAGGTATACCCCAGAGCAGGACACTATGACATTCTCGGAT GGGCTGACCCTGAACCGAACCCAGATGCACAATGCTGGCTTTGGGCCCCTTACAGACC TCGTCTTTGCCTTTGCCGGGCAGCTGCTGCCCCTGGAGATGGATGACACCGAGACTGG GCTACTTAGTGCTATCTGCCTCATCTGTGGAGACCGAATGGACCTGGAAGAGCCCGAG AAGGTGGACAAGCTGCAGGAGCCCCTGCTGGAAGCCCTGAGGCTCTATGCCCGGCGAC GAGACCCAGCCAAACCCTACATGTTCCCAAGGATGCTGATGAAAATCACCGACCTCCG GGGCATCAGCACTAAGGGAGCAGAAAGGGCTATAACCCTGAAGATGGAGATTCCAGGC CCGATGCCACCCCTGATCCGAGAGATGCTGGAGAACCCGGAGATGTTTGAGGACGACT CCTCGAAGCCTGGCCCCCACCCCAAGGCTTCCAGTGAGGACGAAGCTCCAGGGGGCCA GGGCAAAAGGGGCCAAAGTCCCCAACCTGACCAGGGGCCCTGA (SEQ ID NO: 158) RXRA
Human polypeptide sequence:
MDTKHFLPLDFSTQVNSSLTSPTGRGSMAAPSLHPSLGPGIGSPGQLHSPISTLSSPI NGMGPPFSVISSPMGPHSMSVPTTPTLGFSTGSPQLSSPMNPVSSSEDIKPPLGLNGV LKVPAHPSGNMASFTKHICAICGDRSSGKHYGVYSCEGCKGFFKRTVRKDLTYTCRDN KDCLIDKRQRNRCQYCRYQKCLAMGMKREAVQEERQRGKDRNENEVESTSSANEDMPV ERILEAELAVEPKTETYVEANMGLNPSSPNDPVTNICQAADKQLFTLVEWAKRIPHFS ELPLDDQVILLRAGWNELLIASFSHRSIAVKDGILLATGLHVHRNSAHSAGVGAIFDR VLTELVSKMRDMQMDKTELGCLRAIVLFNPDSKGLSNPAEVEALREKVYASLEAYCKH KYPEQPGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLEAPHQMT (SEQ ID NO: 159)
Human polynucleotide sequence:
ATGGACACCAAACATTTCCTGCCGCTCGATTTCTCCACCCAGGTGAACTCCTCCCTCA CCTCCCCGACGGGGCGAGGCTCCATGGCTGCCCCCTCGCTGCACCCGTCCCTGGGGCC TGGCATCGGCTCCCCGGGACAGCTGCATTCTCCCATCAGCACCCTGAGCTCCCCCATC AACGGCATGGGCCCGCCTTTCTCGGTCATCAGCTCCCCCATGGGCCCCCACTCCATGT CGGTGCCCACCACACCCACCCTGGGCTTCAGCACTGGCAGCCCCCAGCTCAGCTCACC TATGAACCCCGTCAGCAGCAGCGAGGACATCAAGCCCCCCCTGGGCCTCAATGGCGTC CTCAAGGTCCCCGCCCACCCCTCAGGAAACATGGCTTCCTTCACCAAGCACATCTGCG CCATCTGCGGGGACCGCTCCTCAGGCAAGCACTATGGAGTGTACAGCTGCGAGGGGTG CAAGGGCTTCTTCAAGCGGACGGTGCGCAAGGACCTGACCTACACCTGCCGCGACAAC AAGGACTGCCTGATTGACAAGCGGCAGCGGAACCGGTGCCAGTACTGCCGCTACCAGA AGTGCCTGGCCATGGGCATGAAGCGGGAAGCCGTGCAGGAGGAGCGGCAGCGTGGCAA GGACCGGAACGAGAATGAGGTGGAGTCGACCAGCAGCGCCAACGAGGACATGCCGGTG GAGAGGATCCTGGAGGCTGAGCTGGCCGTGGAGCCCAAGACCGAGACCTACGTGGAGG CAAACATGGGGCTGAACCCCAGCTCGCCGAACGACCCTGTCACCAACATTTGCCAAGC AGCCGACAAACAGCTTTTCACCCTGGTGGAGTGGGCCAAGCGGATCCCACACTTCTCA GAGCTGCCCCTGGACGACCAGGTCATCCTGCTGCGGGCAGGCTGGAATGAGCTGCTCA TCGCCTCCTTCTCCCACCGCTCCATCGCCGTGAAGGACGGGATCCTCCTGGCCACCGG GCTGCACGTCCACCGGAACAGCGCCCACAGCGCAGGGGTGGGCGCCATCTTTGACAGG GTGCTGACGGAGCTTGTGTCCAAGATGCGGGACATGCAGATGGACAAGACGGAGCTGG GCTGCCTGCGCGCCATCGTCCTCTTTAACCCTGACTCCAAGGGGCTCTCGAACCCGGC CGAGGTGGAGGCGCTGAGGGAGAAGGTCTATGCGTCCTTGGAGGCCTACTGCAAGCAC AAGTACCCAGAGCAGCCGGGAAGGTTCGCTAAGCTCTTGCTCCGCCTGCCGGCTCTGC GCTCCATCGGGCTCAAATGCCTGGAACATCTCTTCTTCTTCAAGCTCATCGGGGACAC ACCCATTGACACCTTCCTTATGGAGATGCTGGAGGCGCCGCACCAAATGACTTAG (SEQ IDNO: 160)
Mouse polypeptide sequence:
MDTKHFLPLDFSTQVNSSSLNSPTGRGSMAVPSLHPSLGPGIGSPLGSPGQLHSPIST LSSPINGMGPPFSVISSPMGPHSMSVPTTPTLGFGTGSPQLNSPMNPVSSTEDIKPPL GLNGVLKVPAHPSGNMASFTKHICAICGDRSSGKHYGVYSCEGCKGFFKRTVRKDLTY TCRDNKDCLIDKRQRNRCQYCRYQKCLAMGMKREAVQEERQRGKDRNENEVESTSSAN EDMPVEKILEAELAVEPKTETYVEANMGLNPSSPNDPVTNICQAADKQLFTLVEWAKR IPHFSELPLDDQVILLRAG NELLIASFSHRSIAVKDGILLATGLHVHRNSAHSAGVG AIFDRVLTELVSKMRDMQMDKTELGCLRAIVLFNPDSKGLSNPAEVEALREKVYASLE AYCKHKYPEQPGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLEAPH QAT (SEQ IDNO: 161) Mouse polynucleotide sequence:
ATGGACACCAAACATTTCCTGCCGCTCGACTTCTCTACCCAGGTGAACTCTTCGTCCC TCAACTCTCCAACGGGTCGAGGCTCCATGGCTGTCCCCTCGCTGCACCCCTCCTTGGG TCCGGGAATCGGCTCTCCACTGGGCTCGCCTGGGCAGCTGCACTCTCCTATCAGCACC CTGAGCTCCCCCATCAATGGCATGGGTCCGCCCTTCTCTGTCATCAGCTCCCCCATGG GCCCGCACTCCATGTCGGTACCCACCACACCCACATTGGGCTTCGGGACTGGTAGCCC CCAGCTCAATTCACCCATGAACCCTGTGAGCAGCACTGAGGATATCAAGCCGCCACTA GGCCTCAATGGCGTCCTCAAGGTTCCTGCCCATCCCTCAGGAAATATGGCCTCCTTCA CCAAGCACATCTGTGCTATCTGTGGGGACCGCTCCTCAGGCAAACACTATGGGGTATA CAGTTGTGAGGGCTGCAAGGGCTTCTTCAAGAGGACAGTACGCAAAGACCTGACCTAC ACCTGCCGAGACAACAAGGACTGCCTGATCGACAAGAGACAGCGGAACCGGTGTCAGT ACTGCCGCTACCAGAAGTGCCTGGCCATGGGCATGAAGCGGGAAGCTGTGCAGGAGGA GCGGCAGCGGGGCAAGGACCGGAATGAGAACGAGGTGGAGTCCACCAGCAGTGCCAAC GAGGACATGCCTGTAGAGAAGATTCTGGAAGCCGAGCTTGCTGTCGAGCCCAAGACTG AGACATACGTGGAGGCAAACATGGGGCTGAACCCCAGCTCACCAAATGACCCTGTTAC CAACATCTGTCAAGCAGCAGACAAGCAGCTCTTCACTCTTGTGGAGTGGGCCAAGAGG ATCCCACACTTTTCTGAGCTGCCCCTAGACGACCAGGTCATCCTGCTACGGGCAGGCT GGAACGAGCTGCTGATCGCCTCCTTCTCCCACCGCTCCATAGCTGTGAAAGATGGGAT TCTCCTGGCCACCGGCCTGCACGTACACCGGAACAGCGCTCACAGTGCTGGGGTGGGC GCCATCTTTGACAGGGTGCTAACAGAGCTGGTGTCTAAGATGCGTGACATGCAGATGG ACAAGACGGAGCTGGGCTGCCTGCGAGCCATTGTCCTGTTCAACCCTGACTCTAAGGG GCTCTCAAACCCTGCTGAGGTGGAGGCGTTGAGGGAGAAGGTGTATGCGTCACTAGAA GCGTACTGCAAACACAAGTACCCTGAGCAGCCGGGCAGGTTTGCCAAGCTGCTGCTCC GCCTGCCTGCACTGCGTTCCATCGGGCTCAAGTGCCTGGAGCACCTGTTCTTCTTCAA GCTCATCGGGGACACGCCCATCGACACCTTCCTCATGGAGATGCTGGAGGCACCACAT CAAGCCACCTAG (SEQ ID NO: 162)
RXRB Human polypeptide sequence:
MS AARPPFLPQRHAAGQCGPVGVRKEMHCGVASRWRRRRPWLDPAAAAAAAVAGGEQ QTPEPEPGEAGRDGMGDSGRDSRSPDSSSPNPLPQGVPPPSPPGPPLPPSTAPSLGGS GAPPPPPMPPPPLGSPFPVISSSMGSPGLPPPAPPGFSGPVSSPQINSTVSLPGGGSG PPEDVKPPVLGVRGLHCPPPPGGPGAGKRLCAICGDRSSGKHYGVYSCEGCKGFFKRT IRKDLTYSCRDNKDCTVDKRQRNRCQYCRYQKCLATGMKREAVQEERQRGKDKDGDGE GAGGAPEEMPVDRILEAELAVEQKSDQGVEGPGGTGGSGSSPNDPVTNICQAADKQLF TLVEWAKRIPHFSSLPLDDQVILLRAGWNELLIASFSHRSIDVRDGILLATGLHVHRN SAHSAGVGAIFDRVLTELVSKMRDMRMDKTELGCLRAIILFNPDAKGLSNPSEVEVLR EKVYASLETYCKQKYPEQQGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFL MEMLEAPHQLA (SEQ ID NO: 163)
Human polynucleotide sequence:
ATGTCTTGGGCCGCTCGCCCGCCCTTCCTCCCTCAGCGGCATGCCGCAGGGCAGTGTG GGCCGGTGGGGGTGCGAAAAGAAATGCATTGTGGGGTCGCGTCCCGGTGGCGGCGGCG ACGGCCCTGGCTGGATCCCGCAGCGGCGGCGGCGGCGGCGGTGGCAGGCGGAGAACAA CAAACCCCGGAGCCGGAGCCAGGGGAGGCTGGACGGGACGGGATGGGCGACAGCGGGC GGGACTCCCGAAGCCCAGACAGCTCCTCCCCAAATCCCCTTCCCCAGGGAGTCCCTCC CCCTTCTCCTCCTGGGCCACCCCTACCCCCTTCAACAGCTCCTACCCTTGGAGGCTCT GGGGCCCCACCCCCACCCCCGATGCCACCACCCCCACTGGGCTCTCCCTTTCCAGTCA TCAGTTCTTCCATGGGGTCCCCTGGTCTGCCCCCTCCAGCTCCCCCAGGATTCTCCGG GCCTGTCAGCAGCCCCCAGATTAACTCAACAGTGTCACTCCCTGGGGGTGGGTCTGGC CCCCCTGAAGATGTGAAGCCACCAGTCTTAGGGGTCCGGGGCCTGCACTGTCCACCCC CTCCAGGTGGCCCTGGGGCTGGCAAACGGCTATGTGCAATCTGCGGGGACAGAAGCTC AGGCAAACACTACGGGGTTTACAGCTGTGAGGGTTGCAAGGGCTTCTTCAAACGCACC ATCCGCAAAGACCTTACATACTCTTGCCGGGACAACAAAGACTGCACAGTGGACAAGC GCCAGCGGAACCGCTGTCAGTACTGCCGCTATCAGAAGTGCCTGGCCACTGGCATGAA GAGGGAGGCGGTACAGGAGGAGCGTCAGCGGGGAAAGGACAAGGATGGGGATGGGGAG GGGGCTGGGGGAGCCCCCGAGGAGATGCCTGTGGACAGGATCCTGGAGGCAGAGCTTG CTGTGGAACAGAAGAGTGACCAGGGCGTTGAGGGTCCTGGGGGAACCGGGGGTAGCGG CAGCAGCCCAAATGACCCTGTGACTAACATCTGTCAGGCAGCTGACAAACAGCTATTC ACGCTTGTTGAGTGGGCGAAGAGGATCCCACACTTTTCCTCCTTGCCTCTGGATGATC AGGTCATATTGCTGCGGGCAGGCTGGAATGAACTCCTCATTGCCTCCTTTTCACACCG ATCCATTGATGTTCGAGATGGCATCCTCCTTGCCACAGGTCTTCACGTGCACCGCAAC TCAGCCCATTCAGCAGGAGTAGGAGCCATCTTTGATCGGGTGCTGACAGAGCTAGTGT CCAAAATGCGTGACATGAGGATGGACAAGACAGAGCTTGGCTGCCTGAGGGCAATCAT TCTGTTTAATCCAGATGCCAAGGGCCTCTCCAACCCTAGTGAGGTGGAGGTCCTGCGG GAGAAAGTGTATGCATCACTGGAGACCTACTGCAAACAGAAGTACCCTGAGCAGCAGG GACGGTTTGCCAAGCTGCTGCTACGTCTTCCTGCCCTCCGGTCCATTGGCCTTAAGTG TCTAGAGCATCTGTTTTTCTTCAAGCTCATTGGTGACACCCCCATCGACACCTTCCTC ATGGAGATGCTTGAGGCTCCCCATCAACTGGCCTGA (SEQ IDNO: 164) Mouse polypeptide sequence :
MSWATRPPFLPPRHAAGQCGPVGVRKEMHCGVASRWRRRRP LDPAAAAAAAGEQQAL EPEPGEAGRDGMGDSGRDSRSPDSSSPNPLSQGIRPSSPPGPPLTPSAPPPPMPPPPL GSPFPVISSSMGSPGLPPPAPPGFSGPVSSPQINSTVSLPGGGSGPPEDVKPPVLGVR GLHCPPPPGGPGAGKRLCAICGDRSSGKHYGVYSCEGCKGFFKRTIRKDLTYSCRDNK DCTVDKRQRNRCQYCRYQKCLATGMKREAVQEERQRGKDKDGDGDGAGGAPEEMPVDR ILEAELAVEQKSDQGVEGPGATGGGGSSPNDPVTNICQAADKQLFTLVEWAKRIPHFS SLPLDDQVILLRAG NELLIASFSHRSIDVRDGILLATGLHVHRNSAHSAGVGAIFDR VLTELVSKMRDMRMDKTELGCLRAIILFNPDAKGLSNPGEVEILREKVYASLETYCKQ KYPEQQGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLEAPHQLA (SEQ ID NO: 165)
Mouse polynucleotide sequence: ATGCCACCCCCGCCACTGGGCTCCCCCTTCCCAGTCATCAGTTCTTCCATGGGGTCCC CTGGTCTGCCCCCTCCGGCTCCCCCAGGATTCTCCGGGCCTGTCAGCAGCCCTCAGAT CAACTCCACAGTGTCGCTCCCTGGGGGTGGGTCTGGCCCCCCTGAAGATGTGAAGCCA CCGGTCTTAGGGGTCCGGGGCCTGCACTGTCCACCCCCTCCAGGTGGTCCTGGGGCTG GCAAACGGCTCTGTGCAATCTGCGGGGACCGAAGCTCAGGCAAGCACTATGGGGTTTA CAGCTGCGAGGGCTGCAAGGGTTTCTTCAAGCGCACCATTCGGAAGGACCTGACCTAC TCGTGTCGTGATAACAAAGACTGTACAGTGGACAAGCGCCAGCGGAATCGCTGTCAGT ACTGTCGCTATCAGAAGTGCCTGGCCACTGGCATGAAAAGGGAGGCGGTTCAGGAGGA GCGTCAACGGGGGAAGGACAAAGACGGGGATGGAGATGGGGCTGGGGGAGCCCCTGAG GAGATGCCTGTGGACAGGATCCTGGAGGCAGAGCTTGCTGTGGAGCAGAAGAGTGACC AAGGCGTTGAGGGTCCTGGGGCCACCGGGGGTGGTGGCAGCAGCCCAAATGACCCAGT GACTAACATCTGCCAGGCAGCTGACAAACAGCTGTTCACACTCGTTGAGTGGGCAAAG AGGATCCCGCACTTCTCCTCCCTACCTCTGGACGATCAGGTCATACTGCTGCGGGCAG GCTGGAACGAGCTCCTCATTGCGTCCTTCTCCCATCGGTCCATTGATGTCCGAGATGG CATCCTCCTGGCCACGGGTCTTCATGTGCACAGAAACTCAGCCCATTCCGCAGGCGTG GGAGCCATCTTTGATCGGGTGCTGACAGAGCTAGTGTCCAAAATGCGTGACATGAGGA TGGACAAGACAGAGCTTGGCTGCCTGCGGGCAATCATACTGTTTAATCCAGACGCCAA GGGCCTCTCCAACCCTGGAGAGGTGGAGATCCTTCGGGAGAAGGTGTACGCCTCACTG GAGACCTATTGCAAGCAGAAGTACCCTGAGCAGCAGGGCCGGTTTGCCAAGCTGCTGT TACGTCTTCCTGCCCTCCGCTCCATCGGCCTCAAGTGTCTGGAGCACCTGTTCTTCTT CAAGCTCATTGGCGACACCCCCATTGACACCTTCCTCATGGAGATGCTTGAGGCTCCC CACCAGCTAGCCTGA (SEQ IDNO: 166)
RXRG
Human polypeptide sequence:
MYGNYSHFMKFPAGYGGSPGHTGSTSMSPSAALSTGKPMDSHPSYTDTPVSAPRTLSA VGTPLNALGSPYRVITSAMGPPSGALAAPPGINLVAPPSSQLNWNSVSSSEDIKPLP GLPGIGNMNYPSTSPGSLVKHICAICGDRSSGKHYGVYSCEGCKGFFKRTIRKDLIYT CRDNKDCLIDKRQRNRCQYCRYQKCLVMGMKREAVQEERQRSRERAESEAECATSGHE DMPVERILEAELAVEPKTESYGDMNMENSTNDPVTNICHAADKQLFTLVEWAKRIPHF SDLTLEDQVILLRAGWNELLIASFSHRSVSVQDGILLATGLHVHRSSAHSAGVGSIFD RVLTELVSKMKDMQMDKSELGCLRAIVLFNPDAKGLSNPSEVETLREKVYATLEAYTK QKYPEQPGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLETPLQIT (SEQ ID NO: 167)
Human polynucleotide sequence:
ATGTATGGAAATTATTCTCACTTCATGAAGTTTCCCGCAGGCTATGGAGGCTCCCCTG GCCACACTGGCTCTACATCCATGAGCCCATCAGCAGCCTTGTCCACAGGGAAGCCAAT GGACAGCCACCCCAGCTACACAGATACCCCAGTGAGTGCCCCACGGACTCTGAGTGCA GTGGGGACCCCCCTCAATGCCCTGGGCTCTCCATATCGAGTCATCACCTCTGCCATGG GCCCACCCTCAGGAGCACTTGCAGCGCCTCCAGGAATCAACTTGGTTGCCCCACCCAG CTCTCAGCTAAATGTGGTCAACAGTGTCAGCAGTTCAGAGGACATCAAGCCCTTACCA GGGCTTCCCGGGATTGGAAACATGAACTACCCATCCACCAGCCCCGGATCTCTGGTTA AACACATCTGTGCTATCTGTGGAGACAGATCCTCAGGAAAGCACTACGGGGTATACAG TTGTGAAGGCTGCAAAGGGTTCTTCAAGAGGACGATAAGGAAGGACCTCATCTACACG TGTCGGGATAATAAAGACTGCCTCATTGACAAGCGTCAGCGCAACCGCTGCCAGTACT GTCGCTATCAGAAGTGCCTTGTCATGGGCATGAAGAGGGAAGCTGTGCAAGAAGAAAG ACAGAGGAGCCGAGAGCGAGCTGAGAGTGAGGCAGAATGTGCTACCAGTGGTCATGAA GACATGCCTGTGGAGAGGATTCTAGAAGCTGAACTTGCTGTTGAACCAAAGACAGAAT CCTATGGTGACATGAATATGGAGAACTCGACAAATGACCCTGTTACCAACATATGTCA TGCTGCTGACAAGCAGCTTTTCACCCTCGTTGAATGGGCCAAGCGTATTCCCCACTTC TCTGACCTCACCTTGGAGGACCAGGTCATTTTGCTTCGGGCAGGGTGGAATGAATTGC TGATTGCCTCTTTCTCCCACCGCTCAGTTTCCGTGCAGGATGGCATCCTTCTGGCCAC GGGTTTACATGTCCACCGGAGCAGTGCCCACAGTGCTGGGGTCGGCTCCATCTTTGAC AGAGTTCTAACTGAGCTGGTTTCCAAAATGAAAGACATGCAGATGGACAAGTCGGAAC TGGGATGCCTGCGAGCCATTGTACTCTTTAACCCAGATGCCAAGGGCCTGTCCAACCC CTCTGAGGTGGAGACTCTGCGAGAGAAGGTTTATGCCACCCTTGAGGCCTACACCAAG CAGAAGTATCCGGAACAGCCAGGCAGGTTTGCCAAGCTGCTGCTGCGCCTCCCAGCTC TGCGTTCCATTGGCTTGAAATGCCTGGAGCACCTCTTCTTCTTCAAGCTCATCGGGGA CACCCCCATTGACACCTTCCTCATGGAGATGTTGGAGACCCCGCTGCAGATCACCTGA (SEQ ID NO: 168)
Mouse polypeptide sequence: MYGNYSHFMKFPTGFGGSPGHTGSTSMSPSVALPTGKPMDSHPSYTDTPVSAPRTLSA VGTPLNALGSPYRVITSAMGPPSGALAAPPGINLVAPPSSQLNWNSVSSSEDIKPLP GLPGIGNMNYPSTSPGSLVKHICAICGDRSSGKHYGVYSCEGCKGFFKRTIRKDLIYT CRDNKDCLIDKRQRNRCQYCRYQKCLVMGMKREAVQEERQRSRERAESEAECASSSHE DMPVERILEAELAVEPKTESYGDMNVENSTNDPVTNICHAADKQLFTLVEWAKRIPHF SDLTLEDQVILLRAGWNELLIASFSHRSVSVQDGILLATGLHVHRSSAHSAGVGSIFD RVLTELVSKMKDMQMDKSELGCLRAIVLFNPDAKGLSNPSEVETLREKVYATLEAYTK QKYPEQPGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDSFLMEMLETPLQIT (SEQ ID NO: 169) Mouse polynucleotide sequence:
ATGTATGGAAATTATTCCCACTTCATGAAGTTTCCCACCGGCTTTGGTGGCTCCCCTG
GTCACACTGGCTCGACGTCCATGAGCCCTTCAGTAGCCTTGCCCACGGGGAAGCCAAT
GGACAGCCACCCCAGCTACACAGACACCCCAGTGAGTGCCCCTCGGACGCTGAGTGCT GTGGGAACCCCCCTCAATGCTCTTGGCTCTCCGTATAGAGTCATCACTTCTGCCATGG GTCCACCCTCAGGAGCACTGGCAGCTCCTCCAGGAATCAACTTGGTGGCTCCACCCAG CTCCCAGCTAAATGTGGTCAACAGTGTCAGCAGCTCTGAGGACATCAAGCCCTTACCA GGTCTGCCTGGGATTGGAAATATGAACTACCCATCCACCAGCCCTGGGTCTCTGGTGA AACACATCTGTGCCATCTGTGGGGACAGATCCTCAGGGAAGCACTACGGTGTGTACAG CTGTGAAGGTTGCAAAGGCTTCTTCAAAAGGACCATCAGGAAAGATCTCATCTACACC TGTCGGGATAACAAAGATTGTCTCATCGACAAGCGCCAGCGCAACCGCTGCCAGTACT GTCGCTACCAGAAGTGCCTGGTCATGGGCATGAAGCGGGAAGCTGTGCAAGAAGAAAG GCAGAGGAGCCGAGAGCGAGCAGAGAGTGAGGCAGAATGTGCCAGTAGTAGCCACGAA GACATGCCCGTGGAGAGGATTCTAGAAGCCGAACTTGCTGTGGAACCAAAGACAGAAT CCTACGGTGACATGAACGTGGAGAACTCAACAAATGACCCTGTTACCAACATATGCCA TGCTGCAGATAAGCAACTTTTCACCCTCGTTGAGTGGGCCAAACGCATCCCCCACTTC TCAGATCTCACCTTGGAGGACCAGGTCATTCTACTCCGGGCAGGGTGGAATGAACTGC TCATTGCCTCCTTCTCCCACCGCTCGGTTTCCGTCCAGGATGGCATCCTGCTGGCCAC GGGCCTCCACGTGCACAGGAGCAGCGCTCACAGCGCGGGAGTCGGCTCCATCTTCGAC AGAGTCCTTACAGAGTTGGTGTCCAAGATGAAAGACATGCAGATGGATAAGTCAGAGC TGGGGTGCCTACGGGCCATCGTGCTGTTTAACCCAGATGCCAAGGGTTTATCCAACCC CTCTGAGGTGGAGACTCTTCGAGAGAAGGTTTATGCCACCCTGGAGGCCTATACCAAG CAGAAGTATCCGGAACAGCCAGGCAGGTTTGCCAAGCTTCTGCTGCGTCTCCCTGCTC TGCGCTCCATCGGCTTGAAATGCCTGGAACACCTCTTCTTCTTCAAGCTCATTGGAGA CACTCCCATCGACAGCTTCCTCATGGAGATGTTGGAGACCCCACTGCAGATCACCTGA
(SEQ IDNO: 170)
SHP
Human polypeptide sequence:
MSTSQPGACPCQGAASRPAILYALLSSSLKAVPRPRSRCLCRQHRPVQLCAPHRTCRE ALDVLAKTVAFLRNLPSF QLPPQDQRRLLQGCWGPLFLLGLAQDAVTFEVAEAPVPS ILKKILLEEPSSSGGSGQLPDRPQPSLAAVQWLQCCLESF SLELSPKEYACLKGTIL FNPDVPGLQAASHIGHLQQEAHWVLCEVLEPWCPAAQGRLTRVLLTASTLKSIPTSLL GDLFFRPIIGDVDIAGLLGDMLLLR (SEQ IDNO: 171)
Human polynucleotide sequence:
TGAGCACCAGCCAACCAGGGGCCTGCCCATGCCAGGGAGCTGCAAGCCGCCCCGCCAT TCTCTACGCACTTCTGAGCTCCAGCCTCAAGGCTGTCCCCCGACCCCGTAGCCGCTGC CTATGTAGGCAGCACCGGCCCGTCCAGCTATGTGCACCTCATCGCACCTGCCGGGAGG CCTTGGATGTTCTGGCCAAGACAGTGGCCTTCCTCAGGAACCTGCCATCCTTCTGGCA GCTGCCTCCCCAGGACCAGCGGCGGCTGCTGCAGGGTTGCTGGGGCCCCCTCTTCCTG CTTGGGTTGGCCCAAGATGCTGTGACCTTTGAGGTGGCTGAGGCCCCGGTGCCCAGCA TACTCAAGAAGATTCTGCTGGAGGAGCCCAGCAGCAGTGGAGGCAGTGGCCAACTGCC AGACAGACCCCAGCCCTCCCTGGCTGCGGTGCAGTGGCTTCAATGCTGTCTGGAGTCC TTCTGGAGCCTGGAGCTTAGCCCCAAGGAATATGCCTGCCTGAAAGGGACCATCCTCT TCAACCCCGATGTGCCAGGCCTCCAAGCCGCCTCCCACATTGGGCACCTGCAGCAGGA GGCTCACTGGGTGCTGTGTGAAGTCCTGGAACCCTGGTGCCCAGCAGCCCAAGGCCGC CTGACCCGTGTCCTCCTCACGGCCTCCACCCTCAAGTCCATTCCGACCAGCCTGCTTG GGGACCTCTTCTTTCGCCCTATCATTGGAGATGTTGACATCGCTGGCCTTCTTGGGGA CATGCTTTTGCTCAGGTGA (SEQ IDNO: 172) Mouse polypeptide sequence:
MSSGQSGVCPCQGSAGRPTILYALLSPSPRTRPVAPASHSHCLCQQQRPVRLCAPHRT CREALDVLAKTVAFLRNLPSFCHLPHEDQRRLLECC GPLFLLGLAQDAVTFEVAEAP VPSILKKILLEEASSGTQGAQPSDRPQPSLAAVQWLQRCLESFWSLELGPKEYAYLKG TILFNPDVPGLRASCHIAHLQQEAHWALCEVLEPWYPASQGRLARILLMASTLKNIPG TLLVDLFFRPIMGDVDITELLEDMLLLR (SEQ IDNO: 173) Mouse polynucleotide sequence:
ATGAGCTCCGGCCAGTCAGGGGTCTGCCCATGCCAGGGCTCTGCAGGTCGTCCGACTA TTCTGTATGCACTTCTGAGCCCCAGCCCCAGGACCAGGCCCGTTGCACCTGCATCTCA CAGCCACTGCCTGTGCCAGCAGCAGCGGCCTGTGCGTCTGTGTGCTCCGCACCGCACC TGCAGGGAGGCCTTGGATGTCCTAGCCAAGACAGTAGCCTTCCTCAGGAACCTGCCGT CCTTCTGCCACCTGCCCCATGAGGATCAGCGGCGGCTGCTAGAGTGCTGCTGGGGCCC TCTCTTCCTGCTTGGGTTGGCCCAGGATGCTGTGACCTTCGAGGTGGCTGAGGCTCCG GTGCCCAGTATACTTAAGAAGATCCTGCTAGAGGAAGCCAGCAGCGGTACCCAGGGTG CCCAGCCATCAGACCGGCCACAACCCTCACTGGCTGCAGTTCAGTGGCTGCAGCGCTG CCTGGAGTCTTTCTGGAGCCTTGAGCTGGGTCCCAAGGAGTATGCGTACCTGAAGGGC ACGATCCTCTTCAACCCAGATGTGCCAGGCCTCCGTGCCTCCTGCCACATCGCACACC TGCAACAGGAGGCTCACTGGGCACTGTGTGAAGTCTTGGAGCCCTGGTACCCAGCCAG CCAAGGCCGCCTGGCCCGAATCCTCCTCATGGCCTCTACCCTCAAGAACATTCCAGGC ACCCTTCTGGTAGATCTCTTCTTCCGCCCTATCATGGGAGACGTTGACATCACTGAAC TCCTTGAAGACATGCTTTTGCTGAGGTGA (SEQ ID NO: 174)
STF1 Human polypeptide sequence:
MDYSYDEDLDELCPVCGDKVSGYHYGLLTCESCKGFFKRTVQNNKHYTCTESQSCKID KTQRKRCPFCRFQKCLTVGMRLEAVRADRMRGGRNKFGPMYKRDRALKQQKKAQIRAN GFKLETGPPMGVPPPPPPAPDYVLPPSLHGPEPKGLAAGPPAGPLGDFGAPALPMAVP GAHGPLAGYLYPAFPGRAIKSEYPEPYASPPQPGLPYGYPEPFSGGPNVPELILQLLQ LEPDEDQVRARILGCLQEPTKSRPDQPAAFGLLCRMADQTFISIVDWARRCMVFKELE VADQMTLLQNC SELLVFDHIYRQVQHGKEGSILLVTGQEVELTTVATQAGSLLHSLV LRAQELVLQLLALQLDRQEFVCLKFIILFSLDLKFLNNHILVKDAQEKANAALLDYTL CHYPHCGDKFQQLLLCLVEVRALSMQAKEYLYHKHLGNEMPRNNLLIEMLQAKQT (SEQ ID NO: 175)
Human polynucleotide sequence:
ATGGACTATTCGTACGACGAGGACCTGGACGAGCTGTGCCCCGTGTGCGGGGACAAGG TGTCCGGCTACCACTACGGACTGCTCACGTGTGAGAGCTGCAAGGGCTTCTTCAAGCG
CACGGTGCAGAACAACAAGCACTACACGTGCACCGAGAGCCAGAGCTGCAAGATCGAC
AAGACGCAGCGCAAGCGCTGTCCCTTCTGCCGCTTCCAGAAATGCCTGACGGTGGGGA
TGCGCCTGGAAGCCGTGCGCGCTGACCGTATGAGGGGTGGCCGGAACAAGTTTGGGCC
GATGTACAAGCGGGACCGGGCCCTGAAACAGCAGAAGAAGGCACAGATTCGGGCCAAT GGCTTCAAGCTGGAGACAGGGCCCCCGATGGGGGTGCCCCCGCCGCCCCCTCCCGCAC
CGGACTACGTGCTGCCTCCCAGCCTGCATGGGCCTGAGCCCAAGGGCCTGGCCGCCGG
TCCACCTGCTGGGCCACTGGGCGACTTTGGGGCCCCAGCACTGCCCATGGCCGTGCCC
GGTGCCCACGGGCCACTGGCTGGCTACCTCTACCCTGCCTTTCCTGGCCGTGCCATCA
