US20080260744A1 - G protein coupled receptors and uses thereof - Google Patents

G protein coupled receptors and uses thereof Download PDF

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US20080260744A1
US20080260744A1 US11/940,917 US94091707A US2008260744A1 US 20080260744 A1 US20080260744 A1 US 20080260744A1 US 94091707 A US94091707 A US 94091707A US 2008260744 A1 US2008260744 A1 US 2008260744A1
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disorder
polypeptide
gpcr
disease
compound
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George A. Gaitanaris
John E. Bergmann
Alexander Gragerov
John Hohmann
Fusheng Li
Linda Madisen
Kellie L. Mcllwain
Maria N. Pavlova
Demetri Vassilatis
Hongkui Zeng
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Omeros Medical Systems Inc
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Priority to US46132903P priority
Priority to PCT/US2003/028226 priority patent/WO2004040000A2/en
Priority to US10/527,265 priority patent/US20060134109A1/en
Priority to US85947306P priority
Priority to US85947006P priority
Priority to US85946906P priority
Application filed by Omeros Medical Systems Inc filed Critical Omeros Medical Systems Inc
Priority to US11/940,917 priority patent/US20080260744A1/en
Assigned to OMEROS CORPORATION reassignment OMEROS CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LI, FUSHENG, VASSILATIS, DEMETRI, MADISEN, LINDA, HOHMANN, JOHN, GRAGEROV, ALEXANDER, ZENG, HONGKUI, BERGMANN, JOHN E., GAITANARIS, GEORGE A., PAVLOVA, MARIA N.
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    • G01N33/5023Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on expression patterns
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    • G01N2333/705Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00Detection or diagnosis of diseases
    • G01N2800/50Determining the risk of developing a disease

Abstract

The present invention provides GPCR 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 GPCR polypeptides and polynucleotides of the invention, and for treating conditions associated with GPCR dysfunction with the GPCR polypeptides, polynucleotides, or identified compounds. The invention also provides diagnostic assays for detecting diseases or disorders associated with inappropriate GPCR activity or levels.