AGTCTGAGTACCCGGAGCCTTATGCCAGCCCCCCACAGCCTGGGCTGCCGTACGGCTA CCCAGAGCCCTTCTCTGGAGGCCCCAACGTGCCTGAGCTCATCCTGCAGCTGCTGCAG CTGGAGCCGGATGAGGACCAGGTGCGGGCCCGCATCTTGGGCTGCCTGCAGGAGCCCA CCAAAAGCCGCCCCGACCAGCCGGCGGCCTTCGGCCTCCTGTGCAGAATGGCCGACCA GACCTTCATCTCCATCGTGGACTGGGCACGCAGGTGCATGGTCTTCAAGGAGCTGGAG GTGGCCGACCAGATGACGCTGCTGCAGAACTGCTGGAGCGAGCTGCTGGTGTTCGACC ACATCTACCGCCAGGTCCAGCACGGCAAGGAGGGCAGCATCCTGCTGGTCACCGGGCA GGAGGTGGAGCTGACCACAGTGGCCACCCAGGCGGGCTCGCTGCTGCACAGCCTGGTG TTGCGGGCGCAGGAGCTGGTGCTGCAGCTGCTTGCGCTGCAGCTGGACCGGCAGGAGT TTGTCTGCCTCAAGTTCATCATCCTCTTCAGCCTGGATTTGAAGTTCCTGAATAACCA CATCCTGGTGAAAGACGCTCAGGAGAAGGCCAACGCCGCCCTGCTTGACTACACCCTG TGCCACTACCCGCACTGCGGGGACAAATTCCAGCAGCTGCTGCTGTGCCTGGTGGAGG TGCGGGCCCTGAGCATGCAGGCCAAGGAGTACCTGTACCACAAGCACCTGGGCAACGA GATGCCCCGCAACAACCTGCTCATCGAAATGCTGCAAGCCAAGCAGACTTGA (SEQ ID NO: 176) Mouse polypeptide sequence :
MDYSYDEDLDELCPVCGDKVSGYHYGLLTCESCKGFFKRTVQNNKHYTCTESQSCKID KTQRKRCPFCRFQKCLTVGMRLEAVRADRMRGGRNKFGPMYKRDRALKQQKKAQIRAN GFKLETGPPMGVPPPPPPPPDYMLPPSLHAPEPKALVSGPPSGPLGDIGAPSLPMSVP GPHGPLAGYLYPAFSNRTIKSEYPEPYASPPQQPGPPYSYPEPFSGGPNVPELILQLL QLEPEEDQVRARIVGCLQEPAKSGSDQPAPFSLLCRMADQTFISIVD ARRCMVFKEL EVADQMTLLQNCWSELLVLDHIYRQVQYGKEDSILLVSGQEVELSTVAVQAGSLLHSL VLRAQELVLQLHALQLDRQEFVCLKFLILFSLDVKFLNNHSLVKDAQEKANAALLDYT LCHYPHCGDKFQQLLLCLVEVRALSMQAKEYLYHKHLGNEMPRNNLLIEMLQAKQT (SEQ ID NO: 177)
Mouse polynucleotide sequence:
ATGGAAATGCATCGAATCCGAGGGTCCCGGATCGGGCGCGGCAGAGGCGGCGAGGAAG CAGCCCTGGAACGCGGCGGGTGGCTGAGCTGCAGCGCAGGGACATGGCCCACAAACCC CCGCACCCGGCCCGGGCTGGGGACCGCCCCGTGTGCACAGACCAGGGCAATCCCAAGC CAGTCGCCGTCGGCCCGCGCTGACCCGATCCTCCTTCCACAGGCGGACGCCGCGGGCA TGGACTACTCGTACGACGAGGACCTGGACGAGCTGTGTCCAGTGTGTGGTGACAAGGT GTCGGGCTACCACTACGGGCTGCTCACGTGCGAGAGCTGCAAGGGCTTCTTCAAGCGC ACAGTCCAGAACAACAAGCATTACACGTGCACCGAGAGTCAGAGCTGCAAAATCGACA AGACGCAGCGTAAGCGCTGTCCCTTCTGCCGCTTCCAGAAGTGCCTGACGGTGGGCAT GCGCCTGGAAGCTGTGCGTGCTGATCGAATGCGGGGTGGCCGGAACAAGTTTGGGCCC ATGTACAAGAGAGACCGGGCCTTGAAGCAGCAGAAGAAAGCACAGATTCGGGCCAATG GCTTCAAGCTGGAGACCGGACCACCGATGGGGGTGCCCCCTCCACCCCCTCCCCCACC GGACTACATGTTACCCCCTAGCCTGCACGCACCGGAGCCCAAGGCCCTGGTCTCTGGC CCACCCAGTGGGCCGCTGGGTGACATTGGAGCCCCATCTCTACCCATGTCTGTGCCTG GTCCCCACGGACCTCTGGCTGGCTACCTCTATCCTGCCTTCTCTAACCGCACCATCAA GTCTGAGTATCCAGAGCCCTATGCCAGCCCCCCACAACAGCCAGGGCCACCCTACAGC TATCCAGAGCCCTTCTCAGGAGGGCCCAATGTACCAGAGCTCATATTGCAGCTGCTGC AACTAGAGCCAGAGGAGGACCAGGTGCGCGCTCGCATCGTGGGCTGTCTGCAGGAGCC AGCCAAAAGCGGCTCTGACCAGCCAGCGCCCTTCAGCCTCCTCTGCAGAATGGCCGAC CAGACCTTTATCTCCATTGTCGACTGGGCACGAAGGTGCATGGTCTTTAAGGAGCTGG AGGTGGCTGACCAGATGACACTGCTGCAGAACTGTTGGAGCGAGCTGCTGGTGTTGGA CCACATCTACCGCCAAGTCCAGTACGGCAAGGAAGACAGCATCCTGCTGGTTAGTGGA CAGGAGGTAACTGAACTGGTCAAACCCCTAGTCCTGCATAATCCCAGGCCTCTCAGGG CTGACTCGGGACACCCCAAATTCCAAATTCAGGGACATGCACTAGCCAGGCTTCTCTG TGTCCTGGGGCCATTTGAGGAGCCACAGTGTGGAATGGTCAGTGGAAGTTCTTATAGG AGATAA (SEQ ID NO: 178) THA
Human polypeptide sequence: MEQKPSKVECGSDPEENSARSPDGKRKRKNGQCSLKTSMSGYIPSYLDKDEQCWCGD KATGYHYRCITCEGCKGFFRRTIQKNLHPTYSCKYDSCCVIDKITRNQCQLCRFKKCI AVGMAMDLVLDDSKRVAKRKLIEQNRERRRKEEMIRSLQQRPEPTPEE DLIHIATEA HRSTNAQGSH KQRRKFLPDDIGQSPIVSMPDGDKVDLEAFSEFTKIITPAITRWDF AKKLPMFSELPCEDQIILLKGCCMEIMSLRAAVRYDPESDTLTLSGEMAVKREQLKNG GLGWSDAIFELGKSLSAFNLDDTEVALLQAVLLMSTDRSGLLCVDKIEKSQEAYLLA FEHYVNHRKHNIPHF PKLLMKEREVQSSILYKGAAAEGRPGGSLGVHPEGQQLLGMH WQGPQVRQLEQQLGEAGSLQGPVLQHQSPKSPQQRLLELLHRSGILHARAVCGEDDS SEADSPSSSEEEPEVCEDLAGNAASP (SEQ ID NO: 179)
Human polynucleotide sequence:
ATGGAACAGAAGCCAAGCAAGGTGGAGTGTGGGTCAGACCCAGAGGAGAACAGTGCCA GGTCACCAGATGGAAAGCGAAAAAGAAAGAACGGCCAATGTTCCCTGAAAACCAGCAT GTCAGGGTATATCCCTAGTTACCTGGACAAAGACGAGCAGTGTGTCGTGTGTGGGGAC AAGGCAACTGGTTATCACTACCGCTGTATCACTTGTGAGGGCTGCAAGGGCTTCTTTC GCCGCACAATCCAGAAGAACCTCCATCCCACCTATTCCTGCAAATATGACAGCTGCTG TGTCATTGACAAGATCACCCGCAATCAGTGCCAGCTGTGCCGCTTCAAGAAGTGCATC GCCGTGGGCATGGCCATGGACTTGGTTCTAGATGACTCGAAGCGGGTGGCCAAGCGTA AGCTGATTGAGCAGAACCGGGAGCGGCGGCGGAAGGAGGAGATGATCCGATCACTGCA GCAGCGACCAGAGCCCACTCCTGAAGAGTGGGATCTGATCCACATTGCCACAGAGGCC CATCGCAGCACCAATGCCCAGGGCAGCCATTGGAAACAGAGGCGGAAATTCCTGCCCG ATGACATTGGCCAGTCACCCATTGTCTCCATGCCGGACGGAGACAAGGTGGACCTGGA AGCCTTCAGCGAGTTTACCAAGATCATCACCCCGGCCATCACCCGTGTGGTGGACTTT GCCAAAAAACTGCCCATGTTCTCCGAGCTGCCTTGCGAAGACCAGATCATCCTCCTGA AGGGGTGCTGCATGGAGATCATGTCCCTGCGGGCGGCTGTCCGCTACGACCCTGAGAG CGACACCCTGACGCTGAGTGGGGAGATGGCTGTCAAGCGGGAGCAGCTCAAGAATGGC GGCCTGGGCGTAGTCTCCGACGCCATCTTTGAACTGGGCAAGTCACTCTCTGCCTTTA ACCTGGATGACACGGAAGTGGCTCTGCTGCAGGCTGTGCTGCTAATGTCAACAGACCG CTCGGGCCTGCTGTGTGTGGACAAGATCGAGAAGAGTCAGGAGGCGTACCTGCTGGCG TTCGAGCACTACGTCAACCACCGCAAACACAACATTCCGCACTTCTGGCCCAAGCTGC TGATGAAGGAGAGAGAAGTGCAGAGTTCGATTCTGTACAAGGGGGCAGCGGCAGAAGG CCGGCCGGGCGGGTCACTGGGCGTCCACCCGGAAGGACAGCAGCTTCTCGGAATGCAT GTTGTTCAGGGTCCGCAGGTCCGGCAGCTTGAGCAGCAGCTTGGTGAAGCGGGAAGTC TCCAAGGGCCGGTTCTTCAGCACCAGAGCCCGAAGAGCCCGCAGCAGCGTCTCCTGGA GCTGCTCCACCGAAGCGGAATTCTCCATGCCCGAGCGGTCTGTGGGGAAGACGACAGC AGTGAGGCGGACTCCCCGAGCTCCTCTGAGGAGGAACCGGAGGTCTGCGAGGACCTGG CAGGCAATGCAGCCTCTCCCTGA (SEQ IDNO: 180)
Mouse polypeptide sequence:
MEQKPSKVECGSDPEENSARSPDGKRKRKNGQCPLKSSMSGYIPSYLDKDEQCWCGD KATGYHYRCITCEGCKGFFRRTIQKNLHPTYSCKYDSCCVIDKITRNQCQLCRFKKCI AVGMAMDLVLDDSKRVAKRKLIEQNRERRRKEEMIRSLQQRPEPTPEE DLIHVATEA HRSTNAQGSHWKQRRKFLPDDIGQSPIVSMPDGDKVDLEAFSEFTKIITPAITRWDF AKKLPMFSELPCEDQIILLKGCCMEIMSLRAAVRYDPESDTLTLSGEMAVKREQLKNG GLGWSDAIFELGKSLSAFNLDDTEVALLQAVLLMSTDRSGLLCVDKIEKSQEAYLLA FEHYVNHRKHNIPHFWPKLLMKEREVQSSILYKGAAAEGRPGGSLGVHPEGQQLLGMH WQGPQVRQLEQQFGEAGSLRGPVLQHQSPKSPQQRLLELLHRSGILHSRAVCGEDDS
SEASSLSSSSSDEDTEVFEDLAGKAASP
(SEQ IDNO: 181) Mouse polynucleotide sequence:
ATGTCAGGGTATATCCCTAGTTACCTGGACAAAGACGAGCAGTGTGTCGTGTGTGGGG ACAAGGCCACCGGTTATCACTACCGCTGTATCACTTGTGAGGGCTGCAAGGGCTTCTT TCGCCGTACAATCCAGAAGAACCTCCATCCCACCTATTCCTGCAAATATGACAGCTGC TGCGTCATCGACAAGATCACCCGGAATCAGTGCCAGTTGTGCCGCTTCAAGAAGTGCA TCGCTGTGGGCATGGCCATGGACCTGGTTCTAGACGATTCAAAGCGGGTGGCCAAACG CAAGCTGATTGAGCAGAACCGGGAGAGGAGGCGAAAGGAGGAGATGATCCGCTCGCTG CAGCAACGACCAGAGCCCACTCCTGAAGAGTGGGATCTGATCCACGTTGCTACAGAGG CCCATCGCAGCACCAATGCCCAGGGCAGCCATTGGAAACAGAGGCGAAAATTCCTGCC GGATGACATTGGCCAGTCACCTATTGTCTCCATGCCGGACGGAGACAAGGTAGACCTA GAGGCCTTCAGCGAGTTTACCAAGATCATCACCCCGGCCATCACCCGCGTGGTGGACT TTGCCAAAAAACTGCCCATGTTCTCCGAGCTGCCTTGTGAAGACCAGATCATCCTCCT GAAGGGCTGCTGCATGGAGATCATGTCCCTGCGGGCAGCTGTCCGCTATGACCCTGAG AGCGACACCCTGACCCTGAGTGGGGAGATGGCGGTTAAGCGGGAGCAGCTCAAGAATG GTGGCTTGGGTGTAGTCTCCGACGCCATCTTTGAACTGGGCAAGTCACTCTCTGCCTT TAACCTGGATGATACGGAAGTGGCTCTGCTGCAGGCTGTGCTGTTAATGTCAACAGAC CGCTCTGGCCTGCTGTGTGTGGACAAGATCGAGAAGAGTCAGGAGGCCTACCTGCTGG CGTTTGAGCACTACGTCAACCACCGCAAACACAACATTCCGCACTTCTGGCCCAAGCT GCTGATGAAGGAGAGAGAAGTGCAGAGTTCGATTCTGTACAAGGGGGCAGCGGCAGAA GGCCGGCCGGGCGGGTCACTGGGCGTCCACCCGGAAGGACAGCAGCTTCTCGGAATGC ATGTTGTTCAGGGTCCGCAGGTCCGGCAGCTTGAGCAGCAGTTTGGTGAAGCGGGAAG TCTCCGAGGGCCGGTTCTTCAGCACCAGAGCCCGAAGAGCCCGCAGCAGCGTCTCCTG GAGCTGCTCCACCGAAGCGGAATTCTCCATTCCCGAGCGGTCTGTGGGGAAGACGACA GCAGTGAGGCAAGCTCCCTGAGCTCCTCTTCCTCTGACGAGGACACGGAGGTCTTCGA GGACCTGGCAGGCAAGGCAGCCTCTCCCTGA (SEQ ID NO: 182)
THRB1 Human polypeptide sequence:
MTPNSMTENGLTADKPKHCPDREHD KLVGMSEACLHRKSHSERRSTLKNEQSSPHL IQTTWTSSIFHLDHDDVNDQSVSSAQTFQTEEKKCKGYIPSYLDKDELCWCGDKATG YHYRCITCEGCKGFFRRTIQKNLHPSYSCKYEGKCVIDKVTRNQCQECRFKKCIYVGM ATDLVLDDSKRLAKRKLIEENREKRRREELQKSIGHKPEPTDEEWELIKTVTEAHVAT NAQGSHWKQKRKFLPEDIGQAPIVNAPEGGKVDLEAFSHFTKIITPAITRWDFAKKL PMFCELPCEDQIILLKGCCMEIMSLRAAVRYDPESETLTLNGEMAVTRGQLKNGGLGV VSDAIFDLGMSLSSFNLDDTEVALLQAVLLMSSDRPGLACVERIEKYQDSFLLAFEHY INYRKHHVTHFWPKLLMKVTDLRMIGACHASRFLHMKVECPTELFPPLFLEVFED (SEQ IDNO: 183)
Human polynucleotide sequence:
ATGACAGAAAATGGCCTTACAGCTTGGGACAAACCGAAGCACTGTCCAGACCGAGAAC ACGACTGGAAGCTAGTAGGAATGTCTGAAGCCTGCCTACATAGGAAGAGCCATTCAGA GAGGCGCAGCACGTTGAAAAATGAACAGTCGTCGCCACATCTCATCCAGACCACTTGG ACTAGCTCAATATTCCATCTGGACCATGATGATGTGAACGACCAGAGTGTCTCAAGTG CCCAGACCTTCCAAACGGAGGAGAAGAAATGTAAAGGGTACATCCCCAGTTACTTAGA CAAGGACGAGCTCTGTGTAGTGTGTGGTGACAAAGCCACCGGGTATCACTACCGCTGT ATCACGTGTGAAGGCTGCAAGGGTTTCTTTAGAAGAACCATTCAGAAAAATCTCCATC CATCCTATTCCTGTAAATATGAAGGAAAATGTGTCATAGACAAAGTCACGCGAAATCA GTGCCAGGAATGTCGCTTTAAGAAATGCATCTATGTTGGCATGGCAACAGATTTGGTG CTGGATGACAGCAAGAGGCTGGCCAAGAGGAAGCTGATAGAGGAGAACCGGGAGAAAA GACGGCGGGAAGAGCTGCAGAAGTCCATCGGGCACAAGCCAGAGCCCACAGACGAGGA ATGGGAGCTCATCAAAACTGTCACCGAAGCCCATGTGGCGACCAACGCCCAAGGCAGC CACTGGAAGCAAAAACCGAAATTTCTGCCAGAAGACATTGGACAAGCACCAATAGTCA ATGCCCCAGAAGGTGGAAAGGTTGACTTGGAAGCCTTCAGCCATTTTACAAAAATCAT CACACCAGCAATTACCAGAGTGGTGGATTTTGCCAAAAAGTTGCCTATGTTTTGTGAG CTGCCATGTGAAGACCAGATCATCCTCCTCAAAGGCTGCTGCATGGAGATCATGTCCC TTCGCGCTGCTGTGCGCTATGACCCGGAAAGTGAGACTTTAACCTTGAATGGGGAAAT GGCAGTGATACGGGGCCAGCTGAAAAATGGGGGTCTTGGGGTGGTGTCAGACGCCATC TTTGACCTAGGCATGTCTCTGTCTTCTTTCAACCTGGATGACACTGAAGTAGCCCTCC TTCAGGCCGTCCTGCTGATGTCTTCAGATCGCCCGGGGCTTGCCTGTGTTGAGAGAAT AGAAAAGTACCAAGATAGTTTCCTGCTGGCCTTTGAACACTATATCAATTACCGAAAA CACCACGTGACACACTTTTGGCCAAAACTCCTGATGAAGGTGACAGATCTGCGGATGA TAGGAGCCTGCCATGCCAGCCGCTTCCTGCACATGAAGGTGGAATGCCCCACAGAACT CCTCCCCCCTTTGTTCCTGGAAGTGTTCGAGGATTAG (SEQ ID NO: 184) Mouse polypeptide sequence:
MTPNSMTENGLPAWDKQKPRPDRGQDWKLVGMSEACLHRKSHVERRGALKNEQTSPHL IQAT TSSIFHLDPDDVNDQSISSAQTFQTEEKKCKGYIPSYLDKDELCWCGDKATG YHYRCITCEGCKGFFRRTIQKSLHPSYSCKYEGKCIIDKVTRNQCQECRFKKCIYVGM ATDLVLDDSKRLAKRKLIEENREKRRREELQKSIGHKPEPTDEEWELIKTVTEAHVAT NAQGSHWKQKRKFLPEDIGQAPIVNAPEGGKVDLEAFSHFTKIITPAITRWDFAKKL PMFCELPCEDQIILLKGCCMEIMSLRAAVRYDPDSETLTLNGEMAVTRGQLKNGGLGV VSDAIFDLGMSLSSFNLDDTEVALLQAVLLMSSDRPGLACVERIEKYQDSFLLAFEHY INYRKHHVTHF PKLLMKVTDLRMIGACHASRFLHMKVECPTELFPPLFLEVFED (SEQ ID NO: 185)
Mouse polynucleotide sequence:
ATGACTCCTAACAGTATGACAGAAAATGGCCTTCCAGCCTGGGACAAGCAGAAGCCCC GTCCAGACCGAGGCCAGGACTGGAAGCTGGTAGGAATGTCTGAAGCCTGCCTGCACAG GAAGAGCCACGTGGAGAGGCGTGGTGCACTGAAGAATGAGCAGACTTCCCCACACCTT ATCCAGGCCACTTGGACAAGCTCTATATTCCACCTGGATCCTGACGATGTGAACGATC AGAGCATCTCAAGTGCCCAGACTTTCCAGACTGAAGAGAAGAAATGTAAAGGGTATAT CCCCAGCTATTTAGACAAAGATGAGCTCTGTGTAGTGTGTGGGGACAAAGCCACAGGG TACCACTATCGCTGCATCACCTGTGAAGGCTGCAAGGGCTTCTTTAGAAGAACCATTC AGAAAAGTCTCCATCCATCTTATTCCTGTAAATATGAAGGAAAGTGCATCATAGACAA AGTCACCCGCAACCAGTGCCAGGAATGTCGCTTTAAGAAATGCATCTATGTTGGCATG GCAACAGACTTGGTGCTGGATGACAGCAAGAGGCTAGCCAAGCGGAAGCTTATAGAGG AGAACCGTGAGAAGAGGCGGCGGGAAGAGCTACAGAAATCAATTGGGCACAAGCCAGA ACCCACGGATGAGGAGTGGGAGCTCATCAAGACAGTCACTGAGGCCCACGTGGCCACC AATGCCCAGGGCAGCCACTGGAAGCAGAAGCGGAAATTCCTGCCAGAAGACATTGGAC AAGCACCCATCGTGAATGCCCCAGAAGGTGGCAAGGTTGACCTGGAAGCCTTCAGTCA TTTTACAAAAATCATCACACCAGCAATTACCAGAGTGGTGGATTTTGCCAAAAAGTTG CCCATGTTTTGTGAGCTGCCATGTGAAGACCAGATCATCCTCCTCAAAGGCTGCTGCA TGGAGATCATGTCCCTTCGAGCTGCTGTGCGCTATGACCCAGACAGCGAGACTCTAAC TTTGAATGGGGAAATGGCAGTGACACGAGGCCAGCTGAAAAATGGGGGCCTTGGGGTG GTTTCAGATGCCATCTTTGACCTGGGCATGTCTCTGTCATCTTTCAACCTGGATGACA CTGAAGTCGCCCTGCTTCAGGCCGTCCTGCTAATGTCTTCAGATCGCCCAGGGCTAGC CTGTGTTGAGAGAATAGAGAAATACCAAGACAGTTTCCTGTTAGCCTTTGAACACTAT ATCAATTACCGGAAGCACCATGTGACACACTTTTGGCCCAAACTCCTGATGAAGGTGA CAGACCTGCGGATGATTGGAGCTTGCCATGCCAGCCGCTTCCTCCACATGAAGGTGGA GTGCCCCACTGAGCTCTTCCCGCCTCTGTTCTTAGAAGTATTTGAGGACTAA (SEQ ID NO: 186)
TR2
Human polypeptide sequence:
MATIEEIAHQIIEQQMGEIVTEQQTGQKIQIVTALDHNTQGKQFILTNHDGSTPSKVI LARQDSTPGKVFLTTPDAAGVNQLFFTTPDLSAQHLQLLTDNSPDQGPNKVFDLCWC GDKASGRHYGAVTCEGCKGFFKRSIRKNLVYSCRGSKDCIINKHHRNRCQYCRLQRCI AFGMKQDSVQCERKPIEVSREKSSNCAASTEKIYIRKDLRSPLTATPTFVTDSESTRS TGLLDSGMFMNIHPSGVKTESAVLMTSDKAESCQGDLSTLANWTSLANLGKTKDLSQ NSNEMSMIESLSNDDTSLCEFQEMQTNGDVSRAFDTLAKALNPGESTACQSSVAGMEG SVHLITGDSSINYTEKEGPLLSDSHVAFRLTMPSPMPEYLNVHYIGESASRLLFLSMH ALSIPSFQALGQENSISLVKAYWNELFTLGLAQCWQVMNVATILATFVNCLHNSLQQ DAKVIAALIHFTRRAITDL (SEQ IDNO: 187)
Human polynucleotide sequence:
ATGGCAACCATAGAAGAAATTGCACATCAAATTATTGAACAACAGATGGGAGAGATTG TTACAGAGCAGCAAACTGGGCAGAAAATCCAGATTGTGACAGCACTTGATCATAATAC CCAAGGCAAGCAGTTCATTCTGACAAATCACGACGGCTCTACTCCAAGCAAAGTCATT CTGGCCAGGCAAGATTCCACTCCGGGAAAAGTTTTCCTTACAACTCCAGATGCAGCAG GTGTCAACCAGTTATTTTTTACCACTCCTGATCTGTCTGCACAACACCTGCAGCTCCT AACAGATAATTCTCCAGACCAAGGACCAAATAAGGTTTTTGATCTTTGCGTAGTATGT GGAGACAAAGCATCAGGACGTCATTATGGAGCAGTAACTTGTGAAGGCTGCAAAGGAT TTTTTAAAAGAAGCATCCGAAAAAATTTAGTATATTCATGTCGAGGATCAAAGGATTG TATTATTAATAAGCACCACCGAAACCGCTGTCAATACTGCAGGTTACAGAGATGTATT GCGTTTGGAATGAAGCAAGACTCTGTCCAATGTGAAAGAAAACCCATTGAAGTATCAC GAGAAAAATCTTCCAACTGTGCCGCTTCAACAGAAAAAATCTATATCCGAAAGGACCT TCGTAGCCCATTAACTGCAACTCCAACTTTTGTAACAGATAGTGAAAGTACAAGGTCA ACAGGACTGTTAGATTCAGGAATGTTCATGAATATTCATCCATCTGGAGTAAAAACTG AGTCAGCTGTGCTGATGACATCAGATAAGGCTGAATCATGTCAGGGAGATTTAAGTAC ATTGGCCAATGTGGTTACATCATTAGCGAATCTTGGAAAAACTAAAGATCTTTCTCAA AATAGTAATGAAATGTCTATGATTGAAAGCTTAAGCAATGATGATACCTCTTTGTGTG AATTTCAAGAAATGCAGACCAACGGTGATGTTTCAAGGGCATTTGACACTCTTGCAAA AGCATTGAATCCTGGAGAGAGCACAGCCTGCCAGAGCTCAGTAGCGGGCATGGAAGGA AGTGTACACCTAATCACTGGAGATTCAAGCATAAATTACACCGAAAAAGAGGGGCCAC TTCTCAGCGATTCACATGTAGCTTTCAGGCTCACCATGCCTTCTCCTATGCCTGAGTA CCTGAATGTGCACTACATTGGGGAGTCTGCCTCCAGACTGCTGTTCTTATCAATGCAC TGGGCACTTTCGATTCCTTCTTTCCAGGCTCTAGGGCAAGAAAACAGCATATCACTGG TGAAAGCTTACTGGAATGAACTTTTTACTCTTGGTCTTGCCCAGTGCTGGCAAGTGAT GAATGTAGCAACTATATTAGCAACATTTGTCAATTGTCTTCACAATAGTCTTCAACAA GATGCCAAGGTAATTGCAGCCCTCATTCATTTCACAAGACGAGCAATCACTGATTTAT AA (SEQ IDNO: 188)
Mouse polypeptide sequence:
MATIEEIAHQIIDQQMGEIVTEQQTGQKMQIVTALDHSTQGKQFILANHEGSTPGKVF LTTPDAAGVNQLFFTSPDLSAPHLQLLTEKSPDQGPNKVFDLCWCGDKASGRHYGAI TCEGCKGFFKRSIRKNLVYSCRGSKDCVMNKHHRNRCQYCRLQRCIAFGMKQDSVQCE RKPIEVSREKSSNCAASTEKIYIRKDLRSPLAATPTFVTDSETARSAGLLDSGMFVNI HPSGIKTEPAMLMAPDKAESCQGDLSTLASWTSLANLGKAKDLSHCGGDMPWQSLR NGDTSSVLFIMIFKTNGDVSRAFDTLAKALTPGESTSCQSPEEGMEGSPHLIAGEPSF
VEKEGPLLSESHIAFRLTMPSPMPEYLNAHYIGESASRLLFLSMH ALSIPSFQALGQ
ENSISLVKAY NELFTLGLAQCWQVMNVATILATFVNCLHSSLQQDKMSAERRKSLME
HIFKLQEFCNSMVKLCIDGHEYAYLKAIVLFSPDHPGLENMELIERFQEKAYVEFQDY
ITRTYPDDTYRLSRLLLRLPALRLMNATITEELFFKGLIGNVRIDSVIPHILKMEPAD
YNSQIIGHSL
(SEQ ID NO: 189)
Mouse polynucleotide sequence:
ATGGCGACCATAGAAGAAATTGCACATCAAATTATCGACCAACAGATGGGTGAGATTG TTACAGAGCAGCAGACCGGACAGAAAATCCAGATTGTGACAGCACTTGACCACAGCAC ACAGGGCAAGCAGTTCATTCTGGCAAACCACGAGGGATCCACGCCAGGGAAAGTCTTC CTCACAACTCCAGACGCCGCAGGTGTCAACCAGTTGTTTTTTACCAGTCCTGATCTGT CCGCACCACACCTCCAGCTCTTAACAGAAAATTCTCCTGACCAGGGACCAAATAAGGT TTTTGATCTTTGTGTCGTGTGTGGAGACAAAGCATCAGGGCGTCATTACGGAGCAATA ACTTGTGAAGGCTGCAAAGGATTCTTTAAAAGAAGCATCCGGAAAAACCTAGTCTATT CCTGTCGAGGATCCAAAGACTGCGTTATCAATAAGCACCACCGAAACCGCTGCCAGTA CTGCAGGCTGCAGCGGTGCATTGCCTTCGGGATGAAGCAAGACTCTGTTCAGTGTGAA AGAAAACCCATTGAAGTTTCCCGAGAAAAATCTTCCAACTGTGCAGCTTCAACAGAAA AAATCTACATTCGCAAAAACCTCCGAAGCCCTCTAGCCGCAACGCCAACCTTTGTAAC AGACAGCGAGACTGCCAGGTCAGCTGGACTGTTGGATTCAGGAATGTTTGTGAATATT CATCCATCTGGAATAAAAACAGAGCCAGCTATGCTAATGGCACCAGATAAGGCTGAAT CGTGTCAGGGAGACTTAAGCACATTGGCCAGTGTGGTCACATCATTAGCGAATCTCGG CAAAACTAAAGACCTTTCTCACTGCGGTGGGGATATGCCTGTGGTGCAGAGCTTACGC AATGGGGATACATCCTTCGGTGCTTTTCATCATGATATTCAGACCAATGGGGATGTTT CAAGGGCATTTGACACTCTTGCAAAAGCACTGACTCCCGGCGAAAGCACCTCCTGCCA GAGCTCAGAAGAGGGCATGGAGGGAAGCCCGCATCTAATCGCTGGAGAGCCAAGCTTC GTGGAGAAGGAGGGGCCGCTGCTGAGCGAGTCGCACGTAGCTTTCAGGCTCACCATGC CTTCTCCTATGCCCGAGTACCTGAATGTGCACTACATTGGGGAGTCGGCCTCCAGACT GCTGTTCTTATCGATGCACTGGGCACTTTCCATACCTTCTTTCCAGGCGCTAGGGCAG GAGAACAGCATATCACTGGTAAAAGCGTATTGGAATGAGCTTTTTACCCTTGGTCTTG CCCAGTGCTGGCAAGTGATGAACGTGGCAACTATATTAGCAACGTTTGTCAACTGTCT TCACAGTAGCCTTCAGCAAGATAAAATGTCCCCGGAAAGGAGGAAGTCGTTGATGGAG CACATCTTCAAGCTACAGGAGTTCTGCAACAGCATGGTTAAGCTCTGCATCGATGGGC ATGAGTACGCCTACCTCAAGGCCATCGTCCTCTTCAGTCCCGATCACCCAGGCCTGGA GAACATGGAACTAATTGAGAGATTTCAGGAAAAGGCTTATGTGGAATTCCAAGATTAT ATCACCAGGACATATCCAGATGACACCTACAGGCTGTCGCGATTACTTCTCAGACTGC CCGCCTTGCGGCTGATGAACGCCACCATTACTGAAGAGTTGTTCTTCAAAGGTCTCAT TGGCAACGTACGGATCGACAGTGTTATCCCACACATTTTAAAAATGGAGCCTGCAGAT TACAACTCTCAAATAATTGGTCACAGCCTTTGA (SEQ IDNO: 190)
TR4
Human polypeptide sequence:
MTSPSPRIQIISTDSAVASPQRIQIVTDQQTGQKIQIVTAVDASGSPKQQFILTSPDG AGTGKVILASPETSSAKQLIFTTSDNLVPGRIQIVTDSASVERLLGKTDVQRPQWEY CWCGDKASGRHYGAVSCEGCKGFFKRSVRKNLTYSCRSNQDCIINKHHRNRCQFCRL KKCLEMGMKMESVQSERKPFDVQREKPSNCAASTEKIYIRKDLRSPLIATPTFVADKD GARQTGLLDPGMLVNIQQPLIREDGTVLLATDSKAETSQGALGTLANWTSLANLSES LNNGDTSEIQPEDQSASEITRAFDTLAKALNTTDSSSSPSLADGIDTSGGGSIHVISR DQSTPIIEVEGPLLSDTHVTFKLTMPSPMPEYLNVHYICESASRLLFLSMHWARSIPA FQALGQDCNTSLVRACWNELFTLGLAQCAQVMSLSTILAAIVNHLQNSIQEDKLSGDR IKQVMEHIWKLQEFCNSMAKLDIDGYEYAYLKAIVLFSPDHPGLTSTSQIEKFQEKAQ MELQDYVQKTYSEDTYRLARILVRLPALRLMSSNITEELFFTGLIGNVSIDSIIPYIL KMETAEYNGQITGASL (SEQ ID NO: 191)
Human polynucleotide sequence:
ATGACCAGCCCCTCCCCACGCATCCAGATAATCTCCACCGACTCTGCTGTAGCCTCAC CTCAGCGCATTCAGGGCTCTGAACCTGCCTCTGGCCCATTGAGTGTTTTCACATCTTT GAACAAAGAGAAGATTGTCACAGACCAGCAGACAGGACAGAAAATCCAGATAGTCACC GCAGTGGACGCCTCCGGATCCCCCAAACAGCAGTTCATCCTGACCAGCCCAGATGGAG CTGGAACTGGGAAGGTGATCCTGGCTTCCCCAGAGACATCCAGCGCCAAGCAACTCAT ATTCACCACCTCAGACAACCTCGTCCCTGGCAGGATCCAGATTGTCACGGATTCTGCC TCTGTGGAGCGTTTACTGGGGAAGACGGACGTCCAGCGGCCCCAGGTGGTAGAGTACT GTGTGGTCTGTGGCGACAAAGCCTCCGGCCGTCACTATGGGGCTGTCAGTTGTGAAGG TTGCAAAGGTTTCTTCAAAAGGAGTGTGAGGAAAAATTTGACCTACAGCTGCCGGAGC AGCCAAGACTGCATCATCAATAAACATCACCGGAACCGCTGTCAGTTTTGCCGGCTGA AAAAATGCTTAGAGATGGGCATGAAAATGGAATCTGTGCAGAGTGAACGGAAGCCCTT CGATGTGCAACGGGAGAAACCAAGCAATTGTGCTGCTTCAACTGAGAAAATCTATATC CGGAAAGACCTGAGAAGTCCCCTGATAGCTACTCCCACGTTTGTGGCAGACAAAGATG GAGCAAGACAAACAGGTCTTCTTGATCCAGGGATGCTTGTGAACATCCAGCAGCCTTT GATACGTGAGGATGGTACAGTTCTCCTGGCCACGGATTCTAAGGCTGAAACAAGCCAG GGAGCTCTGGGCACACTGGCAAATGTAGTGACCTCCCTTGCCAACCTAAGTGAATCTT TGAACAACGGTGACACTTCAGAAATCCAGCCAGAGGACCAGTCTGCAAGTGAGATAAC TCGGGCATTTGATACCTTAGCTAAAGCACTTAATACCACAGACAGCTCCTCTTCTCCA AGCTTGGCAGATGGGATAGACACCAGTGGAGGAGGGAGCATCCACGTCATCAGCAGAG ACCAGTCGACACCCATCATTGAGGTTGAAGGCCCCCTCCTTTCAGACACACACGTCAC ATTTAAGCTAACAATGCCCAGTCCAATGCCAGAGTACCTCAACGTGCACTACATCTGT GAGTCTGCATCCCGTCTGCTTTTCCTCTCAATGCACCGGGCAAGGTCAATCCCAGCCT TTCAGGGACTTGGACAGGACTGCAACACCAGCCTTGTGCGGGCCTGCTGGAATGAGCT CTTCACCCTCGGCCTGGCCCAGTGTGCCCAGGTCATGAGTCTCTCCACCATCCTGGCT GCCATTGTCAACCACCTGCAGAACAGCATCCAGGAAGATAAACTTTCTGGTGACCGGA TAAAGCAAGTCATGGAGCACATCTGGAAGCTGCAGGAGTTCTGTAACAGCATGGCGAA CTGGGATATAGATGGCTATGAGTATGCATACCTTAAAGCTATAGTTCTCTTTAGCCCC GATCATCCAGGTTTGACCAGCACAAGCCAGATTGAAAAATTCCAAGAAAAGGCACAGA TGGAGTTGCAGGACTATGTTCAGAAAACCTACTCAGAAGACACCTACCGATTGGCCCG GATCCTCGTTCGCCTGCCGGCACTCAGGCTGATGAGCTCCAACATAACAGAAGAACTT TTTTTTACTGGTCTCATTGGCAATGTTTCGATAGACAGCATAATCCCCTACATCCTCA AGATGGAGACAGCAGAGTATAATGGCCAGATCACCGGAGTCAGTCTATAG (SEQ ID NO: 192)
Mouse polypeptide sequence:
MTSPSPRIQIISTDSAVASPQRIQIVTDQQTGQKIQIVTAVDASGSSKQQFILTSPDG AGTGKVILASPETSSAKQLIFTTSDNLVPGRIQIVTDSASVERLLGKADVQRPQWEY
CWCGDKASGRHYGAVSCEGCKGFFKRSVRKNLTYSCRSSQDCIINKHHRNRCQFCRL
KKCLEMGMKMESVQSERKPFDVQREKPSNCAASTEKIYIRKDLRSPLIATPTFVADKD
GARQTGLLDPGMLVNIQQPLIREDGTVLLAADSKAETSQGALGTLANWTSLANLSES
LNNGDASEMQPEDQSASEITRAFDTLAKALNTTDSASPPSLADGIDASGGGSIHVISR DQSTPIIEVEGPLLSDTHVTFKLTMPSPMPEYLNVHYICESASRLLFLSMH ARSIPA
FQALGQDCNTSLVRACWNELFTLGLAQCAQVMSLSTILAAIVNHLQNSIQEDKLSGDR
IKQVMEHI KLQEFCNSMAKLDIDGYEYAYLKAIVLFSPDHPGLTGTSQIEKFQEKAQ
MELQDYVQKTYSEDTYRLARILVRLPALRLMSSNITEELFFTGLIGNVSIDSIIPYIL
KMETAEYNGQITGASL (SEQ ID NO: 193) Mouse polynucleotide sequence:
ATGGCTACAAATATGGAGGGGCTGGTTCAGCACAGAGTGGGGACCCAGCAGGTGGCTG AGGTACCACGTACACAGACCTCTTGGCCGGAATCTCCAGGGATGACCAGCCCCTCCCC GCGCATCCAGATAATTTCCACCGACTCTGCGGTAGCCTCACCTCAGCGCATTCAGATT GTAACAGACCAGCAGACAGGACAAAAGATCCAGATAGTCACCGCAGTGGATGCCTCTG GATCCTCTAAACAGCAGTTCATCCTAACCAGCCCAGATGGAGCTGGAACTGGGAAGGT GATCCTGGCTTCTCCGGAAACATCCAGTGCCAAGCAGCTCATATTCACCACCTCGGAC AACCTTGTCCCTGGCAGGATCCAGATCGTCACGGATTCTGCTTCTGTGGAGCGTTTGC TGGGGAAGGCAGACGTCCAGCGGCCCCAGGTGGTGGAGTACTGTGTGGTCTGTGGCGA CAAAGCCTCTGGCCGGCACTATGGGGCTGTCAGTTGTGAAGGTTGCAAAGGTTTCTTC AAAAGGAGCGTGAGGAAGAATCTGACCTACAGCTGTCGGAGCAGCCAAGACTGCATCA TCAACAAGCACCACCGTAACCGCTGCCAGTTCTGCCGGCTGAAGAAGTGCCTGGAGAT GGGCATGAAAATGGAGTCTGTACAGAGTGAACGGAAGCCCTTTGATGTGCAACGGGAG AAACCAAGCAATTGTGCTGCTTCCACTGAGAAGATCTATATCCGGAAAGACCTGAGAA GTCCTCTGATAGCCACTCCCACATTTGTGGCAGACAAAGATGGAGCAAGACAAACAGG TCTTCTTGATCCAGGGATGCTTGTGAACATCCAACAGCCTTTGATACGTGAGGATGGT ACAGTTCTCCTGGCCGCGGATTCCAAGGCTGAAACAAGCCAAGGAGCTCTAGGTACAC TGGCAAATGTAGTGACCTCTTTGGCCAACCTGAGTGAATCTTTGAACAACGGTGATGC TTCAGAAATGCAGCCAGAGGACCAGTCTGCAAGTGAGATTACTCGGGCATTTGACACC TTAGCGAAAGCACTTAATACCACAGATAGTGCTTCACCTCCAAGCCTGGCAGATGGGA TAGATGCTAGTGGAGGAGGGAGTATCCATGTCATCAGCAGAGATCAGTCAACACCCAT CATTGAAGTTGAAGGCCCTCTCCTTTCAGACACACATGTCACATTCAAGCTTACAATG CCCAGTCCTATGCCAGAGTACCTCAATGTACATTACATCTGTGAGTCTGCATCCCGCC TGCTTTTCCTCTCCATGCACTGGGCAAGGTCAATCCCAGCCTTCCAGGCACTTGGACA
GGACTGTAATACCAGCCTGGTGAGGGCCTGCTGGAATGAGCTCTTCACTCTTGGCCTG
GCCCAGTGTGCCCAGGTCATGAGTCTCTCCACCATCCTGGCAGCCATTGTCAACCACC
TACAGAACAGCATCCAGGAAGATAAGCTTTCTGGTGACCGGATAAAGCAAGTGATGGA GCACATCTGGAAGCTGCAGGAGTTCTGTAACAGCATGGCGAAACTGGATATAGACGGC TATGAGTACGCATACCTTAAAGCTATAGTTCTCTTTAGTCCCGATCATCCAGGTTTGA CAGGCACAAGCCAGATTGAGAAATTTCAGGAGAAGGCACAGATGGAATTACAGGACTA TGTGCAGAAAACCTACTCTGAAGATACTTACAGATTGGCCAGGATTCTTGTCCGCCTA CCAGCACTCAGGCTCATGAGCTCCAACATAACAGAAGAACTTTTTTTTACTGGTCTCA TTGGCAATGTTTCAATAGACAGCATAATTCCTTACATCCTCAAGATGGAGACAGCAGA ATATAATGGCCAGATCACTGGAGCCAGTCTATAG (SEQ ID NO: 194)
VDR Human polypeptide sequence:
MEAMAASTSLPDPGDFDRNVPRICGVCGDRATGFHFNAMTCEGCKGFFRRSMKRKALF TCPFNGDCRITKDNRRHCQACRLKRCVDIGMMKEFILTDEEVQRKREMILKRKEEEAL KDSLRPKLSEEQQRIIAILLDAHHKTYDPTYSDFCQFRPPVRVNDGGGSHPSRPNSRH TPSFSGDSSSSCSDHCITSSDMMDSSSFSNLDLSEEDSDDPSVTLELSQLSMLPHLAD LVSYSIQKVIGFAKMIPGFRDLTSEDQIVLLKSSAIEVIMLRSNESFTMDDMSWTCGN QDYKYRVSDVTKAGHSLELIEPLIKFQVGLKKLNLHEEEHVLLMAICIVSPDRPGVQD AALIEAIQDRLSNTLQTYIRCRHPPPGSHLLYAKMIQKLADLRSLNEEHSKQYRCLSF QPECSMKLTPLVLEVFGNEIS (SEQ ID NO: 195)
Human polynucleotide sequence:
GGAACAGCTTGTCCACCCGCCGGCCGGACCAGAAGCCTTTGGGTCTGAAGTGTCTGTG AGACCTCACAGAAGAGCACCCCTGGGCTCCACTTACCTGCCCCCTGCTCCTTCAGGGA
TGGAGGCAATGGCGGCCAGCACTTCCCTGCCTGACCCTGGAGACTTTGACCGGAACGT GCCCCGGATCTGTGGGGTGTGTGGAGACCGAGCCACTGGCTTTCACTTCAATGCTATG ACCTGTGAAGGCTGCAAAGGCTTCTTCAGGCGAAGCATGAAGCGGAAGGCACTATTCA CCTGCCCCTTCAACGGGGACTGCCGCATCACCAAGGACAACCGACGCCACTGCCAGGC CTGCCGGCTCAAACGCTGTGTGGACATCGGCATGATGAAGGAGTTCATTCTGACAGAT GAGGAAGTGCAGAGGAAGCGGGAGATGATCCTGAAGCGGAAGGAGGAGGAGGCCTTGA AGGACAGTCTGCGGCCCAAGCTGTCTGAGGAGCAGCAGCGCATCATTGCCATACTGCT GGACGCCCACCATAAGACCTACGACCCCACCTACTCCGACTTCTGCCAGTTCCGGCCT CCAGTTCGTGTGAATGATGGTGGAGGGAGCCATCCTTCCAGGCCCAACTCCAGACACA CTCCCAGCTTCTCTGGGGACTCCTCCTCCTCCTGCTCAGATCACTGTATCACCTCTTC AGACATGATGGACTCGTCCAGCTTCTCCAATCTGGATCTGAGTGAAGAAGATTCAGAT GACCCTTCTGTGACCCTAGAGCTGTCCCAGCTCTCCATGCTGCCCCACCTGGCTGACC TGGTCAGTTACAGCATCCAAAAGGTCATTGGCTTTGCTAAGATGATACCAGGATTCAG AGACCTCACCTCTGAGGACCAGATCGTACTGCTGAAGTCAAGTGCCATTGAGGTCATC ATGTTGCGCTCCAATGAGTCCTTCACCATGGACGACATGTCCTGGACCTGTGGCAACC AAGACTACAAGTACCGCGTCAGTGACGTGACCAAAGCCGGACACAGCCTGGAGCTGAT TGAGCCCCTCATCAAGTTCCAGGTGGGACTGAAGAAGCTGAACTTGCATGAGGAGGAG CATGTCCTGCTCATGGCCATCTGCATCGTCTCCCCAGATCGTCCTGGGGTGCAGGACG CCGCGCTGATTGAGGCCATCCAGGACCGCCTGTCCAACACACTGCAGACGTACATCCG CTGCCGCCACCCGCCCCCGGGCAGCCACCTGCTCTATGCCAAGATGATCCAGAAGCTA GCCGACCTGCGCAGCCTCAATGAGGAGCACTCCAAGCAGTACCGCTGCCTCTCCTTCC AGCCTGAGTGCAGCATGAAGCTAACGCCCCTTGTGCTCGAAGTGTTTGGCAATGAGAT CTCCTGACTAGGACAGCCTGTGCGGTGCCTGGGTGGGGCTGCTCCTCCAGGGCCACGT GCCAGGCCCGGGGCTGGCGGCTACTCAGCAGCCCTCCTCACCCGTCTGGGGTTCAGCC CCTCCTCTGCCACCTCCCCTATCCACCCAGCCCATTCTCTCTCCTGTCCAACCTAACC CCTTTCCTGCGGGCTTTTCCCCGGTCCCTTGAGACCTCAGCCATGAGGAGTTGCTGTT TGTTTGACAAAGAAACCCAAGTGGGGGCAGAGGGCAGAGGCTGGAGGCAGGCCTTGCC CAGAGATGCCTCCACCGCTGCCTAAGTGGCTGCTGACTGATGTTGAGGGAACAGACAG GAGAAATGCATCCATTCCTCAGGGACAGAGACACCTGCACCTCCCCCCACTGCAGGCC CCGCTTGTCCAGCGCCTAGTGGGGTCTCCCTCTCCTGCCTTACTCACGATAAATAATC GGCCCACAGCTCCCACCCCACCCCCTTCAGTGCCCACCAACATCCCATTGCCCTGGTT ATATTCTCACGGGCAGTAGCTGTGGTGAGGTGGGTTTTCTTCCCATCACTGGAGCACC AGGCACGAACCCACCTGCTGAGAGACCCAAGGAGGAAAAACAGACAAAAACAGCCTCA CAGAAGAATATGACAGCTGTCCCTGTCACCAAGCTCACAGTTCCTCGCCCTGGGTCTA AGGGGTTGGTTGAGGTGGAAGCCCTCCTTCCACGGATCCATGTAGCAGGACTGAATTG TCCCCAGTTTGCAGAAAAGCACCTGCCGACCTCGTCCTCCCCCTGCCAGTGCCTTACC TCCTGCCCAGGAGAGCCAGCCCTCCCTGTCCTCCTCGGATCACCGAGAGTAGCCGAGA GCCTGCTCCCCCACCCCCTCCCCAGGGGAGAGGGTCTGGAGAAGCAGTGAGCCGCATC TTCTCCATCTGGCAGGGTGGGATGGAGGAGAAGAATTTTCAGACCCCAGCGGCTGAGT CATGATCTCCCTGCCGCCTCAATGTGGTTGCAAGGCCGCTGTTCACCACAGGGCTAAG AGCTAGGCTGCCGCACCCCAGAGTGTGGGAAGGGAGAGCGGGGCAGTCTCGGGTGGCT AGTCAGAGAGAGTGTTTGGGGGTTCCGTGATGTAGGGTAAGGTGCCTTCTTATTCTCA CTCCACCACCCAAAAGTCAAAAGGTGCCTGTGAGGCAGGGGCGGAGTGATACAACTTC AAGTGCATGCTCTCTGCAGGTCGAGCCCAGCCCAGCTGGTGGGAAGCGTCTGTCCGTT TACTCCAAGGTGGGTCTTTGTGAGAGTGAGCTGTAGGTGTGCGGGACCGGTACAGAAA GGCGTTCTTCGAGGTGGATCACAGAGGCTTCTTCAGATCAATGCTTGAGTTTGGAATC GGCCGCATTCCCTGAGTCACCAGGAATGTTAAAGTCAGTGGGAACGTGACTGCCCCAA CTCCTGGAAGCTGTGTCCTTGCACCTGCATCCGTAGTTCCCTGAAAACCCAGAGAGGA ATCAGACTTCACACTGCAAGAGCCTTGGTGTCCACCTGGCCCCATGTCTCTCAGAATT CTTCAGGTGGAAAAACATCTGAAAGCCACGTTCCTTACTGCAGAATAGCATATATATC GCTTAATCTTAAATTTATTAGATATGAGTTGTTTTCAGACTCAGACTCCATTTGTATT ATAGTCTAATATACAGGGTAGCAGGTACCACTGATTTGGAGATATTTATGGGGGGAGA ACTTACATTGTGAAACTTCTGTACATTAATTATTATTGCTGTTGTTATTTTACAAGGG TCTAGGGAGAGACCCTTGTTTGATTTTAGCTGCAGAACTGTATTGGTCCAGCTTGCTC TTCAGTGGGAGAAAAACACTTGTAAGTTGCTAAACGAGTCAATCCCCTCATTCAGGAA AACTGACAGAGGAGGGCGTGACTCACCCAAGCCATATATAACTAGCTAGAAGTGGGCC AGGACAGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCAGTTTGGGAGGTCGAGG TAGGTGGATCACCTGAGGTCGGGAGTTCGAGACCAACCTGACCAACATGGAGAAACCC TGTCTCTATTAAAAATACAAAAAAAAAAAAAAAAAAAAATAGCCGGGCATGGTGGCGC AAGCCTGTAATCCCAGCTACTCAGGAGGCTGAGGCAGAAGAATTGAACCCAGGAGGTG GAGGTTGCAGTGAGCTGAGATCGTGCCGTTACTCTCCAACCTGGACAACAAGAGCGAA ACTCCGTCTTAGAAGTGGACCAGGACAGGACCAGATTTTGGAGTCATGGTCCGGTGTC CTTTTCACTACACCATGTTTGAGCTCAGACCCCCACTCTCATTCCCCAGGTGGCTGAC CCAGTCCCTGGGGGAAGCCCTGGATTTCAGAAAGAGCCAAGTCTGGATCTGGGACCCT TTCCTTCCTTCCCTGGCTTGTAACTCCACCAAGCCCATCAGAAGGAGAAGGAAGGAGA CTCACCTCTGCCTCAATGTGAATCAGACCCTACCCCACCACGATGTGCCCTGGCTGCT GGGCTCTCCACCTCAGGCCTTGGATAATGCTGTTGCCTCATCTATAACATGCATTTGT CTTTGTAATGTCACCACCTTCCCAGCTCTCCCTCTGGCCCTGCTTCTTCGGGGAACTC CTGAAATATCAGTTACTCAGCCCTGGGCCCCACCACCTAGGCCACTCCTCCAAAGGAA GTCTAGGAGCTGGGAGGAAAAGAAAAGAGGGGAAAATGAGTTTTTATGGGGCTGAACG GGGAGAAAAGGTCATCATCGATTCTACTTTAGAATGAGAGTGTGAAATAGACATTTGT AAATGTAAAACTTTTAAGGTATATCATTATAACTGAAGGAGAAGGTGCCCCAAAATGC AAGATTTTCCACAAGATTCCCAGAGACAGGAAAATCCTCTGGCTGGCTAACTGGAAGC ATGTAGGAGAATCCAAGCGAGGTCAACAGAGAAGGCAGGAATGTGTGGCAGATTTAGT GAAAGCTAGAGATATGGCAGCGAAAGGATGTAAACAGTGCCTGCTGAATGATTTCCAA AGAGAAAAAAAGTTTGCCAGAAGTTTGTCAAGTCAACCAATGTAGAAAGCTTTGCTTA TGGTAATAAAAATGGCTCATACTTATATAGCACTTACTTTGTTTGCAAGTACTGCTGT AAATAAATGCTTTATGCAAACC (SEQ IDNO: 196)
Mouse polypeptide sequence: MEAMAASTSLPDPGDFDRNVPRICGVCGDRATGFHFNAMTCEGCKGFFRRSMKRKALF TCPFNGDCRITKDNRRHCQACRLKRCVDIGMMKEFILTDEEVQRKREMIMKRKEEEAL KDSLRPKLSEEQQHIIAILLDAHHKTYDPTYADFRDFRPPIRADVSTGSYSPRPTLSF SGDSSSNSDLYTPSLDMMEPASFSTMDLNEEGSDDPSVTLDLSPLSMLPHLADLVSYS IQKVIGFAKMIPGFRDLTSDDQIVLLKSSAIEVIMLRSNQSFTMDDMSWDCGSQDYKY DITDVSRAGHTLELIEPLIKFQVGLKKLNLHEEEHVLLMAICIVSPDRPGVQDAKLVE AIQDRLSNTLQTYIRCRHPPPGSHQLYAKMIQKLADLRSLNEEHSKQYRSLSFQPENS MKLTPLVLEVFGNEIS (SEQ IDNO: 197) Mouse polynucleotide sequence:
ATGGAGGCAATGGCAGCCAGCACCTCCCTGCCTGACCCTGGTGACTTTGACCGGAATG TGCCTCGGATCTGTGGAGTGTGTGGAGACCGAGCCACGGGCTTCCACTTCAACGCTAT GACCTGTGAAGGCTGCAAGGGTTTCTTCAGGCGGAGCATGAAGCGCAAGGCCCTGTTC ACCTGCCCCTTCAATGGAGATTGCCGCATCACCAAGGACAACCGGCGACACTGCCAGG CCTGCCGGCTCAAACGCTGCGTGGACATTGGCATGATGAAGGAGTTCATCCTCACAGA TGAGGAGGTGCAGCGTAAGCGAGAGATGATCATGAAGAGGAAGGAGGAAGAGGCCTTG AAGGACAGTCTGAGGCCCAAGCTGTCTGAGGAGCAACAGCACATTATCGCCATCCTGC TCGATGCCCACCACAAGACCTACGACCCCACCTATGCCGACTTCCGGGACTTCCGGCC TCCAATTCGTGCAGACGTAAGTACAGGGAGCTATTCTCCAAGGCCCACACTCAGCTTC TCCGGAGACTCCTCCTCAAACTCTGATCTGTACACCCCCTCACTGGACATGATGGAAC CGGCCAGCTTTTCCACGATGGATCTGAATGAAGAAGGCTCCGATGACCCCTCTGTGAC CCTGGACCTGTCTCCGCTCTCCATGCTGCCCCACCTGGCTGATCTTGTCAGTTACAGC ATCCAAAAGGTCATCGGCTTTGCCAAGATGATCCCTGGCTTCAGGGACCTCACCTCTG ATGACCAGATTGTCCTGCTTAAGTCAAGTGCCATTGAGGTGATCATGTTGCGCTCCAA CCAGTCTTTTACCATGGATGACATGTCCTGGGACTGTGGCAGCCAAGACTACAAATAT GACATCACTGATGTCTCCAGAGCTGGGCACACCCTGGAGCTGATCGAACCCCTCATAA AGTTCCAGGTGGGGCTGAAGAAGCTGAACCTCCATGAGGAAGAACATGTGCTGCTCAT GGCCATCTGCATTGTCTCCCCAGACCGACCTGGGGTACAGGACGCTAAGCTGGTTGAA GCCATTCAGGACCGCCTATCCAACACGCTGCAGACCTACATCCGCTGCCGCCACCCGC CCCCGGGCAGCCACCAGCTCTACGCCAAGATGATCCAGAAGCTGGCTGACCTGCGAAG CCTCAATGAGGAGCACTCCAAACAGTACCGTTCCCTCTCCTTCCAGCCGGAGAACAGC ATGAAGCTCACACCCCTTGTGCTAGAGGTGTTTGGCAATGAGATCTCCTGA
(SEQ ID NO: 198)
Other Embodiments
All publications and references, including but not limited to patents and patent applications, cited in this specification are herein incoφorated by reference in their entirety as if each individual publication or reference were specifically and individually indicated to be incoφorated by reference herein as being fully set forth. Other embodiments are within the claims.
What is claimed is:

Claims

Claims
1. A method for determining whether a patient has an increased risk for developing a neurological disease or disorder, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14, wherein the presence of said mutation indicates that said patient has an increased risk for developing a neurological disease or disorder.
2. A method for determining whether a patient has an increased risk for developing a neurological disease or disorder, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a neurological disease or disorder.
3. A method for determining whether a patient has an increased risk for developing a neurological disease or disorder, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a neurological disease or disorder.
4. The method of claim 3, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
5. The method of claim 3, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
6. A method for determining whether a patient has an increased risk for developing a neurological disease or disorder, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14, wherein the presence of said polymoφhism associated with a neurological disease or disorder indicates the person has an altered risk for developing a neurological disease or disorder.
7. A method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland, said method comprising deteπnining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the adrenal gland.
8. A method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the adrenal gland.
9. A method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the adrenal gland.
10. The method of claim 9, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
11. The method of claim 9, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
12. A method for determining whether a patient has an increased risk for developing a disease or disorder of the adrenal gland, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15, wherein the presence of said polymoφhism associated with a disease or disorder of the adrenal gland indicates the person has an altered risk for developing a disease or disorder of the adrenal gland.
13. A method for determining whether a patient has an increased risk for developing a disease or disorder of the colon, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the colon.
14. A method for determining whether a patient has an increased risk for developing a disease or disorder of the colon, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the colon.
15. A method for determining whether a patient has an increased risk for developing a disease or disorder of the colon, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the colon.
16. The method of claim 15, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
17. The method of claim 15, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
18. A method for determining whether a patient has an increased risk for developing a disease or disorder of the colon, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16, wherein the presence of said polymoφhism associated with a disease or disorder of the colon indicates the person has an altered risk for developing a disease or disorder of the colon.
19. A method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17, wherein the presence of said mutation indicates that said patient has an increased risk for developing a cardiovascular disease or disorder.
20. A method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a cardiovascular disease or disorder.
21. A method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a cardiovascular disease or disorder.
22. The method of claim 21, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
23. The method of claim 21, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
24. A method for determining whether a patient has an increased risk for developing a cardiovascular disease or disorder, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17, wherein the presence of said polymoφhism associated with a cardiovascular disease or disorder indicates the person has an altered risk for developing a cardiovascular disease or disorder.
25. A method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the intestine.
26. A method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the intestine.
27. A method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the intestine.
28. The method of claim 27, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
29. The method of claim 27, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
30. A method for determining whether a patient has an increased risk for developing a disease or disorder of the intestine, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18, wherein the presence of said polymoφhism associated with a disease or disorder of the intestine indicates the person has an altered risk for developing a disease or disorder of the intestine.