Description

    CROSS-REFERENCES TO RELATED APPLICATIONS
  • This application is a continuation-in-part of U.S. patent application Ser. No. 10/527,265, filed Jan. 26, 2006, now pending, which is a U.S. national stage application of PCT Patent Application No. PCT/US03/28226, filed Sep. 9, 2003, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 60/409,303, filed Sep. 9, 2002, and U.S. Provisional Patent Application No. 60/461,329, filed Apr. 9, 2003. This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 60/859,469, filed Nov. 15, 2006, U.S. Provisional Patent Application No. 60/859,473, filed Nov. 15, 2006, and U.S. Provisional Patent Application No. 60/859,470, filed Nov. 15, 2006, where all of the above applications are incorporated herein by reference in their entireties.
  • STATEMENT REGARDING SEQUENCE LISTING
  • The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 700128401C1_SEQUENCE_LISTING.txt. The text file is 4,998 KB, was created on Nov. 15, 2007, and is being submitted electronically via EFS-Web, concurrent with the filing of the specification.
  • BACKGROUND OF THE INVENTION
  • The invention relates to the fields of medicine and drug discovery.
  • Mammalian G protein coupled receptors (GPCRs) constitute a superfamily of diverse proteins with thousands of members. GPCRs act as receptors for a multitude of different signals. Chemosensory GPCRs (csGPCR) are receptors for sensory signals of external origin that are sensed as odors, pheromones, or tastes. Most other GPCRs respond to endogenous signals, such as peptides, lipids, neurotransmitters, or nucleotides. GPCRs falling in the latter group are involved in numerous physiological processes, including the regulation of neuronal excitability, metabolism, reproduction, development, hormonal homeostasis, and behavior, and are differentially expressed in many cell types in the body.
  • Of all currently marketed drugs, greater than 30% are modulators of specific GPCRs. Only 10% of GPCRs (excluding csGPCRs) are targeted by these drugs, emphasizing the potential of the remaining 90% of the gene family for the treatment of human disease.
  • Despite the importance of GPCRs in physiology and disease, the size of the GPCR superfamily is still uncertain. Analyses of genome sequences have generated markedly varied estimates (Venter, J. C. et al., Science 291, 1304-51 (2001); Lander, E. S. et al., Nature 409, 860-921 (2001); Takeda, S. et al., FEBS Lett 520, 97-101 (2002)). In addition, while most GPCRs are known to be selectively expressed in subsets of cells, the expression patterns of most GPCRs are incomplete or unknown. Thus, there is a need for GPCR 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 GPCR 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 GPCR polypeptides and polynucleotides of the invention, and for treating conditions associated with GPCR dysfunction with the GPCR polypeptides, polynucleotides, or identified compounds. The invention also provides diagnostic assays for detecting diseases or disorders associated with inappropriate GPCR activity or levels.
  • In one aspect, the invention features a variety of substantially pure GPCR polypeptides. Such polypeptides include: (a) polypeptides including a polypeptide sequence having at least 90%, 95%, 97%, 98%, or 99% identity to a polypeptide listed in Table 2; (b) polypeptides that include a polypeptide listed in Table 2; (c) polypeptides having at least 90%, 95%, 97%, 98%, or 99% sequence identity to a polypeptide listed in Table 2; and (d) polypeptides listed in Table 2.
  • Polypeptides of the present invention also include variants of the aforementioned polypeptides, including all allelic forms and splice variants. Such polypeptides vary from the reference polypeptide by insertions, deletions, and substitutions that may be conservative or non-conservative, or any combination thereof. Particularly desirable variants are those in which several, for instance from 50 to 30, from 30 to 20, from 20 to 10, from 10 to 5, from 5 to 3, from 3 to 2, or from 2 to I amino acids are inserted, substituted, or deleted, in any combination.
  • Polypeptides of the present invention also include polypeptides that include an amino acid sequence having at least 30, 50, or 100 contiguous amino acids from any of the polypeptides listed in Table 2. Polypeptides of the invention are desirably biologically active or are antigenic or immunogenic in an animal, especially in a human.
  • The polypeptides of the present invention may be in the form of the “mature” polypeptide, or may be a part of a larger polypeptide such as a precursor or a fusion protein. It is often advantageous to include an additional amino acid sequence that contains secretory or leader sequences, pro-sequences, sequences that aid in purification, for instance multiple histidine residues, or an additional sequence for stability during recombinant production.
  • Polypeptides of the present invention can be prepared in any suitable manner, for instance by isolation from naturally occurring sources, from genetically engineered host cells comprising expression systems, or by chemical synthesis, using for instance automated peptide synthesizers, or a combination of such methods. For example, polypeptides of the invention may be produced by expressing in a cell (e.g., a yeast, bacterial, mammalian, or insect cell) a vector containing a polynucleotide that encodes a GPCR of the invention under condition in which the polypeptide (e.g., one listed in Table 2) is expressed. Means for preparing such polypeptides are well understood in the art.
  • In another aspect, the invention features substantially pure GPCR polynucleotides. Such polynucleotides include: (a) polynucleotides that include a polynucleotide sequence having at least 90%, 95%, 97%, 98%, or 99% sequence identity to a polynucleotide listed in Table 2; (b) polynucleotides that include a polynucleotide sequence having at least 90%, 95%, 97%, 98%, or 99% sequence identity to the reverse complement of polynucleotide listed in Table 2; (c) polynucleotides that include a polynucleotide listed in Table 2; (d) polynucleotides that are the reverse complement of polynucleotide listed in Table 2; (e) polynucleotides having at least 90%, 95%, 97%, 98%, or 99% sequence identity to a polynucleotide listed in Table 2; (f) polynucleotides having at least 90%, 95%, 97%, 98%, or 99% sequence identity to the reverse complement of polynucleotide listed in Table 2; (g) polynucleotides listed in Table 2; (h) reverse complement of polynucleotides listed in Table 2; (i) polynucleotides that include a polynucleotide sequence encoding a polypeptide sequence having at least 90%, 95%, 97%, 98%, or 99% identity to a polypeptide listed in Table 2; (j) polynucleotides including a nucleotide sequence encoding a polypeptide listed in Table 2; and (k) polynucleotides encoding a polypeptide listed in Table 2. Preferred GPCR polynucleotides of the present invention have at least 15, 30, 50 or 100 contiguous nucleotides from any of the polynucleotides listed in Table 2.
  • In one embodiment, the polynucleotide is operably linked to a promoter for expression of the polypeptide encoded by the polynucleotide. In certain embodiments, the promoter is a constitutive promoter, is inducible by one or more external agents, or is cell-type specific.
  • In another aspect, the invention features a vector that includes a GPCR polynucleotide of the invention, the vector being capable of directing expression of the polypeptide encoded by the polynucleotide in a vector-containing cell.
  • In another 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a neurological disease or disorder. The GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide in the transgenic non-human mammal, wherein altered biological activity, relative to that of the GPCR 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 GPCR polypeptide listed in any one of Tables 3-14 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Tables 3-14 and 33; (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 GPCR 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 and 33, 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 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in any one of Tables 3-14 and 33, wherein increased or decreased levels in the GPCR 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 and 33, 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.
  • 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 GPCR polypeptide listed in Tables 15 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 15 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 15 and 33; (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 GPCR 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 Tables 15 and 33, 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 Tables 15 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 15 and 33, wherein increased or decreased levels in the GPCR 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 Tables 15 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 16 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 16 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 16 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 16 and 33; (b) contacting the transgenic non-human mammal with the candidate compound;