31. A method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the kidney.
32. A method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the kidney.
33. A method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the kidney.
34. The method of claim 33, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
35. The method of claim 33, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
36. A method for determining whether a patient has an increased risk for developing a disease or disorder of the kidney, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19, wherein the presence of said polymoφhism associated with a disease or disorder of the kidney indicates the person has an altered risk for developing a disease or disorder of the kidney.
37. A method for determining whether a patient has an increased risk for developing a disease or disorder of the liver, said method comprising deteπnining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the liver.
38. A method for determining whether a patient has an increased risk for developing a disease or disorder of the liver, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the liver.
39. A method for determining whether a patient has an increased risk for developing a disease or disorder of the liver, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the liver.
40. The method of claim 39, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
41. The method of claim 39, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
42. A method for determining whether a patient has an increased risk for developing a disease or disorder of the liver, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20, wherein the presence of said polymoφhism associated with a disease or disorder of the liver indicates the person has an altered risk for developing a disease or disorder of the liver.
43. A method for determining whether a patient has an increased risk for developing a lung disease or disorder, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21, wherein the presence of said mutation indicates that said patient has an increased risk for developing a lung disease or disorder.
44. A method for determining whether a patient has an increased risk for developing a lung disease or disorder, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21, wherein an altered level in said biological activity, relative to nomial, indicates that said patient has an increased risk for developing a lung disease or disorder.
45. A method for determining whether a patient has an increased risk for developing a lung disease or disorder, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21, wherein altered levels in said expression, relative to normal levels, indicates that'said patient has an increased risk for developing a lung disease or disorder.
46. The method of claim 45, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
47. The method of claim 45, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
48. A method for determining whether a patient has an increased risk for developing a lung disease or disorder, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21, wherein the presence of said polymoφhism associated with a lung disease or disorder indicates the person has an altered risk for developing a lung disease or disorder.
49. A method for determining whether a patient has an increased risk for developing a muscular disease or disorder, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22, wherein the presence of said mutation indicates that said patient has an increased risk for developing a muscular disease or disorder.
50. A method for determining whether a patient has an increased risk for developing a muscular disease or disorder, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a muscular disease or disorder.
51. A method for determining whether a patient has an increased risk for developing a muscular disease or disorder, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a muscular disease or disorder.
52. The method of claim 51 , wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
53. The method of claim 51 , wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
54. A method for determining whether a patient has an increased risk for developing a muscular disease or disorder, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22, wherein the presence of said polymoφhism associated with a muscular disease or disorder indicates the person has an altered risk for developing a muscular disease or disorder.
55. A method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the ovary.
56. A method for determining whether a patient has an increased risk for developing a disease or disorder of the ovary, said method comprising measuring in said patient or in a cell from said patient the level- of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the ovary.
57. A method for. determining whether a patient has an increased risk for developing a disease or. disorder of the ovary, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the ovary.
58. The method of claim 57, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
59. The method of claim 57, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
60. A method for determining whether a patient has an increased risk for developing a disease or'disorder of the ovary, comprising deteπnining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23, wherein the presence of said polymoφhism associated with a disease or disorder of the ovary indicates the person has an altered risk for developing a disease or disorder of the ovary.
61. A method for determining whether a patient has an increased risk for developing a blood disease or disorder, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24, wherein the presence of said mutation indicates that said patient has an increased risk for developing a blood disease or disorder.
62. A method for determining whether a patient has an increased risk for developing a blood disease or disorder, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a blood disease or disorder.
63. A method for determining whether a patient has an increased risk for developing a. blood disease or disorder, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a blood disease or disorder.
64. The method of claim 63, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
65. The method of claim 63, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
66. A method for determining whether a patient has an increased risk for developing a blood disease or disorder, comprising detenriining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24, wherein the presence of said polymoφhism associated with a blood disease or disorder indicates the person has an
, altered risk for developing a blood disease or disorder.
67. A method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the prostate.
68. A method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the prostate.
69. A method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25, wherein' altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the prostate.
70. The method of claim 69, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
71. The method of claim 69, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
72. A method for determining whether a patient has an increased risk for developing a disease or disorder of the prostate, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25, wherein the presence of said polymoφhism associated with a disease or disorder of the prostate indicates the person has an altered risk for developing a disease or disorder of the prostate.
73. A method for determining whether a patient has an increased risk for developing a disease or disorder of the skin, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the skin.
74. A method for detenriining whether a patient has an increased risk for developing a disease or disorder of the skin, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the skin.
75. A method for determining whether a patient has an increased risk for developing a disease or disorder of the skin, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the skin.
76. The method of claim 75, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
77. The method of claim 75, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
78. A method for determining whether a patient has an increased risk for developing a disease or disorder of the skin, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26, wherein the presence of said polymoφhism associated with a disease or disorder of the skin indicates the person has an altered risk for developing a disease or disorder of the skin.
79. A method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the spleen.
80. A method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the spleen.
81. A method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the spleen.
82. The method of claim 81, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
83. The method of claim 81, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
84. A method for determining whether a patient has an increased risk for developing a disease or disorder of the spleen, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27, wherein the presence of said polymoφhism associated with a disease or disorder of the spleen indicates the person has an altered risk for developing a disease or disorder of the spleen.
85. A method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the stomach.
86. A method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the stomach.
87. A method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the stomach.
88. The method of claim 87, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
89. The method of claim 87, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
90. A method for determining whether a patient has an increased risk for developing a disease or disorder of the stomach, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28, wherein the presence of said polymoφhism associated with a disease or disorder of the stomach indicates the person has an altered risk for developing a disease or disorder of the stomach.
91. A method for determining whether a patient has an increased risk for developing a disease or disorder of the testes, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the testes.
92. A method for determining whether a patient has an increased risk for developing a disease or disorder of the testes, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the testes.
93. A method for determining whether a patient has an increased risk for developing a disease or disorder of the testes, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the testes.
94. The method of claim 93, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
95. The method of claim 93, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
96. A method for determining whether a patient has an increased risk for developing a disease or disorder of the testes, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29, wherein the presence of said polymoφhism associated with a disease or disorder of the testes indicates the person has an altered risk for developing a disease or disorder of the testes.
97. A method for determining whether a patient has ail increased risk for developing a disease or disorder of the thymus, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the thymus.
98. A method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the thymus.
99. A method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the thymus.
100. The method of claim 99, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
101. The method of claim 99, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
102. A method for determining whether a patient has an increased risk for developing a disease or disorder of the thymus, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30, wherein the presence of said polymoφhism associated with a disease or disorder of the thymus indicates the person has an altered risk for developing a disease or disorder of the thymus.
103. A method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the thyroid.
104. A method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the thyroid.
105. A method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the thyroid.
106. The method of claim 105, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
107. The method of claim 105, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
108. A method for determining whether a patient has an increased risk for developing a disease or disorder of the thyroid, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31, wherein the presence of said polymoφhism associated with a disease or disorder of the thyroid indicates the person has an altered risk for developing a disease or disorder of the thyroid.
109. A method for determining whether a patient has an increased risk for developing a disease or disorder of the uteras, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the uteras.
110. A method for determining whether a patient has an increased risk for developing a disease or disorder of the uterus, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the uterus.
111. A method for determining whether a patient has an increased risk for developing a disease or disorder of the uteras, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the uterus.
112. The method of claim 111, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
113. The method of claim 111, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
114. A method for determining whether a patient has an increased risk for developing a disease or disorder of the uterus, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32, wherein the presence of said polymoφhism associated with a disease or disorder of the uteras indicates the person has an altered risk for developing a disease or disorder of the uteras.
115. A method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the pancreas.
116. A method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the pancreas.
117. A method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 , wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the pancreas.
118. The method of claim 117, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
119. The method of claim 117, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
120. A method for determining whether a patient has an increased risk for developing a disease or disorder of the pancreas, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein the presence of said polymoφhism associated with a disease or disorder of the pancreas indicates the person has an altered risk for developing a disease or disorder of the pancreas.
121. A method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the bone and joints. ι
122. A method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 , wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the bone and joints.
123. A method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 , wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the bone and joints.
124. The method of claim 123, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
125. The method of claim 123, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
126. A method for determining whether a patient has an increased risk for developing a disease or disorder of the bone and joints, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein the presence of said polymoφhism associated with a disease or disorder of the bone and joints indicates the person has an altered risk for developing a disease or disorder of the bone and joints.
127. A method for determining whether a patient has an increased risk for developing a disease or disorder of the breast, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the breast.
128. A method for determining whether a patient has an increased risk for developing a disease or disorder of the breast, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the breast.
129. A method for determining whether a patient has an increased risk for developing a disease or disorder of the breast, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 , wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the breast.
130. The method of claim 129, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
131. The method of claim 129, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
132. A method for determining whether a patient has an increased risk for developing a disease or disorder of the breast, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein the presence of said polymoφhism associated with a disease or disorder of the breast indicates the person has an altered risk for developing a disease or disorder of the breast.
133. A method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 , wherein the presence of said mutation indicates that said patient has an increased risk for developing a disease or disorder of the immune system.
134. A method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 , wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a disease or disorder of the immune system.
135. A method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a disease or disorder of the immune system.
136. The method of claim 135, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
137. The method of claim 135, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
138. A method for determining whether a patient has an increased risk for developing a disease or disorder of the immune system, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein the presence of said polymoφhism associated with a disease or disorder of the immune system indicates the person has an altered risk for developing a disease or disorder of the immune system.
139. A method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder, said method comprising determining the presence of a mutation in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 , wherein the presence of said mutation indicates that said patient has an increased risk for developing a metabolic or nutritive disease or disorder.
140. A method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder, said method comprising measuring in said patient or in a cell from said patient the level of biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein an altered level in said biological activity, relative to normal, indicates that said patient has an increased risk for developing a metabolic or nutritive disease or disorder.
141. A method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder, said method comprising measuring in said patient or in a cell from said patient the expression of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein altered levels in said expression, relative to normal levels, indicates that said patient has an increased risk for developing a metabolic or nutritive disease or disorder.
142. The method of claim 141, wherein said expression is determined by measuring levels of said nuclear receptor polypeptide.
143. The method of claim 141, wherein said expression is determined by measuring levels of RNA encoding said nuclear receptor polypeptide.
144. A method for determining whether a patient has an increased risk for developing a metabolic or nutritive disease or disorder, comprising determining the presence of a polymoφhism in the patient's gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, wherein the presence of said polymoφhism associated with a metabolic or nutritive disease or disorder indicates the person has an altered risk for developing a metabolic or nutritive disease or disorder.
145. A method of treating or preventing a neurological disease or disorder in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14.
146. A method of treating or preventing a neurological disease or disorder in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14.
147. A method of treating or preventing a neurological disease or disorder in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14.
148. A method of treating or preventing a disease or disorder of the adrenal gland in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
149. A method of treating or preventing a disease or disorder of the adrenal gland in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
150. A method of treating or preventing a disease or disorder of the adrenal gland in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15.
151. A method of treating or preventing a disease or disorder of the colon in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
152. A method of treating or preventing a disease or disorder of the colon in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
153. A method of treating or preventing a disease or disorder of the colon in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16.
154. A method of treating or preventing a cardiovascular disease or disorder in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
155. A method of treating or preventing a cardiovascular disease or disorder in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
156. A method of treating or preventing a cardiovascular disease or disorder in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17.
157. A method of treating or preventing a disease or disorder of the intestine in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
158. A method of treating or preventing a disease or disorder of the intestine in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
159. A method of treating or preventing a disease or disorder of the intestine in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18.
160. A method of treating or preventing a disease or disorder of the kidney in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
161. A method of treating or preventing a disease or disorder of the kidney in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
162. A method of treating or preventing a disease or disorder of the kidney in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19.
163. A method of treating or preventing a disease or disorder of the liver in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
164. A method of treating or preventing a disease or disorder of the liver in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
165. A method of treating or preventing a disease or disorder of the liver in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20.
166. A method of treating or preventing a lung disease or disorder in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
167. A method of treating or preventing a lung disease or disorder in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
168. A method of treating or preventing a lung disease or disorder in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21.
169. A method of treating or preventing a muscular disease or disorder in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
170. A method of treating or preventing a muscular disease or disorder in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
171. A method of treating or preventing a muscular disease or disorder in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22.
172. A method of treating or preventing a disease or disorder of the ovary in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
173. A method of treating or preventing a disease or disorder of the ovary in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
174. A method of treating or preventing a disease or disorder of the ovary in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23.
175. A method of treating or preventing a blood disease or disorder in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
176. A method of treating or preventing a blood disease or disorder in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
177. A method of treating or preventing a blood disease or disorder in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24.
178. A method of treating or preventing a disease or disorder of the prostate in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
179. A method of treating or preventing a disease or disorder of the prostate in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
180. A method of treating or preventing a disease or disorder of the prostate in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25.
181. A method of treating or preventing a disease or disorder of the skin in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
182. A method of treating or preventing a disease or disorder of the skin in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
183. A method of treating or preventing a disease or disorder of the skin in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26.
184. A method of treating or preventing a disease or disorder of the spleen in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
185. A method of treating or preventing a disease or disorder of the spleen in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
186. A method of treating or preventing a disease or disorder of the spleen in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27.
187. A method of treating or preventing a disease or disorder of the stomach in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
188. A method of treating or preventing a disease or disorder of the stomach in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
189. A method of treating or preventing a disease or disorder of the stomach in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28.
190. A method of treating or preventing a disease or disorder of the testes in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
191. A method of treating or preventing a disease or disorder of the testes in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
192. A method of treating or preventing a disease or disorder of the testes in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29.
193. A method of treating or preventing a disease or disorder of the thymus in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
194. A method of treating or preventing a disease or disorder of the thymus in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
195. A method of treating or preventing a disease or disorder of the thymus in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30.
196. A method of treating or preventing a disease or disorder of the thyroid in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
197. A method of treating or preventing a disease or disorder of the thyroid in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
198. A method of treating or preventing a disease or disorder of the thyroid in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31.
199. A method of treating or preventing a disease or disorder of the uterus in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
200. A method of treating or preventing a disease or disorder of the uteras in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
201. A method of treating or preventing a disease or disorder of the uteras in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32.
202. A method of treating or preventing a disease or disorder of the pancreas in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
203. A method of treating or preventing a disease or disorder of the pancreas in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
204. A method of treating or preventing a disease or disorder of the pancreas in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
205. A method of treating or preventing a disease or disorder of the bone and joint in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
206. A method of treating or preventing a disease or disorder of the bone and joint in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
207. A method of treating or preventing a disease or disorder of the bone and joint in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
208. A method of treating or preventing a disease or disorder of the breast in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
209. A method of treating or preventing a disease or disorder of the breast in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
210. A method of treating or preventing a disease or disorder of the breast in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
211. A method of treating or preventing a disease or disorder of the immune system in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
212. A method of treating or preventing a disease or disorder of the immune system in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
213. A method of treating or preventing a disease or disorder of the immune system in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
214. A method of treating or preventing a metabolic or nutritive disease or disorder in a patient, said method comprising administering to said patient a nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
215. A method of treating or preventing a metabolic or nutritive disease or disorder in a patient, said method comprising administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
216. A method of treating or preventing a metabolic or nutritive disease or disorder in a patient, said method comprising administering to said patient a compound that modulates the biological activity of a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1.
217. A method for identifying a compound that may be useful for the freatment or prevention of a neurological disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a neurological disease or disorder.
218. A method for identifying a compound that may be useful for the treatment or prevention of a neurological disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the freatment or prevention of a neurological disease or disorder.
219. A method for identifying a compound that may be useful for the freatment or prevention of a neurological disease or disorder, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a neurological disease or disorder.
220. A method for identifying a compound that may be useful for the treatment or prevention of a neurological disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a neurological disease or disorder.
221. A method for identifying a compound that may be useful for the treatment or prevention of a neurological disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a neurological disease- or disorder.
222. A method for identifying a compound that may be useful for the treatment or prevention of a neurological disease or disorder, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a neurological disease or disorder.
223. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the adrenal gland.
224. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland.
225. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland.
226. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland.
227. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland.
228. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 15, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the adrenal gland.
229. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the colon, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the colon.
230. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the colon, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the colon.
231. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the colon, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the colon.
232. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the colon, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the colon.
233. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the colon, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the colon.
234. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the colon, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 16, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the colon.
235. A method for identifying a compound that may be useful for the treatment or prevention of a cardiovascular disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a cardiovascular disease or disorder.
236. A method for identifying a compound that may be useful for the treatment or prevention of a cardiovascular disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the freatment or prevention of a cardiovascular disease or disorder.
237. A method for identifying a compound that may be useful for the treatment or prevention of a cardiovascular disease or disorder, said method comprising the steps of: ,
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a cardiovascular disease or disorder.
238. A method for identifying a compound that may be useful for the treatment or prevention of a cardiovascular disease or disorder, said method comprising the steps t of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a cardiovascular disease or disorder.
239. A method for identifying a compound that may be useful for the treatment or prevention of a cardiovascular disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a cardiovascular disease or disorder.
240. A method for identifying a compound that may be useful for the freatment or prevention of a cardiovascular disease or disorder, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 17, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a cardiovascular disease or disorder. X
241. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the intestine, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the intestine.
242. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the intestine, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the intestine.
243. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the intestine, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the intestine.
244. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the intestine, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the intestine.
245. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the intestine, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the intestine.
246. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the intestine, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 18, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the intestine.
247. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the kidney.
248. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney.
249. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney.
250. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney.
251. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19 and disposed in a lipid membrane with a candidate compound; and
' deten ning whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney.
252. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the kidney, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 19, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the kidney.
253. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the liver, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20 with a candidate compound; and (b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the liver.
254. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the liver, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the liver.
255. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the liver, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the liver.
256. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the liver, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the liver.
257. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the liver, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the liver.
258. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the liver, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 20, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the liver.
259. A method for identifying a compound that may be useful for the treatment or prevention of a lung disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a lung disease or disorder.
260. A method for identifying a compound that may be useful for the treatment or prevention of a lung disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the freatment or prevention of a lung disease or disorder.
261. A method for identifying a compound that may be useful for the treatment or prevention of a lung disease or disorder, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21- operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a lung disease or disorder.
262. A method for identifying a compound that may be useful for the treatment or prevention of a lung disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a lung disease or disorder.
263. A method for identifying a compound that may be useful for the treatment or prevention of a lung disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a lung disease or disorder.
264. A method for identifying a compound that may be useful for the treatment or prevention of a lung disease or disorder, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 21, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a lung disease or disorder.
265. A method for identifying a compound that may be useful for the treatment or prevention of a muscular disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a muscular disease or disorder.
266. A method for identifying a compound that may be useful for the treatment or prevention of a muscular disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the freatment or prevention of a muscular disease or disorder.
267. A method for identifying a compound that may be useful for the treatment or prevention of a muscular disease or disorder, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a muscular disease or disorder.
268. A method for identifying a compound that may be useful for the treatment or prevention of a muscular disease or disorder, said method comprismg the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a muscular disease or disorder.
269. A method for identifying a compound that may be useful for the treatment or prevention of a muscular disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a muscular disease or disorder.
270. A method for identifying a compound that may be useful for the treatment or prevention of a muscular disease or disorder, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 22, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a muscular disease or disorder.
271. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the ovary, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the ovary.
272. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the ovary, said method comprising the steps of: (a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the ovary.
273. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the ovary, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the ovary.
274. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the ovary, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the ovary.
275. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the ovary, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the ovary.
276. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the ovary, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 23, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the ovary.
277. A method for identifying a compound that may be useful for the treatment or prevention of a blood disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a blood disease or disorder.
278. A method for identifying a compound that may be useful for the treatment or prevention of a blood disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a blood disease or disorder.
279. A method for identifying a compound that may be useful for the treatment or prevention of a blood disease or disorder, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a blood disease or disorder.
280. A method for identifying a compound that may be useful for the treatment or prevention of a blood disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment or prevention of a blood disease or disorder.
281. A method for identifying a compound that may be useful for the treatment or prevention of a blood disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a blood disease or disorder.
282. A method for identifying a compound that may be useful for the treatment or prevention of a blood disease or disorder, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 24, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a blood disease or disorder.
283. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the prostate.
284. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate.
285. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate.
286. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate.
287. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate.
288. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the prostate, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 25, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the prostate.
289. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the skin, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the skin.
290. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the skin, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the skin.
291. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the skin, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the skin.
292. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the skin, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the skin.
293. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the skin, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the skin.
294. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the skin, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 26, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the skin.
295. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the spleen, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the spleen.
296. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the spleen, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the freatment or prevention of a disease or disorder of the spleen.
297. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the spleen, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a confrol not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the spleen.
298. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the spleen, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the spleen.
299. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the spleen, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the spleen.
300. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the spleen, said method comprising the steps of: (a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 27, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the spleen.
301. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the stomach, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative - to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the stomach.
302. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the stomach, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the stomach.
303. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the stomach, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the stomach.
304. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the stomach, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment or prevention of a disease or disorder of the stomach.
305. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the stomach, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the stomach.
306. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the stomach, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 28, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the freatment or prevention of a disease or disorder of the stomach.
307. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the testes, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the testes.
308. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the testes, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the testes.
309. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the testes, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the testes.
310. • A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the testes, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment or prevention of a disease or disorder of the testes.
311. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the testes, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29 and disposed in a lipid membrane with a candidate compound; and detemiining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the testes.
312. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the testes, said method comprising the steps of: (a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 29, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the testes.
313. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus, said method comprising the steps of:
• • (a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thymus.
314. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus, said method comprising the steps of:
(a) contacting a cell- expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus.
315. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus.
316. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus.
317. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus.
318. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thymus, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 30, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the thymus.
319. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thyroid, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the thyroid.
320. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thyroid, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the thyroid.
321. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thyroid, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the thyroid.
322. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thyroid, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the thyroid.
323. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the thyroid, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the thyroid.
324. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the thyroid, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 31, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the freatment or prevention of a disease or disorder of the thyroid.
325. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the uterus, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the uterus.
326. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the uterus, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32 with a candidate compound; and
(b) measμring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the uteras.
327. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the uteras, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the uterus.
328. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the uteras, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the uteras.
329. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the uterus, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the uteras.
330. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the uteras, said method comprising the steps of: (a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 32, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the uterus.
331. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the pancreas, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the pancreas.
332. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the pancreas, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the pancreas.
333. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the pancreas, said method comprising the steps of: (a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the pancreas.
334. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the pancreas, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment or prevention of a disease or disorder of the pancreas.
335. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the pancreas, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the pancreas.
336. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the pancreas, said method comprising the steps of: (a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 , and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherem an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the pancreas.
337. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the bone and joints, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the bone and joints.
338. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the bone and joints, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the freatment or prevention of a disease or disorder of the bone and joints.
339. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the bone and joints, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the bone and joints.
340. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the bone and joints, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the bone and joints.
341. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the bone and joints, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the bone and joints.
342. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the bone and joints, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the bone and joints.
343. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the breast, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the breast.
344. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the breast, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the freatment or prevention of a disease or disorder of the breast.
345. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the breast, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the breast.
346. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the breast, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the breast.
347. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the breast, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the breast.
348. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the breast, said method comprising the steps of: (a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the breast.
349. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the immune system, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment of a disease or disorder of the immune system.
350. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the immune system, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a disease or disorder of the immune system.
351. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the immune system, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a control not contacted with said candidate compound, indicates that said candidate compound is a compound that a compound that may be useful for the treatment or prevention of a disease or disorder of the immune system.
352. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the immune system, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the immune system.
353. A method for identifying a compound that may be useful for the freatment or prevention of a disease or disorder of the immune system, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a disease or disorder of the immune system.
354. A method for identifying a compound that may be useful for the treatment or prevention of a disease or disorder of the immune system, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound that may be useful for the treatment or prevention of a disease or disorder of the immune system.
355. A method for identifying a compound that may be useful for the freatment or prevention of metabolic or nutritive disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring the biological activity of said nuclear receptor polypeptide expressed in said cell, wherein altered biological activity of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the freatment of a metabolic or nutritive disease or disorder.
356. A method for identifying a compound that may be useful for the treatment or prevention of a metabolic or nutritive disease or disorder, said method comprising the steps of:
(a) contacting a cell expressing a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 with a candidate compound; and
(b) measuring expression of said nuclear receptor polypeptide in said cell, wherein altered expression of said nuclear receptor polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a metabolic or nutritive disease pr disorder.
357. A method for identifying a compound that may be useful for the treatment or prevention of metabolic or nutritive disease or disorder, said method comprising the steps of:
(a) providing a nucleic acid molecule comprising a promoter for a gene encoding a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 operably linked to a reporter gene;
(b) contacting said nucleic acid molecule with a candidate compound; and
(c) measuring expression of said reporter gene, wherein altered reporter gene expression, relative to a confrol not contacted with said candidate compound, indicates that said candidate compound is a compound that may be useful for the treatment or prevention of a metabolic or nutritive disease or disorder.
358. A method for identifying a compound that may be useful for the treatment or prevention of a metabolic or nutritive disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide, wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a metabolic or nutritive disease or disorder.
359. A method for identifying a compound that may be useful for the treatment or prevention of a metabolic or nutritive disease or disorder, said method comprising the steps of contacting a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1 and disposed in a lipid membrane with a candidate compound; and determining whether said candidate compound interacts said nuclear receptor polypeptide wherein interaction between said candidate compound and said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment or prevention of a metabolic or nutritive disease or disorder.
360. A method for identifying a compound that may be useful for the treatment or prevention of a metabolic or nutritive disease or disorder, said method comprising the steps of:
(a) providing (i) a nuclear receptor polypeptide substantially identical to a polypeptide listed in Table 1, and (ii) a second polypeptide that interacts said nuclear receptor polypeptide;
(b) contacting said polypeptides with a candidate compound; and
(c) measuring interaction of said nuclear receptor polypeptide and said second polypeptide, wherein an alteration in interaction of said nuclear receptor polypeptide and said second polypeptide identifies said candidate compound as one that may be useful for the treatment or prevention of a metabolic or nutritive disease or disorder.
361. The method of any of claims 1-6, 145-147, and 217-222, wherein said neurological disease or disorder is selected from the group consisting of abetalipoproteinemia, abnormal social behaviors, absence (petit mal) epilepsy, absence - seizures, abulia, acalculia, acidophilic adenoma, acoustic neuroma, acquired aphasia, acquired aphasia with epilepsy (landau-kleffher syndrome)specifϊc reading disorder, acquired epileptic aphasia, acromegalic neuropathy, acromegaly, action myoclonus-renal insufficiency syndrome, acute autonomic neuropathy, acute cerebellar ataxia in children, acute depression, acute disseminated encephalomyelitis, acute idiopathic sensory neuronopathy, acute intermittent poφhyria, acute mania, acute mixed episode, acute pandysautonomia, acute polymoφhic disorder with symptoms of schizophrenia, acute polymoφhic psychotic disorder without symptoms of schizophrenia, acute purulent meningitis, addiction, addison syndrome, adenovirus serotypes, adjustment disorders, adrenal hyperfunction, adrenal hypofunction, adrenoleukodystrophy, adrenomyeloneuropathy, advanced sleep-phase syndrome, affective disorder syndromes, agenesis of the coφus callosum, agnosia, agoraphobia, agraphia, agyria, agyria- pachygyria, ahylognosia, aicardi syndrome, AIDS, akathisia, akinesia, akinetic mutism, akinetopsia, alcohol abuse, alcohol dependence syndrome, alcohol neuropathy, alcohol related disorders, alcoholic amblyopia, alcoholic blackouts, alcoholic cerebellar degeneration, alcoholic dementia, alcoholic hallucinosis, alcoholic polyneuropathy, alcohol-induced anxiety disorders, alcohol-induced dementia, alcohol-induced mood disorders, alcohol-induced psychosis, alcoholism, alexander's syndrome, alexia, alexia with agraphia, alexia without agraphia, alien hand syndrome, alper's disease, altered sexuality syndromes, alternating hemiplagia, alzheimer's disease, alzheimer-like senile dementia, alzheimer's disease, Alzheimer-like juvenile dementia, amenonea, aminoacidurias, amnesia, amnesia for offences, amok-type reactions, amoφhognosia, amphetamine addiction, amphetamine or amphetamine-like related disorders, amphetamine withdrawal, amyloid neuropathy, amyotrophic lateral sclerosis, anencephaly, aneurysms, angelman syndrome, angioblastic meningiomas, angleman's syndrome, anhidrosis, anisocoria, anomia, anomic aphasia, anorexia nervosa, anosmia, anosognosia, anterior cingulate syndrome, anterograde amnesia, antibiotic-induced neuromuscular blockade, antisocial personality disorder, anton's syndrome, anxiety and obsessive-compulsive disorder syndromes, anxiety disorders, apathy syndromes, aphasia, aphemia, aplasia, apnea, apraxia, arachnoid cyst, archicerebellar syndrome, arnold-chiari malformation, arousal disorders, anhinencephaly, arsenic poisoning, arteriosclerotic parkinsonism, arteriovenous aneurysm, arteriovenous malformations, aseptic meningeal reaction, asperger's syndrome, astereognosis, asthenia, astrocytomas, asymbolia, asynergia, ataque de nervios, ataxia, ataxia telangiectasia, ataxic cerebral palsy, ataxic dysarthria, athetosis, atonia, atonic seizures, attention deficit disorder, attention-deficit and disruptive behavior disorders , attention-deficit hyperkinetic disorders, atypical alzheimer's disease, atypical autism, autism, autism spectrum disorder, avoidant personality disorder, axial dementias, bacterial endocarditis, bacterial infections, balint's syndrome, ballism, balo disease, basophilic adenoma, bassen- komzweig syndrome, batten disease, battered woman syndrome, behcet syndrome, bell' palsy, benign essential tremor, benign focal epilepsies of childhood, benign intracranial hypertension, benxodiazepine dependence, bilateral cortical dysfunction, binswanger's disease, bipolar disorder, bipolar type 1 disorder, bipolar type 2 disorder, blepharospasm, body dysmoφhic disorder, bogaert-berfrand disease, bogarad syndrome, borderline personality disorder, botulism, bouffee delirante-type reactions, brachial neuropathy, bradycardia, bradykinesia, brain abscess, brain edema, brain fag, brain stem glioma, brainstem encephalitis, brief psychotic disorder, broca's aphasia, brucellosis, bulimia, bulimia nervosa, butterfly glioma, cachexia, caffeine related disorders, California encephalitis, callosal agenesis, canavan's syndrome, cancer pain, cannabis dependence, cannabis flashbacks, cannabis psychosis, cannabis related disorders, carcinoma-associated retinopathy, cardiac anest, cavernous malformations, cellular (cytotoxic) edema, central facial paresis, central herniation syndrome, central neurogenic hyperventilation, central pontine myelinolysis, central post-stroke syndrome (thalamic pain syndrome), cerebellar hemonhage, cerebellar tonsillar herniation syndrome, cerebral amyloid (congophilic) angiopathy, cerebral hemonhage, cerebral malaria, cerebral palsy, cerebral subdural empyema, cerebrotendinous xanthomatosis, cerebrovascular disorders, cervical tumors, cestodes, charcot-marie-tooth disease, chediak-higashi disease, cheiro-oral syndrome, chiari malformation with hydrocephalus, childhood disintegrative disorder, childhood feeding problems, childhood sleep problems, cholesteatomas, chordomas, chorea, chorea gravidaram, choreoathetosis, chromophobe adenoma, chromosomal disorders, chronic biplar major depression, chronic bipolar disorder, chronic demyelinating polyneuritis, chronic depression, chronic fatigue syndrome, chronic gm2 gangliosidosis, chronic idiopathic sensory neuropathy, chronic inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, chronic pain , clironic paroxysmal hemicrania, chronic sclerosing panencephalitis, clironic traumatic encphalopathy, chronobiological disorders, circadian rhythm disorder, circadian rhythm disorders, claude's syndrome, clonic seizures, cluster headache, cocaine addiction, cocaine withdrawal, cocaine-related disorders, Cockayne's syndrome, colloid cysts of the third ventricle, Colorado tick fever, coma, communicating hydrocephalus, communication disorders, complex partial seizures, compression neuropathy, compulsive buying disorder, conceptual apraxia, conduct disorders, conduction aphasia, conduction apraxia, congenital analgesia, congenital cytomegalovirus disease, congenital hydrocephalus, congenital hypothyroidism, congenital muscular dystrophy, congenital myasthenia, congenital myotonic dystrophy, congenital rubella syndrome, congophilic angiopathy, constipation, coprophilia, comedlia de lange syndrome, cortical dementias, cortical heteropias, corticobasal degeneration, corticobasal ganglionic degeneration, coxsackievirus, cranial meningoceles, craniopharyngioma, craniorachischisis, craniosynostosis, cranium bifidum, cretinism, creutzfeldt-jakob disease, cri-du-chat syndrome, craciate hemiplegia, cryptococcal granulomas, cryptococcosis, culturally related syndromes, culturally stereotyped reactions to extreme environmental conditions (arctic hysteria), cushing syndrome, cyclothymia, cysticercosis, cytomegalovirus, dandy- walker malformation, deafness, defects in the metabolism of amino acids, dehydration, dejerine-roussy syndrome, dejerine-sottas disease, delayed and advanced sleep phase syndromes, delayed ejaculation, delayed puberty, delayed-sleep-phase syndrome, delerium due to alcohol, delerium due to intoxication, delerium due to withdrawal, delirium, delirium, dementia, and amnestic and other cognitive disorders, delusional disorder, delusional disorder: erotomania subtype, delusional disorder: grandiose subtype, delusional disordeπjealousy subtype, delusional misidentification syndromes, dementia due to HIV disease, dementia pugilistica, dementias, dementias associated with extrapyramidal syndrome, dentatorabral-pallidoluysian atrophy, dependent personality disorder, depersonalization disorder, depression, depressive personality disorder, dermoids, developmental speech and language disorder, devic syndrome, devivo disease, diabetes, diabetes insipidus, diabetic neuropathy, dialysis demential, dialysis dysequilibrium syndrome, diencephalic dementias, diencephalic dysfunction, diencephalic syndrome of infancy, diencephalic vascular dementia, diffuse sclerosis, digestive disorders, diphtheria, diplopia, disarthria, disassociation apraxia, disorders of carbohydrate metabolism, disorders of excessive somnolence, disorders of metal metabolism, disorders of purine metabolism, disorders of sexual arousal, disorders of sexual aversion, disorders of sexual desire, disorders of the sleep-wake schedule, dissociative disorders, dorsolateral tegmental pontine syndrome, down syndrome, down syndrome with dementia, drug dependance, drag overdose, drag-induced myasthenia, duchenne muscular dystrophy, dwarfism, dysarthria, dysdiadochokinesia, dysembryoplastic neuroepithelial tumor, dysexecutive syndrome, dysgraphia, dyskinesia, dyskinetic cerebral palsy, dyslexia, dysmetria, dysomnia, dysosmia, dyspareunia, dysphagia, dysphasia, dysphonia, dysplasia, dyspnea, dysprosody, dyssomnia, dyssynergia, dysthesia, dysthymia, dystonia, dystrophinopathies, early adolescent gender identity disorder, early infantile epileptic encephalopthy (ohtahara syndrome, early myoclonic epileptic encephalopathy, eaton-lambert syndrome, echinococcus (hydatid cysts), echolalia, echoviras, eclampsia, edward's syndrome, elimination disorders, embolismintracerebral hemonhage, emery-dreifuss muscular dystrophy, encephalitis lethargica, encephaloceles, encephalotrigeminal angiomatosis, enophthalmos, enteroviras, enuresis, eosinophilic meningitis, ependymoma, epidural spinal cord compression, epilepsy, episodic ataxia, epstein-ban, equine encephalomyelitis, erectile dysfunction, essential thrombocythemia, essential tremor, esthesioneuroblastoma, excessive daytime somnolence, excessive secretion of antidiuretic hormone, excessive sleepiness, exhibitionism, expressive language disorder, extramedullary tumors, extrasylvian aphasias, extratemporal neocortical epilepsy, fabry's disease, facioscapulohumeral muscular dystrophy, factitious disorder, factitious disorders, false memories, familial dysautonomia, familial periodic paralysis, familial spastic paraparesis, familial spastic paraplegias, fear disorders, feeding and eating disorders of infancy or early childhood , female sexual arousal disorder, fetal alcohol syndrome, fetishism, flaccid dysarthria, floppy infant syndrome, focal inflammatory demyelinating lesions with mass effect, focal neonatal hypotonia, folie a deux, foramen magnum tumors, foville's syndrome, fragile-x syndrome, freidrich's ataxia, frolich syndrome, frontal alexia, frontal convexity syndrome, frontotemporal dementia, frontotemporal dementias, frotteurism, fungal infection, galactocerebroside lipidosis, galactonhea, ganglioneuroma, gaucher disease, gaze palsy, gender identity disorder, generalized anxiety disorder, genital shrinking syndrome (koro, suo-yang), germ cell tumors, gerstmann's syndrome, gerstmann-straussler syndrome, gerstmann-straussler-schenker disease, gestational substance abuse syndromes, giant axonal neuropathy, gigantism, gilles de la tourette syndrome, glioblastoma multiforme, gliomas, gliomatosis cerebri, global aphasia, glossopharyngeal neuralgia, glycogen storage diseases, gml- gangliosidosis, gm2-gangliosidoses, granular cell tumor, granulocytic brain edema, granulomas, granulomatous angiitis of the brain, grave's disease, growth hormone deficit , growth-hormone secreting adenomas, guam-parkinson complex dementia, guillain-baπe syndrome, hallervorden-spatz disease, hallucinogen persisting perception disorder, hallucinogen related disorders, hartnup disease, headache, helminthic infections (trichinellosis), hemangioblastomas, hemangiopericytomas, hemiachromatopsia, hemianesthesia, hemianopsia, hemiballism, hemiballismus, hemihypacusis, hemihypesthesia, hemiparesis, hemispatial neglect, hemophilus influenza meningitis, hemonhagic cerebrovascular disease, hepatic coma, hepatic encephalopathy, hepatolenticular degeneration (wilson disease), hereditary amyloid neuropathy, hereditary ataxias, hereditary cerebellar ataxia, hereditary neuropathies, hereditary nonprogressive chorea, hereditary predisposition to pressure palsies, hereditary sensory autonomic neuropathy, hereditary sensory neuropathy, hereditary spastic paraplegia, hereditary tyrosinemia, hermichorea, hermifacial spasm, herniation syndromes, heφes encephalitis, heφes infections, heφes zoster, heφres simplex, heterotopia, hexacarbon neuropathy, histrionic personality disorder, HIV, holmes-adie syndrome, homonymous quadrantaposia, homer's syndrome, human β-mannosidosis, hunter's syndrome, huntington's chorea, huntington's disease, hurler's syndrome, hwa- byung, hydraencephaly, hydrocephalus, hyper thyroidism, hyperacusis, hyperalgesia, hyperammonemia, hypereosinophilic syndrome, hyperglycemia, hyperkalemic periodic paralysis, hyperkinesia, hyperkinesis, hyperkinetic dysarthria, hyperosmia, hyperosmolar hyperglygemic nonketonic diabetic coma, hypeφarathyroidism, hypeφhagia, hypeφituitarism, hypeφrolactinemia, hypersexuality, hypersomnia, hypersomnia secondary to drug intake, hypersomnia-sleep-apnea syndrome, hypersomnolence, hypertension, hypertensive encephalopathy, hyperthermia, hyperthyroidism (graves disease), hypertonia, hypnagogic (predormital) hallucinations, hypnogenic paroxysmal dystonia, hypoadrenalism, hypoalgesia, hypochondriasis, hypoglycemia, hypoinsulinism, hypokalemic periodic paralysis, hypokinesia, hypokinetic dysarthria, hypomania, hypoparathyroidism, hypophagia, hypopituitarism, hypoplasia, hyposmia, hyposthenuria, hypotension, hypothermia, hypothyroid neuropathy, hypothyroidism, hypotonia, hyrler syndrome, hysteria, ideational apraxia, ideomotor apraxia, idiopathic hypersomnia, idiopathic intracranial hypertension, idiopathic orthostatic hypotension, immune mediated neuropathies, impersistence, impotence, impulse confrol disorders, impulse dyscontrol and aggression syndromes, impulse-control disorders, incontinence, incontinentia pigmenti, infantile encephalopathy with cheny-red spots, infantile neuraxonal dystrophy, infantile spasms, infantilism, infarction, infertility, influenza, inhalant related disorders, insomnias, insufficient sleep syndrome, intention tremor, intermittent explosive disorder, internuclear ophthalmoplegia, interstitial (hydrocephalic) edema, intoxication, intracranial epidural abscess, intracranial hemonhage, intracranial hypotension, intracranial tumors, intracranial venous-sinus thrombosis, intradural hematoma, intramedullary tumors, intravascular lymphoma, ischemia, ischemic brain edema, ischemic cerebrovascular disease, ischemic neuropathies, isolated inflammatory demyelinating CNS syndromes, jackson-collet syndrome, jakob-creutzfeld disease, Japanese encephalitis, jet lag syndrome, Joseph disease, joubert's syndrome, juvenile neuroaxonal dystrophy, kayak-svimmel, kearns- sayre syndrome, kinky hair disease (menkes syndrome), kleine-levin syndrome, kleptomania, klinefelter's syndrome, kluver-bucy syndrome, koerber-salus-elschnig syndrome, korsakoff syndrome, korsakoff s syndrome, krabbe disease, krabbe leukodystrophy, kugelberg-welander syndrome, kuru, lafora's disease, language deficits, 004/045369
language related disorders, latah-type reactions, lateral mass herniation syndrome, lateropulsation, lathyrism, laurence-moon biedl syndrome, laurence-moon syndrome, lead poisoning, learning disorders, leber hereditary optic atrophy, left ear extinction, legionella pneumophilia infection, leigh's disease, lennoc-gastaut syndrome, lennox- gastaut's syndrome, leprosy, leptospirosis, lesch-nyhan syndrome, leukemia, leukodysfrophies, levy-roussy syndrome, lewy body dementia, lewy body disease, limb girdle muscular dystrophies, limbic encephalitis, limbic encephalopathy, lissencephaly, localized hypertrophic neuropathy, locked-in syndrome, logoclonia, low pressure headache, lowe syndrome, lumbar tumors, lupus anticoagulants, lyme disease, lyme neuropathy, lymphocytic choriomeningitis, lymphomas, lysosomal and other storage diseases, macroglobinemia, major depression with melancholia, major depression with psychotic features, major depression without melancholia, major depressive (unipolar) disorder, male orgasmic disorder, malformations of septum pellucidum, malignant peripheral nerve sheath tumors, malingers, mania, mania with psychotic features, mania without psychotic features, maple syrup urine disease, marchiafara-bignami disease, marchiafava-bignami syndrome, marcus gunn syndrome, marie-foix syndrome, marinesco-sjόgren syndrome, maroteaux-lamy syndrome, masochism, masturbatory pain, measles, medial frontal syndrome, medial medullary syndrome, medial tegmental syndrome, medication-induced movement disorders, medullary dysfunction, medulloblastomas, medulloepithelioma, megalencephaly, melanocytic neoplasms, memory disorders, memory disturbances, meniere syndrome, meningeal carcinomatosis, meningeal sarcoma, meningial gliomatosis, meningiomas, meningism, meningitis, meningococcal meningitis, mental neuropathy (the numb chin syndrome), mental retardation, mercury poisoning, metabolic neuropathies, metachromatic leukodystrophy, metastatic neuropathy, metastatic tumors, metazoal infections, microcephaly, microencephaly, micropolygyria, midbrain dysfunction, midline syndrome, migraine, mild depression, millard-gubler syndrome, miller-dieker syndrome, minimal brain dysfunction syndrome, miosis, mitochondrial encephalopathy with lactic acidosis and stroke (melas), mixed disorders of scholastic skills, mixed dysarthrias, mixed transcortical aphasia, mόbius syndrome, mollaret meningitis, monoclonal gammopathy, mononeuritis nultiplex, monosymptomatic hypochondriacal psychosis, mood disorders, moritz benedikt syndrome, morquio syndrome, morion's neuroma, motor neuron disease, motor neurone disease with dementia, motor neuropathy with multifocal conduction block, motor skills disorder , mucolipidoses, mucopolysaccharide disorders, mucopolysaccharidoses, multifocal eosinophilic granuloma, multiple endocrine adenomatosis, multiple myeloma, multiple sclerosis, multiple system atrophy, multiple systems atrophy, multisystemic degeneration with dementia, mumps, munchausen syndrome, munchausen syndrome by proxy, muscular hypertonia, mutism, myasthenia gravis, mycoplasma pneumoniae infection, myoclonic seizures, myoclonic-astatic epilepsy (doose syndrome), myoclonus, myotonia congenita, myotonic dystrophy, myotonic muscular dystrophy, nacolepsy, narcissistic personality disorder, narcolepsy, narcolepsy-cataplexy syndrome, necrophilia, nectrotizing encephalomyelopathy, nelson's syndrome, neocerebellar syndrome, neonatal myasthenia, neonatal seizures, nervios, nerves, neurasthenia, neuroacanthocytosis, neuroaxonal dystrophy, neurocutaneous disorders, neurofibroma, neurofibromatosis, neurogenic orthostatic hypotension, neuroleptic malignant syndrome, neurologic complications of renal transplantation, neuromyelitis optica, neuromyotonia (isaacs syndrome), neuronal ceroid lipofuscinoses, neuro-ophthalamic disorders, neuropathic pain , neuropathies associated with infections, neuropathy associated with cryoglobulins, neuropathy associated with hepatic diseases, neuropathy induced by cold, neuropathy produced by chemicals, neuropathy produced by metals, neurosyphilis, new variant creutzfeldt-jakob disease, nicotine dependence, nicotine related disorders, nicotine withdrawal, niemann-pick disease, nocturnal dissociative disorders, nocturnal enuresis, nocturnal myoclonus, nocturnal sleep-related eating disorders, noecerbellar syndrome, non-alzherimer frontal- lobe degeneration, nonamyloid polyneuropathies associated with plasma cell dyscrasia, non-lethal suicial behavior, nonlocalizing aphasic syndromes, normal pressure hydrocephalus, nothnagel's syndrome, nystagmus, obesity, obsessive-compulsive (anankastic) personality disorder, obsessive-compulsive disorder, obstetric factitious disorder, obstructive hyrocephalus, obstructive sleep apnea, obstructive sleep apnoea syndrome, obstructive sleep hypopnoea syndrome, occipital dementia, occlusive cerebrovascular disease, oculocerebrorenal syndrome of lowe, oculomotor nerve palsy, oculopharyngeal muscular dystrophy, oligodendrogliomas, olivopontocerebellar atrophy, ondine's curse, one and a half syndrome, onychophagia, opiate dependance, opiate overdose, opiate withdrawal, opioid related disorders, oppositional defiant disorder, opsoclonus, orbitofrontal syndrome, orgasmic anhedonia, orgasmic disorders, osteosclerotic myeloma, other disorders of infancy, childhood, or adolescence, other medication-induced movement disorders, pachygyria, paedophilia, pain, pain syndromes, painful legs-moving toes syndrome, paleocerebellar syndrome, palilalia, panhypopituitarism, panic disorder, panic disorders, papillomas of the choroid plexus, paraganglioma, paragonimiasis, paralysis, paralysis agitans (shaking palsy), paramyotonia congenita, paraneoplastic cerebellar degeneration, paraneoplastic cerebellar syndrome, paraneoplastic neuropathy, paraneoplastic syndromes, paranoia, paranoid personality disorder, paranoid psychosis, paraphasia, paraphilias, paraphrenia, parasitic infections, parasomnia, parasomnia overlab disorder, parenchymatous cerebellar degeneration, paresis, paresthesia, parinaud's syndrome, parkinson's disease, parkinson-dementia complex of guam, parkinsonism, parkinsonism-plus syndromes, parkinson's disease, paroxysmal ataxia, paroxysmal dyskinesia, partial (focal) seizures, partialism, passive-aggressive (negativistic) personality disorder, patau's syndrome, pathological gambling, peduncular hallucinosis, pelizaeus-merzbacher disease, perineurioma, peripheral neuropathy, perisylvian syndromes, periventricular leukomalacia, periventricular white matter disorder, periventricular-infraventricular hemonhage, pernicious anemia, peroneal muscular atrophy, peroxisomal diseases, perseveration, persistence of cavum septi pellucidi, persistent vegetative state, personality disorders, pervasive developmental disorders , phencyclidine (or phencyclidine-like) related disorders, phencyclidine delirium, phencyclidine psychosis, phencyclidine-induced psychotic disorder, phenylketonuria, phobic anxiety disorder, phonic tics, photorecepto degeneration, pibloktoq, pick's disease, pineal cell tumors, pineoblastoma, pineocytoma, pituitary adenoma, pituitary apoplexy, pituitary carcinoma, pituitary dwarfism, placebo effect, plummer's disease, pneumococcal meningitis, poikilolthermia, polio, polycythemia vera, polydipsia, polyglucosan storage, diseases, polymicrogyria, polymyositis, polyneuropathy with dietary deficiency states, polysubstance related disorder, polyuria, pontine dysfunction, pontosubicular neuronal necrosis, porencephaly, poφhyric neuropathy, portal-systemic encephalopathy, postcoital headaches, postconcussion syndrome, postencephalic parkinson syndrome, posthemonhagic hydrocephalus, postinflammatory hydrocephalus, postpartum depression, postpartum psychoses, postpolio syndrome, postpsychotic depression, post- stroke hypersomnia, post-traumatic amnesia, post-traumatic epilepsy, post-traumatic hypersomnia, post-traumatic movement disorders, post-traumatic stress disorder, post- traumatic syndromes, prader-willi syndrome, precocious puberty, prefrontal dorsolateral syndrome, prefrontal lobe syndrome, premenstrual stress disorder, premenstrual syndrome, primary amebic meningoencephalitis, primary CNS lymphoma, primary idiopathic thrombosis, primary lateral sclerosis, primitive neuroectodermal tumors, prion disease, problems related to abuse or neglect, progressive bulbar palsy, progressive frontal lobe dementias, progressive multifocal leukoencephalopathy, progressive muscular atrophy, progressive muscular dystrophies, progressive myoclonic epilepsies, progressive myoclonus epilepsies, progressive non-fluent aphasia, progressive partial epilepsies, progressive rubella encephalitis, progressive sclerosing poliodystrophy (alpers disease), progressive subcortical gliosis, progressive supranuclear palsy, progressive supranuclear paralysis, progrssive external ophthalmoplegia, prolactinemia , prolactin-sectreting adenomas, prosopagnosia, protozoan infection, pseudobulbar palsy, pseudocyesis, pseudodementia, psychic blindness, psychogenic excoriation, psychogenic fugue, psychogenic pain syndromes, psychological mutism, psychosis after brain injury, psychotic syndromes, ptosis, public masturbation, pueφeral panic, pulmonary edema, pure word deafness, pyromania, quadrantanopsia, rabies, radiation neuropathy, ramsay hunt syndrome, rape traume syndrome, rapid cycling disorder, rapid ejaculation, raymond-cestan-chenais syndrome, receptive language disorder, recovered memories, recunent bipolar episodes, recunent brief depression, recunent hypersomnia, recunent major depression, refsum disease, reiterative speech disturbances, relational problems, rem sleep behavior disorder, rem sleep behavioral disorder, repetitive self-mutilation, repressed memories, respiratory dysrhythmia, restless legs syndrome, rett syndrome, reye syndrome, rhythmic movement disorders, rocky mountain spotted fever, rostral basal pontine syndrome, rubella, rubinstein-taybi syndrome, sadistic personality disorder, salla disease, sandhoff disease, sanfilippo syndrome, sarcoid neuropathy, sarcoidosis, scapuloperoneal syndromes, schistosomiasis (bilharziasis), schizencephaly, schizoaffective disorder, schizoid personality disorder, schizophrenia, schizophrenia and other psychotic disorders, schizophrenia-like psychosis, schizophreniform disorder, schizotypal personality disorder, school-refusal anxiety disorder, schwannoma, scrub typhus, seasonal depression, secondary spinal muscular atrophy, secondary thrombosis, sedative hypnotic or anxiolytic-related disorders, seizure disorders, selective mutism, self-defeating (masochistic) personality disorder, semen-loss syndrome (shen-k'uei, dhat, jiryan, sukra prameha), senile chorea, senile dementia, sensory perineuritis, separation anxiety disorder, septal syndrome, septo-optic dysplasia, severe hypoxia, severe myoclonic epilepsy, sexual and gender identity disorders, sexual disorders, sexual dysfunctions, sexual pain disorders, sexual sadism, shapiro syndrome, shift work sleep disorder, shy-drager syndrome, sialidosis, sialidosis type 1 , sibling rivalry disorder, sickle cell anemia, simmonds disease, simple partial seizures, simultanagnosia, sleep disorders, sleep paralysis, sleep tenors, sleep-related enuresis, sleep-related gastroesophageal reflux syndrome, sleep-related headaches, sleep-wake disorders, sleepwalking, smith-magenis syndrome, social anxiety disorder, social phobia, social relationship syndromes, somatoform disorders, somnambulism, sotos syndrome, spasmodic dysphonia, spasmodic torticollis (wry neck), spastic cerebral palsy, spastic dysarthria, specific developmental disorder of motor function, specific developmental disorders of scholastic skills, specific developmental expressive language disorder, specific developmental receptive language disorder, specific disorders of arithmetical skills, specific phobia, specific speech articulation disorder, specific spelling disorder, speech impairment, spina bifida, spinal epidural abcess, spinal muscular atrophies, spinocerebellar ataxias, spirochete infections, spongiform encephalopathies, spongy degeneration of the nervous system, St. louis encephalitis, stammer, staphylococcal meningitis, startle syndromes, status marmoratus, steele-richardson-olszewski syndrome, stereotypic movement disorder, stereotypies, stiff-man syndrome, stiff-person syndrome, stimulant psychosis, strachan syndrome (nutritional neuropathy), streptococcal meningitis, striatonigral degeneration, stroke, strongyloidiasis, sturge-weber disease (krabbe- weber-dimitri disease), stutter, subacute combined degeneration of the spinal cord, subacute motor neuronopathy, subacute necrotic myelopathy, subacute sclerosing panencephalitis, subacute sensory neuronopathy, subarachniod hemonhage, subcortical aphasia, subfalcine herniation syndrome, substance abuse, substance related disorders, sudanophilic leukodystrophis, sudden infant death syndrome, suicide, sulfatide lipidosis, susto, espanto, meido, sydenham chorea, symetric neuropathy associated with carcinoma, sympathotonic orthostatic hypotension, syncope, syndromes related to a cultural emphasis on leamt dissociation, syndromes related to a cultural emphasis on presenting a physical appearance pleasing to others (taijin-kyofu reactions), syndromes related to acculturative stress, syringobulbia , syringomyelia, systemic lupus erythematosus, tachycardia, tachypnea, tangier disease, tardive dyskinesia, tay-sachs disease, telangiectasia, telencephalic leukoencephalopathy, telephone scatologia, temporal lobe epilepsy, temporoparietal dementia, tension-type headache, teratomas, tetanus, tetany, thalamic syndrome, thallium poisoning, thoracic tumors, thrombotic thrombocytopenic puφura, thyroid disorders, tic disorders, tick paralysis, tick-bome encephalitis, tinnitis, tomaculous neuropathy, tonic seizures, tonic-clonic seizures, torticollis, tourette syndrome, toxic neuropathies, toxoplasmosis, transcortical motor aphasia, transcortical sensory aphasia, transient epileptic amnesia, transient global amnesia, transitional sclerosis, fransvestic fetishism, traumatic brain injury, traumatic neuroma, fraumiatic mutism, tremors, trichinosis, trichotillomania, trigeminal neuralgia, trochlear nerve palsy, tropical ataxic neuropathy, tropical spastic paraparesis, trypanosomiasis, tuberculomas, tuberculous meningitis, tuberous sclerosis, tumors, turner's syndrome, typhus fever, ulegyria, uncinate fits, unverricht-lundborg's disease, upper airway resistance syndrome, upward transtentorial herniation syndrome, uremic encephalopathy, uremic neuropathy, urophilia, vaccinia, varicella-zoster, vascular dementia, vascular malformations, vasculitic neuropathies, vasogenic edema, velocardiofacial syndrome, venous malformations, ventilatory anest, vertigo, vincristine toxicity, viral infections, visuospatial impairment, vogt-koyanagi-harada syndrome, von hippel-lindau disease, von racklinghousen disease, voyeurism, waldensfrom's macroglobulinemia, walker-warburg syndrome, wallenburg's syndrome, walleyed syndrome, weber's syndrome, wenicke's encephalopathy, werdnig-hoffmann disease, wernicke's encephalopathy, wernicke-korsakoff syndrome, wernicke's aphasia, west's syndrome, whipple disease, williams syndrome, wilson disease, windigo, witiko, witigo, withdrawal with grand mal seizures, withdrawal with perceptual disturbances, withdrawal without complications, wolman disease, xeroderma pigmentosum, xyy syndrome, zellweger syndrome.
362. The method of any of claims 1-6, 145-147, and 217-222, wherein said neurological disease or disorder involves one or more tissues selected from the group consisting of hypothalamus, amygdala, pituitary, nervous system, brainstem, cerebellum, cortex, frontal cortex, hippocampus, striatum, and thalamus.
363. The method of any of claims 7-12, 148-150, and 223-228, wherein said disease or disorder of the adrenal gland is selected from the group consisting of 11- hydroxylase deficiency, 17-hydroxylase deficiency, 3β-dehydrogenase deficiency, acquired immune deficiency syndrome, ACTH-dependent adrenal hyperfunction (Gushing disease), ACTH-independent adrenal hyperfunction, acute adrenal insufficiency, adrenal abscess, adrenal adenoma, adrenal calcification, adrenal cysts, adrenal cytomegaly, adrenal dysfunction in glycerol kinase deficiency, adrenal hematoma, adrenal hemonhage, adrenal histoplasmosis, adrenal hyperfunction, adrenal hypeφlasia, adrenal medullary hypeφlasia, adrenal myelolipoma, adrenal tuberculosis, adrenocortical adenoma, adrenocortical adenoma with primary hyperaldosteronism (Conn's syndrome), adrenocortical carcinoma, adrenocortical carcinoma with Cushing's syndrome, adrenocortical hyperfunction, adrenocortical insufficiency, adrenocortical neoplasms, adrenoleukodystrophy, amyloidosis, anencephaly, autoimmune Addison's disease, Beckwith-Wiedemann syndrome, bilateral adrenal hypeφlasia, chronic insufficiency of adrenocortical hom one synthesis, complete 21-hydroxylase deficiency, congenital adrenal hypeφlasia, congenital adrenal hypoplasia, cortical hypeφlasia, desmolase deficiency, ectopic ACTH syndrome, excess aldosterone secretion, excess cortisol secretion (Cushing's syndrome), excess secretion of adrenocortical hormones, excess sex hormone secretion, familial glucocorticoid deficiency, functional "black" adenomas, ganglioneuroblastoma, ganglioneuroma, glucocorticoid remediable hyperaldosteronism, heφetic adrenalitis, hyperaldosteronism, idiopathic Addison's disease, idiopathic hyperaldosteronism with bilateral hypeφlasia of zona glomeralosa, latrogenic hypercortisolism, lysosomal storage diseases, macronodular hypeφlasia, macronodular hypeφlasia with marked adrenal enlargement, malignant lymphoma, malignant melanoma, metastatic carcinoma, metastatic tumors, micronocular hypeφlasia, multiple endocrine neoplasia syndromes, multiple endocrine neoplasia type 1 (Wermer syndrome), multiple endocrine neoplasia type 2a (Sipple syndrome), multiple endocrine neoplasia type 2b, neuroblastoma, Niemami-Pick disease, ovarian thecal metaplasia, paraganglioma, partial 21-hydroxylase deficiency, pheochromocytoma, primary aldosteronism (Conn's syndrome), primary chronic adrenal insufficiency (Addison's disease), primary hyperaldosteronism, primary mesenchymal tumors, primary pigmented nodular adrenocortical disease, salt-wasting congenital adrenal hypeφlasia, secondary Addison's disease, secondary hyperaldosteronsim, selective hypoaldosteronism, simple virilizing congenital adrenal hypeφlasia, Waterhouse- Friderichsen syndrome, and Wolman's disease.
364. The method of any of claims 13-18, 151-153, and 229-234, wherein said disease or disorder of the colon is selected from the group consisting of acute self- limited infectious colitis, adenocarcinoma, adenoma, adenoma-carcinoma sequence, adenomatous polyposis coli, adenosquamous carcinomas, allergic (eosinophilic) proctitis and colitis, amebiasis, amyloidosis, angiodysplasia, anorectal malformations, blue rubber bleb nevus syndrome, brown bowel syndrome, Campylobacter fetus infection, carcinoid tumors, carcinoma of the anal canal, carcinoma of the colon and rectum, chlamidial proctitis, Chrohn's disease, clear cell carcinomas, Clostridium difficile pseudomembranous enterocolitis, collagenous colitis, colonic adenoma, colonic diverticulosis, colonic inertia, colonic ischemia, congenital atresia, congenital megacolon (Hirschsprang's disease), congenital stenosis, constipation, Cowden's syndrome, cystic fibrosis, cytomegalovirus colitis, dianhea, dieulafor lesion, diversion colitis, diverticulitis, diverticulosis, drag-induced diseases, dysplasia and malignancy in inflammatory bowel disease, Ehlers-Danlos syndromes, enterobiasis, familial adenomatous polyposis, familial polyposis syndromes, Gardner's syndrome, gastrointestinal stromal neoplasms, hemangiomas and vascular anomalies, hemonhoids, hereditary hemoπhagic telangiectasia, heφes colitis, hypeφlastic polyps, idiopathic inflammatory bowel disease, incontinence, inflammatory bowel syndrome, inflammatory polyps, inherited adenomatous polyposis syndromes, intestinal hamartomas, intestinal pseudo-obstruction, irritable bowel syndrome, ischemic colitis, juvenile polyposis, juvenile polyps, Klippel-Trenaunay- Weber syndrome, leiomyomas, lipomas, lymphocytic (microscopic) colitis, lymphoid hypeφlasia and lymphoma, malakoplakia, malignant lymphoma, malignant neoplasms, malrotation, metastatic neoplasms, mixed hypeφlastic and adenomatous polyps, mucosal prolapse syndrome, neonatal necrotizing enterocolitis, neuroendocrine cell tumors, neurogenic tumors, neufropenic enterocolitis, non-neoplastic polyps, Peutz-Jeghers syndrome, pneumatosis cystoides intestinalis, polyposis coli, pseudomembranous colitis, pseudoxanthoma elasticum, pure squamous carcinomas, radiation colitis, schistosomiasis, Shigella colitis (bacilliary dysentery), spindle cell carcinomas, spirochetosis, stercolar ulcers, stromal tumors, systemic sclerosis and CREST syndrome, trichuriasis, tubular adenoma (adenomatous polyp, polypoid adenoma), Turcot's syndrome, Turner's syndrome, ulcerative colitis, villous adenoma, and volvulus.
365. The method of any of claims 19-24, 154-156, and 235-240, wherein said cardiovascular disease or disorder is selected from the group consisting of acute coronary syndrome, acute idiopathic pericarditis, acute rheumatic fever, American trypanosomiasis (Chagas' disease), angina pectoris, ankylosing spondyhtis, anomalous pulmonary venous connection, anomalous pulmonary venous drainage, aortic atresia, aortic regurgitation, aortic stenosis, aortic valve insufficiency, aortopulmonary septal defect, asymmetric septal hypertrophy, asystole, atrial fibrillation, atrial flutter, atrial septal defect, atrioventricular septal defect, autoimmune myocarditis, bacterial endocarditis, calcific aortic stenosis, calcification of the cental valve, calcification of the valve ring, carcinoid heart disease, cardiac amyloidosis, cardiac aπhythmia, cardiac failure, cardiac myxoma, cardiac rejection, cardiac tamponade, cardiogenic shock, cardiomyopathy of pregnancy, chronic adhesive pericarditis, chronic constrictive pericarditis, chronic left ventricular failure, coarctation of the aorta, complete heart block, complete transposition of the great vessels, congenital bicuspid aortic valves, congenital nano wing of the left ventricular outflow tract, congenital pulmonary valve stenosis, congenitally conected transposition of the great arteries, congestive heart failure, constrictive pericarditis, cor pulmonale, coronary artery origin from pulmonary artery, coronary atherosclerosis, dilated (congestive) cardiomyopathy, diphtheria, double inlet left ventricle, double outlet right ventricle, Ebstein's malformation, endocardial fibroelastosis, endocarditis, endomyocardial fibrosis, eosinophilic endomyocardial disease (Loffler endocarditis), fibroma, glycogen storage diseases, hemochromatosis, hypertensive heart disease, hyperthyroid heart disease, hypertrophic cardiomyopathy, hypothyroid heart disease, idiopathic dilated cardiomyopathy, idiopathic myocarditis, infectious myocarditis, infective endocarditis, ischemic heart disease, left ventricular failure, Libman-Sachs endocarditis, lupus erythematosus, lyme disease, marantic endocarditis, metastatic tumors, mitral insufficiency, mitral regurgitation, mitral stenosis, mitral valve prolapse, mucopolysaccharidoses, multifocal atrial tachycardia, myocardial infarction, myocardial ischemia, myocardial rupture, myocarditis, myxomatuos degeneration, nonatheromatous coronary artery disease, nonbacterial thrombotic endocarditis, noninfectious acute pericarditis, nonviral infectious pericarditis, oblitaerative cardiomyopathy, patent ductus arteriosus, pericardial effusion, pericardial tumors, pericarditis, persistent truncus arteriosis, premature ventricular contraction, progressive infarction, pulmonary atresia with intact ventricular septum, pulmonary atresia with vertricular septal defect, pulmonary insufficiency, pulmonary regurgitation, pulmonary stenosis, pulmonary valve lesions, pulmonary valve stenosis, pyogenic pericarditis, Q fever, radiations myocarditis, restrictive cardiomyopathy, rhabdomyoma, rheumatic aortic stenosis, rheumatic heart disease, rocky mountain spotted fever, rapture of the aortic valve, sarcoid myocarditis, scleroderma, shingolipidoses, sinus brachycardia, sudden death, syphilis, systemic embolism from mural thrombi, systemic lupus erythematosus, tetralogy of fallot, thiamine deficiency (Beriberi) heart disease, thoracic outlet syndrome, Torsade de Pointes, toxic cardiomyopathy, toxic myocarditis, toxoplasmosis, trichinosis, tricuspid atresia, tricuspid insufficiency, tricuspid regurgitation, tricuspid stenosis, tricuspid valve lesions, tuberculuos pericarditis, typhus, ventricular aneurysm, ventricular fibrillation, ventricular septal defect, ventricular tachycardia, ventriculoarterial septal defect, viral pericarditis, and Wolff-Parkinson- White syndrome.
366. The method of any of claims 25-30, 157-159, and 241-246, wherein said disease or disorder of the intestine is selected from the group consisting of abdominal hemia, abetalipoproteinemia, abnormal rotation, acute hypotensive hypoperfusion, acute intestinal ischemia, acute small intestinal infarction, adenocarcinoma, adenoma, adhesions, amebiasis, anemia, arterial occlusion, atypical mycobacteriosis, bacterial dianhea, bacterial overgrowth syndromes, botulism, Campylobacter fetus infection, Campylobacter jejuni, carbohydrate absoφtion defects, carcinoid tumors, celiac disease (nontropical sprue, gluten-induced enteropathy), cholera, Chrohn's disease, chronic intestinal ischemia, Clostridium difficile pseudomembranous enterocolitis, Clostridium perfringens, congenital umbilical hemia, Cronkite-Canada syndrome, cytomegalovirus enterocolitis, dianhea, dianhea caused by invasive bacteria, diverticulitits, diverticulosis, dysentery, enteroinvasive and enterohemonhagic Escherichia coli infection, eosinophilic gastroenteritis, failure of peristalsis, familial polyposis syndromes, food poisoning, fungal enteritis, gangliocytic paragangliomas, Gardner's syndrome, gastrointestinal stromal neoplasms, giardiasis, hemonoids, hemia, hypeφlastic polyps, idiopathic inflammatory bowel disease, ileus, imperforate anus, intestinal (abdominal ischemia), intestinal atresia, intestinal cryptosporidiosis, microsporidiosis & isosporiasis in AIDS, intestinal hamartomas, intestinal helminthiasis, intestinal hemonhage, intestinal infiltrative disorders, intestinal lymphangiectasia, intestinal obstraction, intestinal perforation, intestinal reduplication, intestinal stenosis, intestinal tuberculosis, intussusception, jejunal diverticulosis, juvenile polyposis, juvenile retention polyps, lactase deficiency, lymphomas, malabsoφtion syndrome, malignant lymphoma, malignant neoplasms, malrotations, mechanical obstraction, Meckel's diverticulum, meconium ileus, mediteπanean lymphoma, mesenchymal tumors, mesenteric vasculitis, mesenteric vein thrombosis, metastatic neoplasms, microvillus inclusion disease, mixed hypeφlastic and adenomatous polyps, neonatal necrotizing enterocolitis, nodular duodenum, nonocclusive intestinal ischemia, nonspecific duodenitis, nontyphoidal salmonellosis, omphalocele, parasitic infections, peptic ulcer disease, Peutz-Jeghers syndrome, pneumatosis cystoides intestinalis, poorly differentiated neuroendocrine carcinomas, primary lymphoma, protein-losing enteropathy, Salmonella gasfroenteritis, sarcoidosis, sarcomas, shigellosis, staphlococcal food poisoning, steatonhea, sugar intolerance, thrombosis of the mesenteric veins, toxigenic dianhea, toxigenic Escherichia coli infection, tropical sprue, tubular adenoma (adenomatous polyp, polypoid adenoma), typhoid fever, ulcers, vascular malformations, villous adenoma, viral enteritis, viral gastroenteritis, visceral myopathy, visceral neuropathy, vitelline duct remnants, volvulus, Western-type intestinal lymphoma, Whipple's disease (intestinal lipopystrophy), Yersinia enterocolitica & Yersinia pseudotuberculosis infection, and Zollinger-Ellison syndrome.
367. The method of any of claims 31-36, 160-162, and 247-252, wherein said disease or disorder of the kidney is selected from the group consisting of acquired cystic disease, acute (postmfectious) glomeralonephritis, acute infectious interstitial nephritis, acute interstitial nephritis, acute pyelonephritis, acute renal failure, acute transplant failure, acute tubular necrosis, adult polycystic kidney disease, AL amyloid, analgesic nephropathy, anti- glomeralar basement membrane disease (Goodpasture's Syndrome), asymptomatic hematuria, asymptomatic proteinuria, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Bence Jones cast nephropathy, benign familial hematuria, benign nephrosclerosis and atheromatous embolization, bilateral cortical necrosis, chronic glomeralonephritis, chronic interstitial nephritis, clironic pyelonephritis, chronic renal failure, chronic transplant failure, circulating immune complex nephritis, crescentic glomeralonephritis, cryoglobulinemia, cystic renal dysplasia, diabetic glomerulosclerosis, diabetic nephropathy, dialysis cystic disease, drag induced (allergic) acute interstitial nephritis, ectopic kidney, Fabry's disease, familial juvenile nephronophthisis-medullary cystic disease complex, focal glomeralosclerosis (segmental hyalinosis), glomeralocystic disease, glomerulonephritis, glomeralonephritis associated with bacterial endocarditis, glomerulosclerosis, hemolytic-uremic syndrome, Henoch-Schόnlein puφura, hepatitis-associated glomeralonephritis, hereditary nephritis (Alport syndrome), horseshoe kidney, hydronephrosis, IgA nephropathy, infantile polycystic kidney disease, ischemic acute tubular necrosis, light-chain deposit disease, malignant neplirosclerosis, medullary cystic disease, membranoproliferative (mesangiocapiUary) glomerulonephritis, membranous glomeralonephritis, membranous nephropathy, mesangial proliferative glomeralonephritis (includes Berger's Disease), minimal change glomeralar disease, minimal change nephrotic syndrome, nephritic syndrome, nephroblastoma (Wilms tumor), nephronophthisis (medullary cystic disease complex), nephrotic syndrome, plasma cell dyscrasias (monoclonal immunoglobulin-induced renal damage), polyarteritis nodosa, proteinuria, pyelonephritis, rapidly progressive (crescentic) glomeralonephritis, renal agenesis, renal amyloidosis, renal cell carcinoma, renal dysgenesis, renal dysplasia, renal hypoplasia, renal infection, renal osteodystrophy, renal stones (urolithiasis), renal tubular acidosis, renal vasculitis, renovascular hypertension, scleroderma (progressive systemic sclerosis), secondary acquired glomeralonephritis, simple renal cysts, systemic lupus erythematosus, thin basement membrane nephropathy, thrombotic microangiopathy, thrombotic thrombocytopenic puφura, toxic acute tubular necrosis, tubular defects, tubulointerstitial disease in multiple myeloma, urate nephropathy, urinary obstraction, and vasculitis.
368. The method of any of claims 37-42, 163-165, and 253-258, wherein said disease or disorder of the liver is selected from the group consisting of acute alcoholic hepatitis (acute sclerosing hyaline necrosis of the liver), acute graft-versus-host disease, acute hepatitis, acute hepatocellular injury associated with infectious diseases other than viral hepatitis., acute liver failure, acute viral hepatitis, adenovirus hepatitis, Alagille syndrome, alcoholic cinhosis, alcoholic hepatitis, alcoholic liver disease, alphal- antitrypsin deficiency, amebic abscess, angiolmyolipoma, angiosarcoma, ascending cholangitis, autoimmune chronic active hepatitis (lupoid hepatitis), bile duct adenoma, bile duct cystadenocarcinoma, bile duct cystadenoma, biliary atresia, biliary cinhosis, biliary papillomatosis, bridging necrosis, Budd-Chiari syndrome, Byler disease, cardiac fibrosis of the liver, Caroli disease, cavernous hemangioma, cholangiocarcinoma, cholangitic abcess, choleostasis, cholestatic viral hepatitis, clironic active hepatitis, chronic alcoholic liver disease, chronic graft-versus-host disease, chronic hepatic venous congestion, chronic hepatitis, chronic liver failure, clironic passive congestion, chronic viral hepatitis, cinhosis, combined hepatocellular and cholangiocarcinoma, confluent hepatic necrosis, congenital hepatic fibrosis, Crigler-Najjar syndrome, cryptogenic cinhosis, cystic fibrosis, defects of coagulation, delta hepatitis, Dubin- Johnson syndrome, epithelioid hemangioendothelioma, erythrohepatic protopoφhyria, extrahepatic biliary obstruction (primary biliary cinhosis), fatty change, fatty liver, focal necrosis, focal nodular hypeφlasia, fulminant viral hepatitis, galactosemia, Gilbert's syndrome, glycogen storage diseases, graft-versus-host disease, granulomatous hepatitis, hemangioma, hemangiosarcoma, hemochromatosis, hepatic adenoma, hepatic amebiasis, hepatic encephalopathy, hepatic failure, hepatic schistosomiasis, hepatic veno-occlusive disease, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, hepatoblastoma, hepatocellular adenoma, hepatocellular carcinoma, hepatocellular necrosis, hepatorenal syndrome, hereditary fructose intolerance, hereditary hemochromatosis, heφesviras hepatitis, hydatid cust, hypeφlastic lesions, hypoalbuminenia, infantile hemangioendothelioma, infarction of the liver, infectious mononucleosis hepatitis, inflammatory pseudotumor of the liver, intrahepatic cholangiocarcinoma, intrahepatic cholestasis, intrahepatic protal hypertension, ischemic necrosis (ischemic hepatitis), isoniazid-induced necrosis, jaundice, leptospirosis, liver cell adenoma, liver manifestations of Rocky Mountain spotted fever, macronodular cinhosis, macrovesicular steatosis, malignant vascular neoplasts, mass lesions, massive hepatocellular necrosis, massive necrosis, mesenchymal hamartoma, metastatic tumors, micronodular cinhosis, microvesicular steatosis, neonatal (physiologic) jaundice, neonatal hepatitis, neoplastic lesions, nodular transformation (nodular regenerative hypeφlasia, nonsuppurative infections, nutritional cinhosis, nutritional liver disease, oriental cholangiohepatitis, parasitic infestation of the liver, peliosis hepatis, poφhyria cutaneo tarda, portal hypertension, portal vein thrombosis, posthepatic portal hypertension, predictable (dose-related) toxicity, prehepatic portal hypertension, primary biliary cinhosis, primary sclerosing cholangitis, pyogenic liver abcess, Q-fever hepatitis, Rotor's syndrome, sclerosing bile duct adenoma, sclerosing cholangitis, secondary hemochromatosis, submassive necrosis, syphilis, toxic liver injury, tyrosinemia, undifferentiated sarcoma, unpredictable (idiosyncratic) toxicity, vascular lesions, virus- induced cinhosis, Wilson's disease, and zonal necrosis.
369. The method of any of claims 43-48, 166-168, and 259-264, wherein said lung disease or disorder is selected from the group consisting of abnormal diffusion, abnormal perfusion, abnormal ventilation, accelerated silicosis, actinomycosis, acute air space pneumonia (acute bacterial pneumonia), acute bronchiolitis, acute congestion, acute infections of the lung, acute interstitial pneumonia, acute necrotizing viral pneumonia, acute organic dust toxic syndrome, acute pneumonia, acute radiation pneumonitis, acute rheumatic fever, acute silicosis, acute tracheobronchitis, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adenovirus, adult respiratory distress syndrome (shock lung), agenesis, AIDS, air embolism, allergic bronchopulmonary mycosis, allergic granulomatosis and angiitis (Churg-Strauss), allograft rejection, aluminum pneumoconiosis, alveolar microlithiasis, alveolar proteinosis, amebic lung abscess, amniotic fluid embolism, amyloidosis of the lung, anomalies of pulmonary vasculature, anomalous pulmonary venous return, aspiration pneumonia, aplasia, asbestosis, asbestos-related diseases, aspergillosis, asthma, atelectasis, atriovenous fistulas, atypical mycobacterial infection, bacteremia, bacterial pneumonia, benign clear cell tumor, benign epithelial tumors, benign fibrous mesothelioma, berylliosis, blastomycosis, bromchial atresia, bronchial asthma, bronchial carcinoid tumor, bronchial isomerism, bronchial obstraction, bronchial stenosis, bronchiectasis, bronchiolalveolar carcinoma, bronchiolitis, bronchiolitis obliterans- organizing pneumonia, bronchocentric granulomatosis, bronchogenic cyst, bronchopneumonia, bronchopulmonary dysplasia, bronchopulmonary sequestration, bullae, bullous emphysema, cancer, carcinoid tumors, carcinoma of the lung (bronchogenic carcinoma), central (bronchogenic) carcinoma, central cyanosis, centriacinar emphysema, cetrilobular emphysema, chest pain, Chlamydial pneumonia, chondroid hamartoma, chronic airflow obstraction, chronic bronchitis, chronic diffuse interstitial lung disease, chronic idiopathic pulmonary fibrosis, chronic lung abscess, chronic obstractive pulmonary diseases, chronic radiation pneumonitis, chronic silicosis, chylothorax, ciliary dyskinesia, coal worker's pneumoconiosis (anthracosis), coccidioidomycosis, collagen- vascular diseases, common cold, compensatory emphysema, congenital acinar dysplasia, congenital alveolar capillary dysplasia, congenital bronchobiliary fistula, congenital bronchoesophageal fistula, congenital cystic adenomatoid malformation, congenital pulmonary lymphangiectasis, congenital pulmonary overinflation (congenital emphysema), congestion, cough, cryptococcosis, cyanosis, cystic fibrosis, cysticercosis, cytomegalovirus, desquamative interstitial pneumonitis, destructive lung disease, diatomaceous earth pneumoconiosis, diffuse alveolar damage, diffuse pulmonary hemonhage, diffuse septal amyloidosis, diffuse panbronchiolitis, Dirofilaria immitis, diseases of the pleura, distal acinar (paraceptal) emphysema, drag-induced asthma, drag-induced diffuse alveolar damage, dyspnea, ectopic hormone syndromes, emphysema, empyemma, eosinophilic pneumonias, exercise-induced asthma, exfralobar sequestration, extrinsic allergic asthma, fat emboli, focal dust emphysema, follicular bronchiolitis, follicular bronchitis, foreign-body embolism, Fuller's earth pneumoconiosis, functional resistance to arterial flow (vasoconstriction), fungal granulomas of the lung, fungal infections, Goodpasture's syndrome, graphite pneumoconiosis, gray hepatization, hamartomas, hard metal disease, hemoptysis, hemothorax, herniation of lung tissue, heφes simplex, heterotopic tissues, high-altitude pulmonary edema, histoplasmosis, horseshoe lung, humidifier fever, hyaline membrane disease, hydatid cysts, hydrothorax, hypersensitivity pneumonitis (extrinsic allergic alveolitis), hypoxic vascular remodeling, iatrogenic drug-, chemical-, or radiation-induced interstitial fibrosis, idiopathic interstitial pneumonia, idiopathic organizing pneumonia, idiopathic pulmonary fibrosis (fibrosing alveolitis, Hamman- Rich syndrome, acute interstitial pneumonia), idiopathic pulmonary hemosiderosis, immunologic interstitial fibrosis, immunologic interstitial pneumonitis, immunologic lung disease, infections causing chronic granulomatous inflammation, infections causing clironic suppurative inflammation, infections of the air passages, infiltrative lung disease, inflammatory lesions, inflammatory pseudotumors, influenza, interstitial diseases of uncertain etiology, interstitial lung disease, interstitial pneumonitis in connective tissue diseases, intralobar sequestration of the lung (congenital), intrinsic (nonallergic) asthma, invasive pulmonary aspergillosis, kaolin pneumoconiosis, Kartagner's syndrome, Klebsiella pneumonia, Langerhans' cell histiocytosis (histiocytosis X), large cell undifferentiated carcinoma, larval migration of Ascaris lumbricoides, larval migration of Strongyloides stercoralis, left pulmonary artery "sling", Legionella pneumonia, lipid pneumonia, lobar pneumonia, localized emphysema, long-standing bronchial obstruction, lung abscess, lung collapse, lung fluke, lung transplantation implantation response, lymphangiomyomatosis, lymphocytic interstitial pneumonitis (pseudolymphoma, lymphoma, lymphomatoid granulomatosis, malignant mesothelioma, massive pulmonary hemonhage in the newborn, measles, meconium aspiration syndrome, mesenchymal cystic hamartomas, mesenchymal tumors, mesothelioma, metal-induced lung diseases, metastatic calcification, metastatic neoplasms, metastatic ossification, mica pneumoconiosis, mixed dust fibrosis, mixed epithelial-mesenchymal tumors, mixed type neoplasms, mucoepidermoid tumor, mucoviscidosis (fibrocystic disease of the pancreas, mycoplasma pneumoniae, necrotizing bacterial pneumonia, necrotizing sarcoid granulomatosis, neonatal respiratory distress syndrome, neoplasms of the pleura, neuromuscular syndromes, nocardiosis, nondestructive lung disease, North American blastomycosis, occupational asthma, organic dust disease, panacinar emphysema, Pancoast's syndrome, paracoccidioidomycosis, parainfluenza, paraneoplastic syndromes, paraseptal emphysema (paracicatricial), parasilicosis syndromes, parasitic infections of the lung, peripheral cyanosis, peripheral lung carcinoma, persistent pulmonary hypertension of the newborn, pleural diseases, pleural effusion, pleural plaques, pneumococcal pneumonia, pneumoconioses (inorganic dust diseases), Pneumocystis carinii pneumonia, pneumocystosis, pneumonitis, pneumothorax, precapillary pulmonary hypertension, primary (childhood) tuberculosis, primary (idiopathic) pulmonary hypertension, primary mesothelial neoplasms, primary pulmonary hypertensions, progressive massive fibrosis, psittacosis, pulmonary actinomycosis, pulmonary air-leak syndromes, pulmonary alveolar proteinosis, pulmonary arteriovenous malformation, pulmonary blastoma, pulmonary capillary hemangiomatosis, pulmonary carcinosarcoma, pulmonary edema, pulmonary embolism, pulmonary eosinophilia, pulmonary fibrosis, pulmonary hypertension, pulmonary hypoplasia, pulmonary infarction, pulmonary infiltration and eosinophilia, pulmonary interstitial air (pulmonary interstitial emphysema), pulmonary lesions, pulmonary nocardiosis, pulmonary parenchymal anomalies, pulmonary thromboembolism, pulmonary tuberculosis, pulmonary vascular disorders, pulmonary vascuhtides, pulmonary veno-occlusive disease, pyothorax, radiation pneumonitis, recunent pulmonary emboli, red hepatization, respiration failure, respiratory syncytial viras, Reye's syndrome, rheumatoid lung disease, Rickettsial pneumonia, rupture of pulmonary arteries, sarcoidosis, scar cancer, scimitar syndrome, scleroderma, sclerosing hemangioma, secondary (adult) tuberculosis, secondary bacterial pneumonia, secondary pleural neoplasms, secondary pulmonary hypertension, senile emphysema, siderosis, silicate pneumoconiosis asbestosis, silicatosis, silicosis, simple nodular silicosis, Sjogren's syndrome, small airway lesions, small cell carcinoma, small cell undifferentiated (oat cell) carcinoma,. spontaneous pneumothorax, sporotrichosis, sputum production, squamous (epidermoid) carcinoma, stannosis, staphlococcal pneumonia, suppuration (abscess formation), systemic lupus erythematosus, talcosis, tension pneumothorax, tracheal agenesis, tracheal stenosis, fracheobronchial amyloidosis, tracheobronchomegaly, tracheoesophageal fistula, transient tachypnea of the newborn (neonatal wet lung), tungsten carbide pneumoconiosis, usual interstitial pneumonia, usual interstitial pneumonitis, varicella, viral pneumonia, visceral pleural thickening, Wegener's granulomatosis, and whooping cough (pertussis).
370. The method of any of claims 49-54, 169-171, 265-270, wherein said muscular disease or disorder is selected from the group consisting of abnormalities of ion channel closure, acetylcholine receptor deficiency, acetylcholinesterase deficiency, acid maltase deficiencies (type 2 glycogenosis), acquired myopathies, acquired myotonia, adult myotonic dystrophy, alveolar rhabdomyosarcoma, aminoglycoside drags, amyloidosis, amyotrophic lateral sclerosis, antimyelin antibodies, bacteremic myositis, Batten's disease (neuronal ceroid lipofuscinoses), Becker's muscular dystrophy, benign neoplasms, Bomholm disease, botulism, branching enzyme deficiency (type 4 glycogenosis), carbohydrate storage diseases, carnitine deficiencies, carnitine palmitoylfransferase deficiency, central core disease, centronuclear (myotubular) myopathy, Chagas' disease, chondrodystrophic myotonia, chronic renal disease, congenital fiber type disproportion, congenital muscular dystrophy, congenital myopathies, congenital myotonic dystrophy, congenital paucity of synaptic clefts, cysticercosis, cytoplasmic body myopathy, debranching enzyme deficiency (type 3 glycogenosis), defect in acetylcholine synthesis, denervation, dermatomyositis, diabetes mellitus, diphtheria, disorders of glycolysis, disorders of neuromuscular junction, distal muscular dystrophy, drag induced inflammatory myopathy, Duchenne muscular dystrophy, embryonal rhabdomyosarcoma, Emery-Dreifuss muscular dystrophy, exotoxic bacterial infections, facioscapulohumeral muscular dystrophy, failure of neuromuscular transmission, fiber necrosis, fibromyalgia, fingeφrint body myopathy, Forbe's disease, gas gangrene, Guillain-Baπe syndrome, inclusion body myositis, infantile spinal muscular atrophies, infectious myositis, inflammatory myopathies, influenza, Isaac's syndrome, ischemia, Kearns-Sayre syndrome, lactase dehydrogenase deficiency, Lambert-Eaton syndrome, Leigh's disease, leukodysfrophies, limb girdle muscular dystrophy, lipid storage myopathies, Luft's disease, lysosomal glycogen storage disease with normal acid maltase activity, malignant neoplasms, malignant hyperthermia, McArdle's disease, MELAS syndrome (mitochondrial myopathy, encephalopathy, lacticacidosis, and strokes), MERRF syndrome (myoclonus epilepsy with ragged-red fibers), metabolic myopathies, microfiber myopathy, mitochondrial myopathies, multicore disease (minicore disease), multisystem triglyceride storage disease, muscle wasting from diabetes, muscular dystrophies, myasthenia gravis, myasthenic syndrome (Eaton-Lambert syndrome), myoadenylate deaminase deficiency, myoglobinuria, myopathies, myophosphorylase deficiency (type 5 glycogenosis), myositis, myositis ossificans, myotonia congenita, myotonic muscular dystrophy, nemaline myopathy, ocular muscular dystrophy, oculopharyngeal muscular dystrophy, paramyotonia, parasytic myopathies, periodic paralysis, peripheral neuropathies, phosphofructokinase deficiency (type 7 glycogenosis), phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, pleomoφhic rhabdomyosarcoma, polymyositis, Pompe's disease, progressive muscular atrophy, progressive systemic sclerosis, reducing body myopathy, Refsum's disease, rhabdomyolysis, rhabdomyoma, rhabdomyosarcoma, sarcoidosis, sarcoma botryoides, sarcotubular myopathy, secondary congenital myopathies, slow channel syndrome, spasmodic torticollis, spheroid body myopathy, spinal muscular atrophy, steroid myopathy, stiff-person syndrome, systemic lupus erythematosus, Tauri's disease, tick paralysis, toxic myopathies, toxoplasmosis, trichinosis, trilaminar fiber myopathy, type 2 myofiber afrophy, typhoid fever, vasculitis, viral myositis, and zebra body myopathy.
371. The method of any of claims 55-60, 172-174, and 271-276, wherein said disease or disorder of the ovary is selected from the group consisting of autoimmune oophoritis, brenner tumors, choriocarcinoma, clear cell adenocarcinoma, clear cell carcinoma, coφus luteal cysts, decidual reaction, dysgerminoma, embryonal carcinoma, endometrioid tumors, endometriosis, endometriotic cysts, epithelial inclusion cysts, fibrothecoma, follicular cysts, gonadoblastoma, granulosa-sfroma cell tumors, granulosa-theca cell tumor, gynandroblastoma, hilum cell hypeφlasia, luteal cysts, luteal hematomas, luteoma of pregnancy, massive ovarian edema, metastatic neoplasm, mixed germ cell tumors, monodermal tumors, mucinous tumors, neoplastic cysts, ovarian changes secondary to cytotoxic drugs and radiation, ovarian fibroma, polycystic ovary syndrome, pregnancy luteoma, premature follicle depletion, pseudomyxoma peritonei, resistant ovary, serous tumors, Sertoli-Leydig cell tumor, sex-cord tumor with annular tubules, steroid (lipid) cell tumor, stromal hypeφlasia, stromal hyperthecosis, teratoma, theca lutein cysts, thecomas, transitional cell carcinoma, undifferentiated carcinoma, and yolk sac carcinoma (endodermal sinus tumor).
372. The method of any of claims 61-66, 175-177, and 277-282, wherein said blood disease or disorder is selected from the group consisting of abnormal hemoglobins, abnormalities in granulocyte count, abnormalities in lymphocyte count, abnormalities in monocyte count, abnormalities of blood platelets, abnormalitites of platelet function, acanthocytosis, acquired neutropenia, acute granulocytic leukemia, acute idiopathic thrombocytopenic puφura, acute infections, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloblastic leukemia, acute myelocytic leukemia, acute myeloid leukemia, acute pyogenic bacterial infections, acute red cell aplasia, acute response to endotoxin, adult T-cell leukemial/lymphoma, afibrinogenemia, alpha thalassemia, altered affinity of hemoglobin for oxygen, amyloidosis, anemia, anemia due to acute blood loss, anemia due to chronic blood loss, anemia of chronic disease, anemia of chronic renal failure, anemias associated with enzyme deficiencies, anemias associated with erythrocyte cytoskeletal defects, anemias caused by inherited disorders of hemoglobin synthesis, angiogenic myeloid metaplasia, aplastic anemia, ataxia-telangiectasia, Auer rods, autoimmune hemolytic anemias, B-cell chronic lymphocytic leukemia, B-cell chronic lymphoproliferative disorders, Bemard-Soulier disease, beta thalassemia, Blackfan-Diamond disease, brucellosis, Burkitt's lymphoma, Chediak-Higashi syndrome, cholera, chronic acquired pure red cell aplasia, chronic granulocytic leukemia, chronic granulomatous disease, chronic idiopathic myelofibrosis, chronic idiopathic thrombocytopenic puφura, chronic lymphocytic leukemia, chronic lymphoproliferative disorders, chronic myelocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, congenital dyserythropoietic anemias, congenital dysfibrinogenemia, congenital neutropenia, corticosteriods, cyclic neutropenia, cytoplasmic maturation defect, deficiency of coagulation factors, delta-beta thalassemia, diphtheria, disorders of blood coagulation, disseminated intravascular coagulation & fibrinolysis, Dόhle bodies, drug & chemical- induced hemolysis, drag-induced thrombocytopenia, drugs that suppress granulopoiesis, E. coli, early preleukemic myeloid leukemia, eosinophilia, eosinophilic granuloma, erythrocute enzyme deficiency, erythrocyte membrane defects, essential thrombocythemia, factor 7 deficiency, familial cyclic neutropenia, Felty's syndrome, fibrinolytic activity, folate antagonists, folic acid deficiency, Gaucher disease, Glanzmann's thrombasthenia, glucose-6-phosphate dehydrogenase deficiency, granulated T-cell lymphocyte leukemia, granulocytic sarcoma, granulocytosis, Hageman trait, hairy cell leukemia (leukemic reticuloendotheliosis), Hand-Schϋller-Christian disease, heavy-chain disease, hemoglobin C disease, hemoglobin constant spring, hemoglobin S, hemoglobinopathies, hemolysis caused by infectious agents, hemolytic anemia, hemolytic anemia secondary to mechanical erythrocyte destruction, hemolytic blood transfusion reactions, hemolytic disease of the newborn, hemophagocytic disorders, hemophilia A, hemophilia B (Christmas disease, factor 9 deficiency, hepatitis, hereditary elliptocytosis, hereditary spherocytosis, heterozygous beta thalassemia (Cooley's trait), homozygous beta thalassemia (Cooley's anemia), hypereosinophilic syndrome, hypoxia, idiopathic cold hemagglutinin disease, idiopathic thrombocytopenic puφura, idiopathic warm autoimmune hemolytic anemia, immune drag induced hemolysis, immune-mediated hemolytic anemias, immunodeficiency disease, infantile neutropenia (Kostmann), instability of the hemoglobin molecule, iron deficiency anemia, isoimmune hemolytic anemia, juvenile chronic myeloid leukemia, Langerhans cell histiocytosis, large granular lymphocyte leukemia, lazy leukocyte syndrome, Letterer-Siwe disease, leukemias, leukemoid reaction, leukoerythroblastic anemia, lipid storage diseases, lymphoblastosis, lymphocytopenia, lymphocytosis, lymphoma, lymphopenia, macroangiopathic hemolytic anemia, malaria, manow aplasia, May- Hegglin anomaly, measles, megaloblastic anemia, metabolic diseases, microangiopathic hemolytic anemia, microcytic anemia, miliary tuberculosis, mixed phenotupe acute leukemia, monoclonal gammopathy of undetermined significance, monocytic leukemia, monocytosis, mucopolysaccharidosis, multiple myeloma, myeloblastic luekemia, myelodysplastic syndromes, myelofibrosis (agnogenic myeloid metaplasia), myeloproliferative diseases, myelosclerosis, neonatal thrombocytopenic puφura, neoplasms of hematopoietic cells, neutropenia, neutrophil dysfunction syndromes, neutrophil leukocytosis, neutrophilia, Niemann-Pick disease, nonimmune drag-induced hemolysis, normocytic anemia, nuclear maturation defects, parahemophilia, paroxysmal cold hemoglominuria, paroxysmal nocturnal hemoglobinuria, Pelger-Hϋet anomaly, pernicious (Addisonian) anemia, plasma cell leukemia, plasma cell neoplasia, polycythemia, polycythemia rabra vera, presence of circulating anticoagulants, primary (idiopathic) thrombocythemia, primary neoplasms, prolymphocytic leukemia, Proteus, Pseudomonas, pure red cell aplasia, pyogenic bacterial infection, pyruvate kinase deficiency, radiation, red cell aplasia, refractory anemias, ricketsial infections, Rosenthal's syndrome, secondary absolute polycythemia, septicemia, severe combined immunodeficiency disease, Sezary syndrome, sickle cell disease, sickle cell-beta thalassemia, sideroblastic anemia, solitary plasmacytoma, storage pool disease, stress, structural hemoglobin variants, systemic lupus erythematosus, systemic mastocytosis, tart cell, T-cell clironic lymphoproliferative disorders, T-cell prolymphocytic leukemia, thalassemias, thrombocytopenia, thrombotic thrombocytopenic puφura, toxic granulation, toxic granules in severe infection, typhus, vitamin B12 deficiency, vitamin K deficiency, Von Willebrand's disease, Waldenstrom macroglobulinemia, and Wiskott- aldrich syndrome.
373. The method of any of claims 67-72, 178-180, and 283-288, wherein said disease or disorder of the prostate is selected from the group consisting of acute bacterial prostatitis, acute prostatitis, adenoid basal cell tumor (adenoid cystic-like tumor), allergic (eosinophilic) granulomatous prostatitis, afrophy, atypical adenomatous hypeφlasia, atypical basal cell hypeφlasia, basal cell adenoma, basal cell hypeφlasia, BCG-induced granulomatous prostatitis, benign prostatic hypeφlasia, benign prostatic hypertrophy, blue nevus, carcinosarcoma, chronic abacterial prostatitis, chronic bacterial prostatitis, cribriform hypeφlasia, ductal (endometrioid) adenocarcinoma, granulomatous prostatitis, hematuria, iatrogenic granulomatous prostatitis, idiopathic (nonspecific) granulous prostatitis, impotence, infectious granulomatous prostatitis, inflammatory pseudotumor, leiomyosarcoma, leukemia, lymphoepithelioma-like carcinoma, malakoplakia, malignant lymphoma, mucinous (colloid) carcinoma, nodular hypeφlasia (benign prostatic hypeφlasia), nonbacterial prostatitis, obstraction of urinary outflow, phyllodes tumor, postatrophic hypeφlasia, postinadiation granulomatous prostatitis, postoperative spindle cell nodules, postsurgical granulomatous prostatitis, prostatic adenocarcinoma, prostatic carcinoma, prostatic intraepithelial neoplasia, prostatic melanosis, prostatic neoplasm, prostatitis, rhabdomyosarcoma, sarcomatoid carcinoma of the prostate, sclerosing adenosis, signet ring cell carcinoma, small-cell, undifferentiated carcinoma (high-grade neuroendocrine carcinoma), squamous cell carcinoma of the prostate, stromal hypeφlasia with atypia, transitional cell carcinoma of the prostate, xanthogranulomatous prostatitis, and xanthoma.
374. The method of any of claims 73-78, 181-183, and 289-294, wherein said disease or disorder of the skin is selected from the group consisting of acanthosis nigricans, acne vulgaris, acquired epidermolysis bullosa, acrochordons, acrodermatitis enteropathica, acropustulosis, actinic keratosis, acute cutaneous lupus erythematosus, age spots, allergic dermatitis, alopecia areata, angioedema, angiokeratoma, angioma, anthrax, apocrine tumors, arthropid-bite reactions, atopic deπnatitis, atypical fibroxanthoma, Bart's syndrome, basal cell carcinoma (basal cell epithelioma), Bateman's puφura, benign familial pemphigus (Hailey-Hailey disease), benign keratoses, Berloque dermatitis, blue nevus, borderline leprosy, Bonelia infection (lyme disease), Bowen's disease (carcinoma in situ), bullous pemphigoid, Cafe-au-lait spot, calcification, cellular blue nevus, cellulitis, Chagas' disease, chickenpox (varicella), chloasma, chondrodemiatitis nodularis helicis, chondroid syringoma, clironic actinic dermatitis, chronic cutaneous lupus erythematosus, chronic discoid lesions, cicatricial pemphigoid, collagen abnormalities, compount melanocytic nevus, congenital melanocytic nevus, connective tissue nevus, contact dermatitis, cutaneous leishmaniasis, cutis laxa, cysts of the skin, dandruff, Darier's disease (keratosis follicularis), deep fungal infections, delayed-hypersensitivity reaction, dermal Spitz's nevus, dermatitis, dermatitis heφetiformis, dermatofibroma (cutaneous fibrous histiocytoma), dermatofibrosarcoma protuberans, dermatomyositis, deπxiatophyte infections, dermatophytid reactions, dermoid cyst, dermotropic ricketsial infections, dermotropic viral infections, desmoplastic melanoma, discoid lupus erythematosus, dominant dystrophic epidermolysis bullosa, Dowling-Meara epidermolysis bullosa, dyshidrotic dermatitis, dysplastic nevi, eccrine tumors, ecthyma, eczema, elastic tissue abnoπnalities, elastosis perforans seφiginosa, eosinophilic fasciitis, eosinophilic folliculitis, ephelides (freckles), epidennal cysts, epidermolysis bullosa, epidermolysis bullosa simplex, epidermotropic T-cell lymphoma, epidermotropic viruses, erysipelas, erythema multiforme, erythema nodosum, erythema nodosum leprosum, fibrotic disorders, fibrous tumors, follicular mucinosis, Fordyce's condition, fungal infections, genodermatoses, graft-versus-host disease, granuloma annulare, granulomatous vasculitis, Graver's disease, hair follicle infections, hair follicle tumors, hair loss, halo nevus, heφes simplex, heφes zoster (shingles), hidradenitis suppurativa, histiocytic lesions, HIV infections, hives, human papiUoma virus, hyperhydrosis, ichthyosis, idiopathic skin diseases, impetigo, incontinentia pigmenti, intraepidermal spongiotic vesicles and bullae, invasive malignant melanoma, invasive squamous cell carcinoma, junctional epidermolysis bullosa, junctional melanocytic nevus, juvenile xanthogranuloma, Kaposi's sarcoma, keloids, keratinocytic lesions, keratinocytic tumors, keratoacanthoma, keratoderma blennonhagicum, keratosis pilaris, leiomyoma, lentigo, lentigo maligna (Hutchinson's freckle), lepromatous leprosy, leprosy (Hansen's disease), leukocytoclastic vasculitis; lichen planus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen striatus, lichenoid disorders, lichenoid drag reactions, light eruptions, linear bullous IgA deπnatitis, lipoma, Lucio's phenomenon, lupus erythematosus, lymphatic filariasis, lymphocytic vasculitis, lymphocytoma cutis, lymphoid lesions, lymphomatoid papulosis, malignant blue nevus, malignant lymphomas, malignant melanoma, malignant melanoma in situ (noninvasive malignant melanoma), mast cell neoplasms, mastocytosis, measles, melanocyte disorders, melanocytic lesions, melanocytic neoplasms, melanocytic nevus, melanocytic nevus with dysplasia, melanotic macule, reactive type, melasma, merkel cell (neuroendocrine) carcinoma, metastatic melanoma, miliara, mixed connective tissue disease, molluscum contagiosum, moφhea, mucin deposition, mucocutaneous leishmaniasis, mycetoma, mycobacterial infection, Mycobacterium marinum, Mycobacterium ulcerans, mycosis fungoides (cutaneous T cell lymphoma), myxoid cyst, necrobiosis lipoidica, necrobiosis lipoidica diabeticoram, necrolytic migratory erythema, necrotizing fasciitis, neoplasms of dermal mesenchymal cells, neoplasms of keratinocytes, neoplasms of skin appendages, neoplasms of the epidermis, neural tumors, neuroendocrine carcinoma of the skin, neurothekeoma, nevocellular nevus (melanocytic nevus), nummular dermatitis, obliterative vasculitis, onchocerciasis, Paget's disease, pale cell acanthoma of Degos, palisaded encapsulated neuroma, papillomaviras infections, paraneoplastic pemphigus, parasitic infections, pemphigoid gestationis, pemphigus, pemphigus foliaceus, pemphigus vulgaris, perivascular infiltrates, pilar cysts, pinta, pityriasis alba, pityriasis lichenoides chronica (of Juliusberg), pityriasis lichenoides et varioliformis acuta, pityriasis rosea, pityriasis rabra pilaris, plantar warts, porokeratosis, pressure necrosis, progressive systemic sclerosis, protozoal infections, praritic urticarial papules and plasques of pregnancy, pruritis ani, pseudofolliculitis barbae, pseudoxanthoma elasticum, psoriasis vulgaris, pyogenic granuloma, radial growth phase melanoma, recessive dystrophic epidermolysis bullosa, Reiter's syndrome, ringworm, Rochalimaea henselae infection, rosacea, rubella, sarcoidosis, scabies, Schamberg's disease, scleroderma, sebaceous hypeφlasia, sebaceous tumors, sebonheic dermatitis, sebonheic keratosis, Sezary syndrome, skin manifestations of systemic diseases, small plaque parapsoriasis, smallpox (variola), solitary mastocytoma, spirochetal infections, Spitz's nevus, Spitz's nevus junctional type, squamous cell carcinoma, stasis dermatitis, Stevens- Johnson syndrome, subacute cutaneous lupus erythematosus, subcomeal pustular dermatosis, superficial fungal infections, superficial spreading melanoma in situ, syphilis, syringoma, systemic lupus erythematosus, systemic mastocytosis, tinea (dermatophytosis, tinea versicolor, toxic epidermal necrolysis, transient acantholytic dermatosis, tuberculoid leprosy, tuberculosis, urticaria, urticaria pigmentosa, urticarial vasculitis, vascular tumors, verruca vulgaris (common wart), vertical growth phase melanoma, visceral leishmaniasis, vitiligo,- warty dyskeratoma, Weber-Cockayne epidermolysis bullosa, Woringer-Kolopp disease, xanthomas, xeroderma pigmentosum, xerosis, and yaws.
375. The method of any of claims 79-84, 184-186, and 295-300, wherein said disease or disorder of the spleen is selected from the group consisting of abnormal immunoblastic proliferations of unknown origin, acute infections, acute parasitemias, agnogenic myeloid metaplasia, amyloidosis, angioimmunoblastic lymphadenopathy, antibody-coated cells, asplenia, autoimmune diseases, autoimmune hemolytic anemias, B-cell chronic lymphocytic leukemia and prolymphocytic leukemia, babesiosis, bone manow involvement by carcinoma, bracellosis, carcinoma, ceroid histiocytosis, chronic alcoholism, chronic granulomatous disease, chronic hemolytic anemias, chronic hemolytic disorders, chronic immunologic inflammatory disorders, chronic infections, clironic lymphocytic leukemia, chronic myelogenous leukemia, chronic parasitemias, chronic uremia, cinhosis, cold agglutinin disease, congestive splenomegaly, cryoglobulinemia, disseminated tuberculosis, dysproteinemias, endocrine disorders, erythroblastic leukemia, erythropoiesis, essential thrombocythemia, extramedullary hematopoiesis, Felty syndrome, fibrocongestive splenomegaly, fungal infections, gamma heavy-chain disease, Gaucher's disease, graft rejection, granulomatous infiltration, hairy cell leukemia, hamartomas, Hand-Schϋller-Christian disease, hemangiomas, hemangiosarcomas, hematologic disorders, hemoglobinopathies, hemolytic anemias, hereditary elliptocytosis, hereditary spherocytosis, histiocytic medullary reticulosis, histiocytosis X, Hodgkin's disease, hypersensitivity reactions, hypersplenism, hyposplenism, idiopathic thrombocytopenic puφura, IgA deficiency, immune granulomas, immune thrombocytopenia, immune thrombocytopenic puφura, immunodeficiency disorders, infection associated hemophagocytic syndrome, infectious granulomas, infectious mononucleosis, infective endocarditis, infiltrative splenomegaly, inflammatory pseudotumors, leishmaniasis, Leterer-Siwe disease, leukemia, lipogranulomas, lymphocytic leukemias, lymphoma, malabsoφtion syndromes, malaria, malignant lymphoma, megakaryoblastic leukemia, metastatic tumor, monocytic leukemias, mucopolysaccharidoses, multicentric Castleman's disease, multiple myeloma, myelocytic leukemias, myelofibrosis, myeloproliferative syndromes, neoplasms, Niemann-Pick disease, non-Hodgkin's lymphoma, parasitic disorders, parasitized red blood cells, peliosis, polycythemia rabra vera, portal vein congestion, portal vein stenosis, portal vein thrombosis, portal venous hypertension, rheumatoid arthritis, right-sided cardiac failure, sarcoidosis, sarcoma, secondary amyloidosis, secondary myeloid metaplasia, serum sickness, sickle-cell disease, splenic cysts, splenic infarction, splenic vein hypertension, splenic vein stenosis, splenic vein thrombosis, splenomegaly, storage diseases, systemic lupus erythematosus, systemic vascuhtides, T- cell chronic lymphocytic leukemia, thalasemia, thrombocytopenic puφura, thyrotoxicosis, trapping of immature hematologic cells, tuberculosis, tumorlike conditions, typhoid fever, vascular tumors, vasculitis, and viral infections.
376. The method of any of claims 85-90, 187-189, and 301-306, wherein said disease or disorder of the stomach is selected from the group consisting of acute erosive gastropathy, acute gastric ulcers, adenocarcinomas, adenomas, adenomatous polyps, advanced gastric cancer, ampullary carcinoma, atrophic gastritis, bacterial gastritis, carcinoid tumors, carcinoma of the stomach, chemical gastritis, chronic (nonerosive) gastritis, chronic idiopathic gastritis, chronic nonatrophic gastritis, Cronkite-Canada syndrome, congenital cysts, congenital diaphragmatic hernias, congenital diverticula, congenital duplications, congenital pyloric stenosis, congestive gastropathy, cyclic vomiting syndrome, decreased mucosal resistance to acid, diffuse or infiltrating adenocarcinoma, early gastric cancer, emphysematous gastritis, endocrine cell hypeφlasia, environmental gastritis, eosinophilic gastritis, eosinophilic gastroenteritis, epithelial polyps, erosive (acute) gastritis, fundic gland polyps, fungal gastritis, gangliocytic paragangliomas, gastral anfral vascular ectasia, gastric adenocarcinoma, gastric outlet obstruction (pyloric stenosis), gastric ulcers, gastritis, gastroesophageal reflux, gastroparesis, granulomatous gastritis, H. Pylori infection, hamartomatous polyps, heterotopias, heterotopic pancreatic tissue, heterotopic polyps, hypeφlastic gastropathy, hypeφlastic polyps, hypersecretion of acid, infectious gastritis, inflammatory lesions of the stomach, inflammatory polyps, intestinal metaplasia, invasive carcinoma, ischemia, leiomyoma, linitis plastica, luminally acting toxic chemicals, lymphocytic gastritis, lymphomas, malignant gastric stromal neoplasms, malignant lymphoma, malignant transformation of a benign gastric ulcer, Menentrier's disease (hypertrophic gastritis, ragal hypertrophy), mesenchymal neoplasms, metastatic tumors, mucosal polyps, myoepithelial adenomas, myoepithelial hamartomas, neoplasms, neuroendocrine hypeφlasias, neuroendocrine tumors, nonerosive gastritis and stomach cancer, nonneoplastic polyps, parasitic gastritis, peptic ulcer disease, phlegmonous gastritis, plasma cell gastritis, polypoid (fungating) adenocarcinoma, poorly differentiated neuroendocrine carcinomas, precancerous lesions, Puetz-Jeghers syndrome, pyloric atresia, rapid gastric emptying, reflux of bile, stress ulcers, stromal tumors, superficial gastritis, type A chronic gastritis (autoimmune gastritis and pernicious anemia), type B chronic gastritis (chronic anfral gastritis, H. Pylori gastritis), ulcerating adenocarcinoma, vasculitis, viral gastritis, xanthomatous gastritis, and Zollinger-Ellison syndrome.
377. The method of any of claims 91-96, 190-192, and 307-312, wherein said disease or disorder of the testes is selected from the group consisting of abenant ducts of Haller, abnormal productions of hormones, abnormalities of testicular descent, acute epididymoorhcitis, adenomatoid tumor, adenomatous hypeφlasia of the rete testis, adenovirus, administration of estrogens, adrenal rests, alcoholic cinhosis, amyloidosis, anorchism, appendix testes, bacterial infections, Bracella, cachexia, carcinoma in situ, carcinoma of the rete testis, chlamydia, choriocarcinoma, choristomas, chronic fibrosing epididymoorchitis, coxsackie virus B, cryptorchidism, cystic dysplasia of the rete testis, cytomegalovirus, dystopia, E. coli, Echinococcus granulosus, ectopic testes, embryonal carcinoma, epididymoorchitis, Foumier's scrotal gangrene, fungal infection, germ cell aplasia, germ cell neoplasms, gonadal dysgenesis, gonadal stromal neoplasms, granulomatous orchitis, granulosa cell tumors, Haemophilus influenzae, HIV, hypergonadism, hypogonadotropic hypogonadism, hypopituitarism, hypospermatogenesis, hyrocele, idiopathic granulomatous orchitis, incomplete maturation anest, infarction, infertility, inflammatory diseases, inflammatory lesions, interstitial (Leydig) cell tumors, Klinefelter's syndrome, lafrogenic lesions, Leydig cell tumors, malakoplakia, malignant lymphoma, malnutrition, maturation anest of spermatogenesis, metastatic tumors, mixed germ cell tumors, monorchism, mumps orchitis, mycobacteria, Neisseria gononhoeae, neoplasms, obstraction to outflow of semen, orchitis, parasitic infection, polyorchidism, radiation, Salmonella, sarcoidosis, Schistosoma haematobium, seminoma, Sertoli cell tumors, sex cord stromal tumors, sperm granuloma, spermatocytic seminoma, syphilis, teratocarcinoma, teratoma, testicular atrophy, testicular neoplasms, testicular torsion, Treponema pallidum, tuberculous epididymoorchitis, tumors of nonspecific stroma, undescended testes, uropathogens, varicocele, vascular disturbances, vasculitis, viral infection, Wuchereria bancrofti, and yolk sac carcinoma.
378. The method of any of claims 97-102, 193-195, and 313-318, wherein said disease or disorder of the thymus is selected from the group consisting of accidental involution, acute accidental involution, acute lymphoblastic leukemia of T cell type, agenesis, age-related involution, anaplastic carcinoma, ataxia telangiectasia, atrophy, bacterial infections, bacterial mediastinitis, basaloid carcinoma, bone manow transplantation, Braton's agammaglobulinemia, carcinosarcoma, chronic accidental involution, clear cell carcinoma, cortical thymoma, cytomegalovirus, DiGeorge syndrome, dysgenesis, dysplasia with pattern similar to severe atrophy, dysplasia with pseudoglandular appearance, dysplasia with stromal conticomedullary differentiation, ectopia, germ cell tumors, Grave's disease, histiocytosis X, HIV, Hodgkin's disease, hypeφlasia, infectious mononucleosis, involution, lymphoblastic lymphoma of T-cell type, lymphoepithelioma-like carcinoma, lymphofollicular thymitis, maldescent, malignant lymphomas, malignant thymoma, measles giant cell pneumonia, medullary thymoma, mixed (composite) thymoma, mucoepidermoid carcinoma, myasthenia gravis, neonatal syphilis, neoplasms, Omenn's syndrome, predominantly cortical (organoid) thymoma, primary mediastinal B-cell lymphoma of high-grade malignancy, sarcomatoid carcinoma, seminoma, severe combined immunodeficiency, short limb dwarfism, simple dysplasia, small cell carcinoma, small-cell B-cell lymphoma of MALT type, squamous cell carcinoma, systemic lupus erythematosus, teratoma, thymic carcinoid, thymic carcinoma, thymic cysts, thymic epithelial cysts, thymic epithelial tumors, thymic neoplasms, thymitis with diffuse B-cell infiltrations, thymolipoma, thymoma, true thymic hypeφlasia, varicella-zoster, viral infections, well differentiated thymic carcinoma, and Wiscott-Aldrich syndrome.
379. The method of any of claims 103-108, 196-198, and 319-324, wherein said disease or disorder of the thyroid is selected from the group consisting of abenant thyroid glands, accessory thyroid glands, adenoma with bizane nuclei, agenesis, amphicrine variant of medullary carcinoma, anaplastic (undifferentiated) carcinoma, aplasia, atrophic thyroiditis, atypical adenoma, autoimmune thyroiditis, carcinoma, C- cell hypeφlasia, clear cell tumors, clear cell variant of medullary carcinoma, colloid adenoma, columnar variant of papillary carcinoma, congenital hypothyroidism (cretinism), diffuse nontoxic goiter, diffuse sclerosing variant of papillary carcinoma, dyshormonogenic goiter, embryonal adenoma, encapsulated variant of papillary carcinoma, endemic cretinism, endemic goiter, enzyme deficiency, fetal adenoma, follicular adenoma, follicular carcinoma, follicular variant of medullary carcinoma, follicular variant of papillary carcinoma, fungal infection, giant cell variant of medullary carcinoma, goiter induced by antithyroid agents, goitrous hypothyroidism, Graves' disease, Hashimoto's autoimmune thyroiditis, Hϋrthle cell (oncocytic) adenoma, hyalinized trabecular adenoma, hyperthyroidism, hypothyroid cretinism, hypothyroidism, iodine deficiency, juvenile thyroiditis, latrogenic hypothyroidism, lingual thyroid glands, malignant lymphoma, medullary carcinoma, melanocytic variant of medullary carcinoma, mesenchymal tumors, metastatic tumors, minimally invasive follicular carcinoma, mixed medullary and follicular carcinoma, mixed medullary and papillary carcinoma, mucinous carcinoma, mucoepidermoid carcinoma, multinodular goiter, myxedema, neoplasms, neurologic cretinism, nonspecific lymphocytic (simple chronic) thyroiditis, oncocytic variant of medullary carcinoma, palpation thyroiditis, papillary carcinoma, papillary microcarcinoma, papillary variant of medullary carcinoma, partial agenesis, pituitary thyrotropic adenoma, poorly differentiated carcinoma, primary hypothyroidism, pseudopapillary variant of medullary carcinoma, Riedel's thyroiditis, sclerosing mucoepidermoid carcinoma with eosinophilia, silent thyroiditis, simple adenoma, small cell variant of medullary carcinoma, solitary thyroid nodule, sporadic goiter, squamous cell carcinoma, squamous variant of medullary carcinoma, subacute throiditis (DeQuervain, granulomatous, giant cell thyroiditis), tall cell variant of papillary carcinoma, tertiary syphilis, thyroglossal duct cyst, thyroid agenesis, thyroid nodules, thyroiditis, thyrotoxicosis, toxic adenoma, toxic multinodular goiter, toxic nodular goiter (Plummer's disease), tuberculosis, tubular variant of medullary carcinoma, and widely invasive follicular carcinoma.
380. The method of any of claims 109-114, 199-201, and 325-330, wherein said disease or disorder of the uteras is selected from the group consisting of acute cervicitis, acute endometritis, adenocanthoma, adenocarcinoma, adenocarcinoma in situ, adenoid cystic carcinoma, adenomatoid tumor, adenomyoma, adenomyosis (endometriosis intema), adenosquamous carcinoma, amebiasis, arias-Stella phenomenon, atrophy of the endometrium, atypical hypeφlasia, benign polypoid lesions, benign stromal nodule, carcinoid tumors, carcinoma in situ, cervical intraepithelial neoplasia, chlamydia, clironic cervicitis, chronic nonspecific endometritis, ciliated (tubal) metaplasia, clear cell adenocarcinoma, clear cell carcinoma, clear cell metaplasia, complex hypeφlasia with atypia, complex hypeφlasia without atypia, condyloma aduminatum, congenital abnormalities, coφus cancer syndrome, cystic hypeφlasia, dysfunctional uterine bleeding, dysmenonhea, dysplasia of the cervix (cervical intraepithelial neoplasia, squamous intraepithelial lesion), endocervical adenocarcinoma, endocervical polyp, endolymphatic stromal myosis, endometrial adenocarcinoma, endometrial carcinoma, endometrial hypeφlasia, endometrial polyps, endometrial stromal neoplasms, endometriosis, endometritis, endometroid (pure) adenocarcinoma of the endometrium, endometroid adenocarcinoma with squamous differentiation, eosinophilic metaplasia, epimenonhea, exogenous progestational hormone effect, extrauterine endometriosis (endometriosis externia), gestational trophoplastic disease, gononhea, hemangioma, heφes simplex virus type 2, high-grade squamous intraepithelial lesion, human papillomaviras, hypeφlasia, inadequate luteal phase, infertility, inflammatory cervical lesions, inflammatory lesions of the endometrium, intravenous leiomyomatosis, invasive carcinoma of cervix, invasive squamous cell carcinoma, leiomyoma, leiomyosarcoma, lipoma, low-grade squamous intraepithelial lesion, malignant mixed mesodermal (Mϋllerian) tumor, menonhagia, metaplasia, metastasizing leiomyoma, metastatic carcinoma, microglandular hypeφlasia, microinvasive carcinoma, microinvasive squamous cell carcinoma, mucinous adenocarcinoma, mucinous metaplasia, neoplasms of the cervix, neoplasms of the endometrium, neoplasms of the myometrium, nonneoplastic cervical proliferations, papillary synctial metaplasia, papiUoma, pelvic inflammatory disease, peritoneal leiomyomatosis, persistent luteal phase, postmenopausal bleeding, serous papillary adenocarcinoma, simple hypeφlasia with atypia, simple hypeφlasia without atypia, spontaneous abortion, squamous carcinoma, squamous cell neoplasia, squamous intraepithelial lesions, squamous metaplasia, squamous metaplasia (acanthosis), stromal sarcoma, tuberculous endometritis, unopposed estrogen effect, uterine leiomyomata, verrucou carcinoma, vestigial and heterotopic structures, villoglandular papillary adenocarcinoma, and viral endometritis.
381. The method of any of claims 115-120, 202-204, and 331-336, wherein said disease or disorder of the pancreas is selected from the group consisting of ACTHoma, acute pancreatitis, adult onset diabetes, annulare pancreas, carcinoid syndrome, carcinoid tumors, carcinoma of the pancreas, chronic pancreatitis, congenital cysts, Cushing's syndrome, cystadenocarcinoma, cystic fibrosis (mucoviscidosis, fibrocystic disease), diabetes mellitus, ectopic pancreatic tissue, gastinoma, gastrin excess, glucagon excess, glucagonomas, GRFomas, hereditary pancreatitis, hyperinsulinism, impaired insulin release, infected pancreatic necrosis, insulin resistance, insulinomas, islet cell hypeφlasia, islet cell neoplasms, juvenile onset diabetes, macroamylasemia, maldevelopment of the pancreas, maturity-onset diabetes of the young, metastatic neoplasms, mucinous cystadenoma, neoplastic cysts, nonfunctional pancreatic endocrine tumors, pancreas divisum, pancreatic abcess, pancreatic cancer, pancreatic cholera, pancreatic cysts, pancreatic endocrine tumor causing carcinoid syndrome, pancreatic endocrine tumor causing hypercalcemia, pancreatic endocrine tumors, pancreatic exocrine insufficiency, .pancreatic pleural effusion, pancreatic polypeptide excess, pancreatic pseudocyst, pancreatic trauma, pancreatogenous ascites, serous cystadenoma, Shwachman's syndrome, somatostatin excess, somatostatinoma syndrome, traumatic pancreatitis, type 1 (insulin-dependent) diabetes, type 2 (non-insulin-dependent) diabetes, vasoactive intestinal polypeptide excess, VIPomas, Zollinger-Ellison syndrome.
382. The method of any of claims 121-126, 205-207, and 337-342, wherein said disease or disorder of the bone and joints is selected from the group consisting of achondroplasia, acute bacterial arthritis, acute pyogenic osteomyelitis, Albright's syndrome, alkaptonuria (ochronosis), aneurysmal bone cyst, ankylosing spondyhtis, arthritic, arthropathies associated with hemoglobinopathies, arthropathy of acromegaly, arthropathy of hemocliromatosis, bone cysts, calcium hydroxyapatite deposition disease, calcium pyrophosphate deposition disease, chondrocalcinosis, chondroma, chondrosarcoma, chostochondritis, chrondromblastoma, congenital dislocation of the hip, congenital disorders of joints, echondromatosis (dyschondroplasia, OUier's disease), erosive osteoarthritis, Ewing's sarcoma, Felty's syndrome, fibromyalgia, fibrous cortical defect, fibrous dysplasia (McCune- Albright syndrome, fungal arthritis, ganglion, giant cell tumor, gout, hematogenous osteomyelitis, hemophilic arthropathy, hereditary hypeφhosphatasia, hyperostosis, hyperostosis frontalis intema, hypeφarathyroidism (osteitis fibrosa cystica), hypertrophic osteoarthropathy, infections diseases of joints, juvenile rheumatoid arthritis (Still's disease), lyme disease, lymphoid neoplasms, melorheostosis, metabolic diseases of joints, metastatic carcinoma, metastatic neoplasms, monostatic fibrous dysplasia, multiple exostoses (diaphyseal aclasis, osteochondromatosis), neoplasms, neuropathic joint (Charcot's joint), osteoarthritis, osteoarthrosis, osteoblastoma, osteochondroma- (exostosis), osteogenesis imperfecta (brittle bone disease), osteoid osteoma, osteoma, osteomalacia, osteomyelitis, osteomyelosclerosis, osteopetrosis (marbel bone disease, Albers-Schonberg disease), osteopoikilosis, osteoporosis (osteopenia), osteosarcoma, osteosclerosis, Paget's disease of bone (osteitis deformans), parasitic arthritis, parosteal osteosarcome, pigmented villonodular synovitis, polyostotic fibrous dysplasia, postmfectious or reactive arthritis, progressive diaphyseal dysplasia (Camurati-Engelmann disease), pseudogout, psoriatic arthritis, pyknodysostosis, pyogenic arthritis, reflex sympathetic dystrophy syndrome," relapsing polychondritis, rheumatoid arthritis, rickets, senile osteoporosis, sickle cell disease, spondyloepiphyseal dysplasia, synovial chondromatosis, synovial sarcoma, syphilitic arthritis, talipes calcaneovalgus, talipes equinovarus, thalassemia, Tietze's syndrome, tuberculosis of bone, tuberculous arthritis, unicameral bone cyst (solitary bone cyst), viral arthritis.
383. The method of any of claims 127-132, 208-210, and 343-348, wherein said disease or disorder of the breast is selected from the group consisting of acute mastitis, breast abcess, carcinoma, chronic mastitis, congenital breast anomalies, cystic mastopathy, ductal carcinoma, ductal carcinoma in situ, ductal papiUoma, fat necrosis, fibroadenoma, fibrocystic changes, fibrocystic disease, galactonhea, granular cell tumor, gynecomastia, infiltrating ductal carcinoma, inflammatory breast carcinoma, inflammatory breast lesions, invasive lobular carcinoma, juvenile hypertrophy of the breast, lactating adenoma, lobular carcinoma in situ, neoplasms, Paget's disease of the nipple, phyllodes tumor (cystosarcome phyllodes), polymastia, polymazia, polythelia, silicone granuloma, supernumerary breast, and supernumerary nipples.
384. The method of any of claims 133-138, 211-213, and 349-354, wherein said disease or disorder of the immune system is selected from the group consisting of abnormal neutrophil function, acquired immunodeficiency, acute rejection, Addison's disease, advanced cancer, aging, allergic rhinitis, angioedema, arthras-type hypersensitivity reaction, ataxia-telangiectasia, autoimmune disorders, autoimmune gastritis, autosomal recessive agammaglobulinemia, blood transfusion reactions, Bloom's syndrome, Braton's congenital agammaglobulinemia, bullous pemphigoid,
' Chediak-Higashi syndrome, chronic active hepatitis, chronic granulomatous disease of childhood, chronic rejection, chronic renal failure, common variable immunodeficiency, complement deficiency, congenital (primary) immunodeficiency, contact dermatitis, deficiencies of immune response, deficiency of the vascular response, dermatomyositis, diabetes mellitus, disorders of microbial killing, disorders of phagocytosis, Goodpasture's syndrome, graft rejection, graft-versus-host disease, granulocyt deficiency, granulocytic leukemia, Graves' disease, Hashimoto's thyroiditis, hemolytic anemia, hemolytic disease of the newborn, HIV infection (AIDS), Hodgkin's disease, hyperacute rejection, hyper-IgE syndrome, hypersensitivity pneumonitis, hypoparathyroidism, IgA deficiency, IgG subclass deficiencies, immunodeficiency with thymoma, immunoglobulin deficiency syndromes, immunologic hypersensitivity, immunosupressive drag therapy, infertility, insulin-resistant diabetes mellitus, interferon γ receptor deficiency, interleukin 12 receptor deficiency, iron deficiency, juvenile insulin-dependent diabetes mellitus, Kaposi's sarcoma, lazy leukocyte syndrom, localized type 1 hypersensitivity, lymphocytic leukemia, lymphoma, malignant B cell lymphoma, major histocompatibility complex class 2 deficiency, mixed connective tissue disease, multiple myeloma, myasthenia gravis, myeloperoxidase deficiency, neutropenia, nude syndrome, pemphigus vulgaris, pernicious anemia, postinfectious immunodeficiency, primary biliary cinhosis, primary immunodeficiency, primary T cell immunodeficiency, progressive systemic sclerosis, protein-calorie malnutrition, purine nucleoside phosphorylation deficiency, rheumatic fever, rheumatoid arthritis, secondary immunodeficiency, selective (isolated) IgA deficiency, serum sickness type hypersensitivity reaction, severe combined immunodeficiency, Sjδgren's syndrome, sympathetic ophthalmitis, systemic lupus erythematosus, systemic mastocytosis, systemic type 1 hypersensitivity, T cell receptor deficiency, T lymphopenia (Nezelof s syndrome), thrombocytopenia, thymic hypoplasia (DiGeorge syndrome), thymic neoplasms, thymoma (Goode's syndrome), transient hypogammaglobulinemia of infancy, type 1 (immediate) hypersensitivity (atopy, anaphylaxis), type 2 hypersensitivity, type 3 hypersensitivity (immune complex injury), type 4 (delayed) hypersensitivity, urticaria, variable immunodeficiency, vitiligo, Wiskott-Aldrich syndrom, x-linked agammaglobulinemia, x-linked immunodeficiency with hyper IgM, x-linked lymphoproliferative syndrome, zap70 tyrosine kinase deficiency.
385. The method of any of claims 139-144, 214-216, and 355-360, wherein said metabolic or nutritive disease or disorder is selected from the group consisting of 5,10- methylenetetrahydrofolate reductase deficiency, achondrogenesis type IB, acid α-1,4 glucosidase deficiency, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Banaquer-Simons syndrome), acute intermittent poφhyria, acute panniculitis, adenine phosphoribosyltransferase deficiency, adenosine deaminase deficiency, adenylosuccinate lyase deficiency, adiposis dolorosa (Dercum disease), ALA dehydratase-deficient poφhyria, albinism, alkaptonuria, amulopectinosis, Andersen disease, argininemia, argininosuccinic aciduria, astelosteogenesis type 2, Bartter's syndrome, benign familial neonatal epilepsy, benign fructosuria, benign recunent and progressive familial intrahepatic cholestasis, biotin deficiency, branching enzyme deficiency, calcium deficiency, carnitine transport defect, choline deficiency, choline toxicity, chromium deficiency, chronic fat malabsoφtion, citrallinemia, classic branched-chain ketoaciduria, classic cystinuria, congenital chloridonhea, congenital erythropoietic poφhyria, congenital generalized lipodystrophy, congenital myotonia, copper deficiency, copper toxicity, cystathionine β-synthase deficiency, cystathioninuria, cystic fibrosis, cystinosis, cystinuria, Darier disease, defect in transport of long-chain fatty acids, deficiency of cobalamin coenzyme deficiency, Dent's syndrome, diatrophic dysplasia, dibasic aminoaciduria, dicarboxylic aminoaciduria, dihydropyrimidine dehydrogenase deficiency, distal renal tubular acidosis, dry beriberi, Dubin- Johnson syndrome, dysbetalipoproteinemia, end-organ insensitivity to vitamin D, erythropoietic protopoφhyria, Fabry disease, failure of intestinal absoφtion, familial apoprotein C2 deficiency, familial combined hyperlipidemia, familial defective Apo B100, familial goiter, familial hypercholesterolemia, familial hypertriglyceridemia, familial hypophosphatemic rickets, familial lipoprotein lipase deficiency, familial partial lipodystrophy, Fanconi-Bickel syndrome, fluoride deficiency, folate malabsoφtion, folic adic deficiency, formiminoglutamic aciduria, fructose 1 ,6 diphosphatase deficiency, galactokinase deficiency, galactose 1 -phosphate uridyl transferase deficiency galactosemia, Gaucher disease, Gitelman's syndrome, globoid cell leukodystrophy, glucose-6-phosphatease deficiency, glucose-6-translocase deficiency, glucose-galactose malabsoφtion, glucose-transporter protein syndrome, glutaric aciduria, glycogen storage disease type 2, glycogen storage disease type lb, glycogen storage disease type ID, glycogen synthase deficiency, gout, Hartnup disease, hawkinsinuria, hemocliromatosis, hepatic glycogenosis with renal fanconi syndrome, hepatic lipase deficiency, hepatic poφhyria, hereditary copropoφhyria, hereditary fructose intolerance, hereditary xanthinuria, Hers disease, histidinemia, histidinuria, HIV-1 protease inhibitor-induced lipodystrophy, homocitrallinuria, homocystinuria, homocystinuria, homocystinuria and methylmalonic acidemia, homocystinurias, Hunter syndrome, Hurler disease, Hurler- Scheie disease, hyophosphatemic rickets, hyperammonemia, hyperammonemia, hypercholesterolemia, hypercystinuria, hyperglycinemia, hyperhydroxyprolinemia, hyperkalemic periodic paralysis, hyperleucmeisoleucinemia, hyperlipoprotememias, hyperlysinemia, hypermagnesemia, hypermetabolism, hypermethioninemia, hyperomithinemia, hyperoxaluria, hypeφhenylalaninemia with primapterinuria, hypeφhenylalaninemias, hypeφhosphatemia, hypeφrolinemia, hypertriglyceridemia, hyperuricemia, hypervalinemia, hypervitaminosis A, hypervitaminosis D, hypocholesterolemia, hypometabolism, hypophosphatemia, hypouricemia, hypovitaminosis A, hypoxanthine phosphoribosyltransferase deficiency, iminoglycinuria, iminopeptiduria, intermittent branched-chain ketoaciduria, intestinal malabsoφtion, iodine deficiency, iron deficiency, isovaleric acidemia, Jervell and Lange-Nielsen syndrome, juvenile pernicious anemia, keshan disease, Korsakoff s syndrome, kwashiorkor, leukodysfrophies, Liddle's syndrome, lipodystrophies, lipomatosis, liver glycogenoses, liver phosphorylase kinase deficiency, long QT syndrome, lysinuria, lysosomal storage diseases, magnesium deficiency, malabsoφtive diseases, malignant hypeφhenylalaninemia, manganese deficiency, marasmus, Maroteaux-Lamy disease, McArdle disease, Mefrkes' disease, metachromatic leukodystrophy, methionine malabsoφtion, methylmalonic acidemia, molybdenum deficiency, monosodiumurate gout, Morquio syndrome, mucolipidoses, mucopolysaccharidoses, multiple carboxylase deficiency syndrome, multiple symmetric lipomatosis (Madelung disease, muscle glycogenoses, muscle phosphofructokinase deficiency, muscle phosphorylase deficiency, myoadenylate deaminase deficiency, nephrogenic diabetes insipidus, nesidioblastosis of pancreas, niacin deficiency, niacin toxicity, Niemann-Pick disease, obesity, orotic aciduria, osteomalacia, paramyotonia congenita, pellagra, Pendred syndrome, phenylketonuria, phenylketonuria type 1, phenylketonuria type 2, phenylketonuria type 3, phosphate deficiency, phosphoribosylpyrophosphate synthetase overactivity, polygenic hypercholesterolemia, Pompe disease, poφhyria cutanea tarda, poφhyrias, primary bile acid malabsoφtion, primary hyperoxaluria, primary hypoalphalipoproteinemia, propionic acidemia, protein- energy malnutrition, proximal renal tubular acidosis, purine nucleoside phosphorylase deficiency, pyridoxine deficiency, pyrimidine 5'-nucleotidase deficiency, renal glycosuria, riboflavin deficiency, rickets, Rogers' syndrome, saccharopinuria, Sandhoff disease, Sanfilippo syndromes, sarcosinemia, Scheie disease, scurvy (vitamin C deficiency), selenium deficiency, selenosis, sialic acid storage disease, S-sulfo-L- cysteine, sulfite, thiosulfaturia, Tarai disease, Tay-Sachs disease, thiamine deficiency, tryptophan malabsoφtion, tryptophanuria, type 1 pseudohypoaldosteromsm, type 3 glycogen storage disease (debrancher deficiency, limit dextrinosis), tyrosinemia, tyrosinemia type 1, tyrosinemia type 2, tyrosinemia type 3, uridine diphosphate galactose 4-epimerase deficiency, urocanic aciduria, variegate poφhyria, vitamin B12 deficiency, vitamin C toxicity, vitamin D deficiency, vitamin D-resistant rickets, vitamin d-sensitive rickets, vitamin E deficiency, vitamin E toxicity, vitamin K deficiency, vitamin K toxicity, von Gierke disease, Wernicke's encephalopathy, wet beriberi, Wilson's disease, xanthurenic aciduria, X-linked sideroblastic anemia, zinc deficiency, zinc toxicity, α-ketoadipic aciduria, α-methylacetoacetic aciduria, β-hydroxy-β- methylglutaric aciduria, β-methylcrotonyl glycinuria.
386. A mouse comprising a mutation in a gene encoding a polypeptide that is substantially identical to a polypeptide listed in Table 1.
387. The mouse of claim 386, wherein said mutation is a conditional mutation.
388. The mouse of claim 386, wherein said mutation comprises a deletion of all or a portion of said gene.
389. The mouse of claim 386, wherein said mutation comprises an insertion that disrupts the transcription of the RNA encoding said polypeptide or translation of said polypeptide.
390. The mouse of claim 386, wherein said mutation comprises a point mutation.
391. The mouse of claim 386, wherein said mutation causes over expression of the gene.
392. The mouse of any of claims 386-391, wherein said mutation is in the coding region of said gene.
393. The mouse of any of claims 386-391, wherein said mutation is in the non- coding region of said gene.
394. The mouse of claim 386, wherein said mutation is a dominant-negative mutation.
395. A method of making a mouse exl ibiting altered behavior, said method comprising the step of introducing into said mouse a mutation in a gene encoding a polypeptide comprising a polypeptide listed in any one of Tables 3-14.
396. The method of claim 395, wherein said mutation is a conditional mutation.
397. The method of claim 395, wherein said mutation comprises a deletion of all or a portion of said gene.
398. The method of claim 395, wherein said mutation comprises an insertion that disrupts the transcription of the RNA encoding said polypeptide or translation of said polypeptide.
399. The method of claim 395, wherein said mutation comprises a point mutation.
400. The method of claim 395 wherein said mutation is a dominant-negative mutation.
401. The method of claim 395 wherein said mutation causes over expression of the gene.
402. The method of any of claims 395-401, wherein said mutation is in the coding region of said gene.
403. The method of any of claims 395-401, wherein said mutation is in the non- coding region of said gene.
404. A cell isolated from a non-human mammal comprising a transgene comprising a nucleic acid molecule encoding a nuclear receptor related polypeptide.
405. The cell of claim 404, wherein said non-human mammal is a mouse.
406. A cell isolated from a non-human mammal comprising a mutation in a gene encoding a polypeptide that is substantially identical to a polypeptide listed in Table 1.
407. The cell of claim 406, wherein said non-human mammal is a mouse.
408. The cell of claim 406, wherein said mutation is a conditional mutation.
409. The cell of claim 406, wherein said mutation comprises a deletion of all or a portion of said gene.
410. The mouse of claim 406, wherein said mutation comprises an insertion that disrapts the franscription of the RNA encoding said polypeptide or translation of said polypeptide.
411. The cell of claim 406, wherein said mutation comprises a point mutation.
412. The cell of any of claims 408-411, wherein said mutation is in the coding region of said gene.
413. The cell of any of claims 408-411 , wherein said mutation is in the non- coding region of said gene.
414. The cell of claim 406, wherein said mutation is a dominant-negative mutation.
415. The cell of claim 406, wherein said mutation causes over expression of the gene.
416. A transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1.
417. The transgenic mouse of claim 416, wherein said transgene comprises a mutation.
418. The mouse of claim 417, wherein said mutation is a conditional mutation.
419. The mouse of claim 417, wherein said mutation comprises a deletion of all or a portion of said gene.
420. The mouse of claim 417, wherein said mutation comprises an insertion that disrapts the franscription of the RNA encoding said polypeptide or translation of said polypeptide.
421. The mouse of claim 417, wherein said mutation comprises a point mutation.
422. The mouse of claim 417, wherein said mutation is a dominant-negative mutation.
423. The fransgenic mouse of claim 416, wherein said transgene is overexpressed.
424. The fransgenic mouse of claim 416, wherein said transgene is operably linked to an inducible promoter.
425. The transgenic mouse of claim 416, wherein said transgene is operably linked to a cell-type or tissue-specific promoter.
426. A transgenic mouse expressing a transgene encoding a mouse nuclear receptor polypeptide listed in Table 1.
427. The transgenic mouse of claim 426, wherein said transgene comprises a mutation.
428. The mouse of claim 427, wherein said mutation is a conditional mutation.
429. The mouse of claim 427, wherein said mutation comprises a deletion of all or a portion of said gene.
430. The mouse of claim 427, wherein said mutation comprises an insertion that disrupts the transcription of the RNA encoding said polypeptide or translation of said polypeptide.
431. The mouse of claim 427, wherein said mutation comprises a point mutation.
432. The mouse of claim 427, wherein said mutation is a dominant-negative mutation.
433. The transgenic mouse of claim 426, wherein said transgene is overexpressed.
434. The transgenic mouse of any of claims 416-432, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
435. A cell derived from the transgenic mouse of any of claims 416-434.
436. A method for identifying a compound that may be useful for the treatment of a neurological disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in any one of Tables 3-14; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a neurological disease or disorder.
437. The method of claim 436, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
438. A method for identifying a compound that may be useful for the treatment of a neurological disease or disorder, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing in one its neurological tissues a transgene encoding a human nuclear receptor polypeptide listed in any one of Tables 3- 14, said mouse having a neurological disease or disorder; and determining whether said candidate compound treats said neurological disease or disorder.
439. A method for identifying a compound that may be useful for the freatment of a neurological disease or disorder, said method comprising the steps of contacting a candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in any one of Tables 3-14; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a neurological disease or disorder.
440. The method of claim 439, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
441. A method for identifying a compound that may be useful for the treatment of a neurological disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 3-14; and detennining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a neurological disease or disorder.
442. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the adrenal gland, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 15; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the adrenal gland.
443. The method of claim 442, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
444. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the adrenal gland, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its adrenal gland a transgene encoding a human nuclear receptor polypeptide listed in Table 15, said mouse having a disease or disorder of the adrenal gland; and determining whether said candidate compound treats said disease or disorder of the adrenal gland.
445. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the adrenal gland, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 15; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the adrenal gland.
446. The method of claim 445, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
447. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the adrenal gland, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 15; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the adrenal gland.
448. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the colon, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 16; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the colon.
449. The method of claim 448, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
450. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the colon, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its colon a transgene encoding a human nuclear receptor polypeptide listed in Table 16, said mouse having a disease or disorder of the colon; and determining whether said candidate compound treats said disease or disorder of the colon.
451. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the colon, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 16; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the colon.
452. The method of claim 451 , wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
453. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the colon, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 16; and detem ining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the colon.
454. A method for identifying a compound that may be useful for the treatment of a cardiovascular disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 17; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a cardiovascular disease or disorder.
455. The method of claim 454, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
456. A method for identifying a compound that may be useful for the treatment of a cardiovascular disease or disorder, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing in its cardiovascular system a transgene encoding a human nuclear receptor polypeptide listed in Table 17, said mouse having a cardiovascular disease or disorder; and determining whether said candidate compound treats said cardiovascular disease or disorder.
457. A method for identifying a compound that may be useful for the treatment of a cardiovascular disease or disorder, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 17; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a cardiovascular disease or disorder.
458. The method of claim 457, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
459. A method for identifying a compound that may be useful for the treatment of a cardiovascular disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 17; and deteπ ining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease cardiovascular disease or disorder.
460. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the intestine, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 18; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the intestine.
461. The method of claim 460, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
462. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the intestine, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its intestine a transgene encoding a human nuclear receptor polypeptide listed in Table 18, said mouse having a disease or disorder of the intestine; and determining whether said candidate compound treats said disease or disorder of the intestine.
463. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the intestine, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 18; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a disease or disorder of the intestine.
464. The method of claim 463, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
465. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the intestine, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 18; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the intestine.
466. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the kidney, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 19; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the kidney.
467. The method of claim 466, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
468. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the kidney, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing in its kidney a transgene encoding a human nuclear receptor polypeptide listed in Table 19, said mouse having a disease or disorder of the kidney; and determining whether said candidate compound treats said disease or disorder of the kidney.
469. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the kidney, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 19; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the kidney.
470. The method of claim 469, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
471. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the kidney, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 19; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the kidney.
472. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the liver, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a fransgene encoding a human nuclear receptor polypeptide listed in Table 20; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the liver.
473. The method of claim 472, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
474. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the liver, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its liver a fransgene encoding a human nuclear receptor polypeptide listed in Table 20, said mouse having a disease or disorder of the liver; and detemiining whether said candidate compound treats said disease or disorder of the liver.
475. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the liver, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 20; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the liver.
476. The method of claim 475, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
477. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the liver, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 20; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the liver.
478. A method for identifying a compound that may be useful for the freatment of a lung disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 21; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a lung disease or disorder.
479. The method of claim 478, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
480. A method for identifying a compound that may be useful for the treatment of a lung disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its lung a fransgene encoding a human nuclear receptor polypeptide listed in Table 21, said mouse having a lung disease or disorder; and determining whether said candidate compound treats said lung disease or disorder.
481. A method for identifying a compound that may be useful for the freatment of a lung disease or disorder, said method comprising the steps of contacting candidate compound with a cell from a fransgenic mouse expressing a fransgene encoding a human nuclear receptor polypeptide listed in Table 21; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a lung disease or disorder.
482. The method of claim 481, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
483. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the lung, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 21; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a disease or disorder of the lung.
484. A method for identifying a compound that may be useful for the freatment of a muscular disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a fransgene encoding a human nuclear receptor polypeptide listed in Table 22; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a muscular disease or disorder.
485. The method of claim 484, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
486. A method for identifying a compound that may be useful for the treatment of a muscular disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its muscular tissue a transgene encoding a human nuclear receptor polypeptide listed in Table 22, said mouse having a muscular disease or disorder; and determining whether said candidate compound treats said muscular disease or disorder.
487. A method for identifying a compound that may be useful for the treatment of a muscular disease or disorder, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 22; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a muscular disease or disorder.
488. The method of claim 487, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
489. A method for identifying a compound that may be useful for the treatment of a muscular disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 22; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a muscular disease or disorder.
490. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the ovary, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 23; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a disease or disorder of the ovary.
491. The method of claim 490, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
492. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the ovary, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing in its ovary a fransgene encoding a human nuclear receptor polypeptide listed in Table 23, said mouse having a disease or disorder of the ovary; and determining whether said candidate compound treats said disease or disorder of the ovary.
493. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the ovary, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 23; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the ovary.
494. The method of claim 493, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
495. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the ovary, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 23; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherem an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the ovary.
496. A method for identifying a compound that may be useful for the freatment of a blood disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a fransgene encoding a human nuclear receptor polypeptide listed in Table 24; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a blood disease or disorder.
497. The method of claim 496, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
498. A method for identifying a compound that may be useful for the treatment of a blood disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its peripheral blood lymphocytes a transgene encoding a human nuclear receptor polypeptide listed in Table 24, said mouse having a blood disease or disorder; and determining whether said candidate compound treats said blood disease or disorder.
499. A method for identifying a compound that may be useful for the treatment of a blood disease or disorder, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 24; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a blood disease or disorder.
500. The method of claim 499, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
501. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the blood, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 24; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the blood.
502. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the prostate, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 25; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the prostate.
503. The method of claim 502, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
504. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the prostate, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its prostate a transgene encoding a human nuclear receptor polypeptide listed in Table 25, said mouse having a disease or disorder of the prostate; and determining whether said candidate compound treats said disease or disorder of the prostate.
505. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the prostate, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 25; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the prostate.
506. The method of claim 505, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
507. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the prostate said method comprising the steps of admimstering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 25; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the prostate.
508. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the skin, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 26; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the skin.
509. The method of claim 508, wherem said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
510. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the skin, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its skin a transgene encoding a human nuclear receptor polypeptide listed in Table 26, said mouse having a disease or disorder of the skin; and determining whether said candidate compound treats said disease or disorder of the skin.
511. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the skin, said method comprising the steps of contacting candidate compound with a cell from a fransgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 26; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a disease or disorder of the skin.
512. The method of claim 511, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
513. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the skin, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Table 26; and detemiining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the skin.
514. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the spleen, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 27; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the spleen.
515. The method of claim 514, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
516. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the spleen, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its spleen a fransgene encoding a human nuclear receptor polypeptide listed in Table 27, said mouse having a disease or disorder of the spleen; and determining whether said candidate compound treats said disease or disorder of the spleen.
517. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the spleen, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 27; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the spleen.
518. The method of claim 517, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
519. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the spleen, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Tables 27; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the spleen.
520. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the stomach, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 28; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the stomach.
521. The method of claim 520 wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
522. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the stomach, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its stomach a transgene encoding a human nuclear receptor polypeptide listed in Table 28, said mouse having a disease or disorder of the stomach; and determining whether said candidate compound treats said disease or disorder of the stomach.
523. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the stomach, said method comprising the steps of contacting candidate compound with a cell from a fransgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 28; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a disease or disorder of the stomach.
524. The method of claim 523, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
525. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the stomach, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Table 28; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the stomach.
526. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the testes, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 29; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the testes.
527. The method of claim 526, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
528. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the testes, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its testes a transgene encoding a human nuclear receptor polypeptide listed in Table 29, said mouse having a disease or disorder of the testes; and determining whether said candidate compound treats said disease or disorder of the testes.
529. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the testes, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 29; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the testes.
530. The method of claim 529, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
531. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the testes, said method comprising the steps of administering a candidate compound to a fransgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Table 29; and detenmning whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the testes.
532. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the thymus, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 30; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the thymus.
533. The method of claim 532, wherem said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
534. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the thymus, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its thymus a transgene encoding a human nuclear receptor polypeptide listed in Table 30, said mouse having a disease or disorder of the thymus; and determining whether said candidate compound treats said disease or disorder of the thymus.
535. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the thymus, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 30; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the thymus.
536. The method of claim 535, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
537. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the thymus, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Table 30; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a disease or disorder of the thymus.
538. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the thyroid, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 31; and detemiining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the thyroid.
539. The method of claim 538, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
540. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the thyroid, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing in its thyroid a transgene encoding a human nuclear receptor polypeptide listed in Table 31 , said mouse having a disease or disorder of the thyroid; and determining whether said candidate compound treats said disease or disorder of the thyroid.
541. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the thyroid, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 31; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the thyroid.
542. The method of claim 541, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
543. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the thyroid, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Table 31; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the thyroid.
544. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the uteras, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 32; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the uteras.
545. The method of claim 544, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
546. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the uterus, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its uteras a transgene encoding a human nuclear receptor polypeptide listed in Table 32, said mouse having a disease or disorder of the uteras; and determining whether said candidate compound treats said disease or disorder of the uteras.
547. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the uterus, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 32; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the uteras.
548. The method of claim 547, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
549. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the uteras, said method comprising the steps of administering a candidate compound to a transgenic mouse comprising a mutation in a nuclear receptor polypeptide listed in Table 32; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein an alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the uteras.
550. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the pancreas, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1 ; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the pancreas.
551. The method of claim 550, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
552. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the pancreas, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its pancreas a transgene encoding a human nuclear receptor polypeptide listed in Table 1 , said mouse having a disease or disorder of the pancreas; and detemiining whether said candidate compound treats said disease or disorder of the pancreas.
553. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the pancreas, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a fransgene encoding a human nuclear receptor polypeptide listed in Table 1 ; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the pancreas.
554. The method of claim 553, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
555. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the bone and joints, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1 ; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the bone and joints.
556. The method of claim 555, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
557. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the bone and joints, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its bone and joints a transgene encoding a human nuclear receptor polypeptide listed in Table 1, said mouse having a disease or disorder of the bone and joints; and determining whether said candidate compound treats said disease or disorder of the bone and joints.
558. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the bone and joints, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1 ; and detemiining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a disease or disorder of the bone and joints.
559. The method of claim 558, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
560. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the breast, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1 ; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the breast.
561. The method of claim 560, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
562. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the breast, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its breast a transgene encoding a human nuclear receptor polypeptide listed in Table 1 , said mouse having a disease or disorder of the breast; and determining whether said candidate compound treats said disease or disorder of the breast.
563. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the breast, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the breast.
564. The method of claim 563, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
565. A method for identifying a compound that may be useful for the treatment of a disease or disorder of the immune system, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the immune system.
566. The method of claim 565, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
567. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the immune system, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing in its immune system a transgene encoding a human nuclear receptor polypeptide listed in Table 1, said mouse having a disease or disorder of the immune system; and determining whether said candidate compound treats said disease or disorder of the immune system.
568. A method for identifying a compound that may be useful for the freatment of a disease or disorder of the immune system, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1 ; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a disease or disorder of the immune system.
569. The method of claim 568, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
570. A method for identifying a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder, said method comprising the steps of administering a candidate compound to a fransgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1 ; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder.
571. The method of claim 570, wherein said mouse has a mutation in the endogenous gene that is orthologous to said transgene.
572. A method for identifying a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic mouse expressing a fransgene encoding a human nuclear receptor polypeptide listed in Table 1, said mouse having a metabolic or nutritive disease or disorder; and determining whether said candidate compound treats said metabolic or nutritive disease or disorder.
573. A method for identifying a compound that may be useful for the treatment of a metabolic or nutritive disease or disorder, said method comprising the steps of contacting candidate compound with a cell from a transgenic mouse expressing a transgene encoding a human nuclear receptor polypeptide listed in Table 1 ; and determining whether said candidate compound alters the biological activity of said nuclear receptor polypeptide, wherein a alteration in the biological activity of said nuclear receptor polypeptide identifies said candidate compound as a compound that may be useful for the freatment of a metabolic or nutritive disease or disorder.
574. The method of claim 573, wherein said mouse has a mutation in the endogenous gene that is orthologous to said fransgene.
575. The method of any one of claims 217-222, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said neurological disease or disorder.
576. The method of any one of claims 223-228, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the adrenal gland.
577. The method of any one of claims 229-234, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the colon.
578. The method of any one of claims 235-240, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said cardiovascular disease or disorder.
579. The method of any one of claims 241-246, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the intestine.
580. The method of any one of claims 247-252, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the kidney.
581. The method of any one of claims 253-258, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the liver.
582. The method of any one of claims 259-264, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said lung disease or disorder.
583. The method of any one of claims 265-270, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said muscular disease or disorder.
584. The method of any one of claims 271-276, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the ovary.
585. The method of any one of claims 277-282, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said blood disease or disorder.
586. The method of any one of claims 283-288, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the prostate.
587. The method of any one of claims 289-294, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the skin.
588. The method of any one of claims 295-300, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the spleen.
589. The method of any one of claims 301-306, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the stomach.
590. The method of any one of claims 307-312, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the testes.
591. The method of any one of claims 313-318, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the thymus.
592. The method of any one of claims 319-324, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the thyroid.
593. The method of any one of claims 325-330, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the uteras.
594. The method of any one of claims 331-336, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the pancreas.
595. The method of any one of claims 337-342, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the bone and joints.
596. The method of any one of claims 343-348, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the breast.
597. The method of any one of claims 349-354, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said disease or disorder of the immune system.
598. The method of any one of claims 355-360, further comprising the step of testing said identified candidate compound in a cell- or animal-based model for said metabolic or nutritive disease or disorder.
599. A kit comprising a plurality of polynucleotides, wherein each polynucleotide hybridizes under high stringency conditions to a nuclear receptor polynucleotide of Table 1, wherein at least 50 different polynucleotides, each capable of hybridizing under high stringency conditions to a different human nuclear receptor polynucleotide listed on Table 1 , are present in said kit.
600. A kit comprising a plurality of polynucleotides, wherein polynucleotides that hybridize under high stringency conditions, each to a different nuclear receptor polynucleotide listed on one of Tables 3-14, are present in said kit such that said kit comprises polynucleotides that collectively hybridize to each of said nuclear receptor polynucleotides listed on one of Tables 3-14.
601. A kit comprising a plurality of polynucleotides, wherein polynucleotides that hybridize under high stringency conditions, each to a different nuclear receptor polynucleotide listed on one of Tables 15-32, are present in said kit such that said kit comprises polynucleotides that collectively hybridize to each of said nuclear receptor polynucleotides listed on one of Tables 15-32.
602. A kit comprising a plurality of mice, each mouse having a mutation in a nuclear receptor polynucleotide of Table 1, wherein at least 50 mice, each having a mutation in a different nuclear receptor polynucleotide listed on Table 1, are present in said kit.
603. The kit of claim 602, further comprising a plurality of polynucleotides, wherein each polynucleotide hybridizes under high stringency conditions to a nuclear receptor polynucleotide of Table 1, wherein at least 50 different polynucleotides, each capable of hybridizing under high stringency conditions to a different mouse nuclear receptor polynucleotide listed on Table 1, are present in said kit.
604. A kit comprising a plurality of mice, each mouse having a mutation in a nuclear receptor polynucleotide, wherein, collectively, mice having a mutation in each nuclear receptor polynucleotide listed on one of Tables 3-14 are present in said kit.
605. A kit comprising a plurality of mice, each mouse having a mutation in a nuclear receptor polynucleotide, wherein, collectively, mice having a mutation in each nuclear receptor polynucleotide listed on one of Tables 15-32 are present in said kit.
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