  • and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 16 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 16 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 16 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 16 and 33; (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 GPCR 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 Tables 16 and 33, 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 Tables 16 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 16 and 33, wherein increased or decreased levels in the GPCR 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 Tables 16 and 33, 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 colon. Preferably, the expression levels are determined by measuring levels of polypeptide or mRNA.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 17 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 17 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 17 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a cardiovascular disease or disorder. The GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 17 and 33; (b) contacting the transgenic non-human mammal with the candidate compound, and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 17 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 17 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 17 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 17 and 33; (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 GPCR 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 Tables 17 and 33, 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 Tables 17 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 17 and 33, wherein increased or decreased levels in the GPCR 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 Tables 17 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 18 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 18 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 18 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 18 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 18 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPTR polypeptide listed in Tables 18 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 18 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 18 and 33; (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 GPCR 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 Tables 18 and 33, 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 Tables 18 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 18 and 33, wherein increased or decreased levels in the GPCR 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 Tables 18 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 19 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 19 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 19 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 19 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 19 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 19 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 19 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 19 and 33; (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 GPCR 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 Tables 19 and 33, 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 Tables 19 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 19 and 33, wherein increased or decreased levels in the GPCR 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 Tables 19 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 20 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 20 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 20 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 20 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 20 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 20 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 20 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 20 and 33; (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 GPCR 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 Tables 20 and 33, 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 Tables 20 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 20 and 33, wherein increased or decreased levels in the GPCR 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 Tables 20 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 21 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 21 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 21 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a lung disease or disorder. The GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 21 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 21 and 33; (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 GPCR polypeptide listed in Tables 21 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 21 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 21 and 33; (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 GPCR 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 Tables 21 and 33, 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 Tables 21 and 33, wherein 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 21 and 33, wherein increased or decreased levels in the GPCR 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 Tables 21 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 22 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 22 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 22 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a muscular disease or disorder. The GPCR 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 disruption in a nucleic acid molecule encoding a GPCR polypeptide substantially identical to a polypeptide listed in Tables 22 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 22 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 22 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 22 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 22 and 33; (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 GPCR 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 Tables 22 and 33, 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 Tables 22 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 22 and 33, wherein increased or decreased levels in the GPCR 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 Tables 22 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 23 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 23 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 23 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 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 disruption in a nucleic acid molecule encoding a GPCR polypeptide substantially identical to a polypeptide listed in Tables 23 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 23 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 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 GPCR polypeptide listed in Tables 23 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 23 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 23 and 33; (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 GPCR 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 Tables 23 and 33, 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 Tables 23 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 23 and 33, wherein increased or decreased levels in the GPCR-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 Tables 23 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 24 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 24 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 24 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a blood disease or disorder. The GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 24 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 24 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 24 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 24 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 24 and 33; (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 blood disease or disorder. Preferably the GPCR 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 Tables 24 and 33, 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 Tables 24 and 33, 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 GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 24 and 33, wherein increased or decreased levels in the GPCR 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 Tables 24 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 25 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 25 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 25 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 25 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 25 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 25 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 25 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 25 and 33; (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 GPCR 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 Tables 25 and 33, wherein 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 polymorphism in a gene encoding a polypeptide listed in Tables 25 and 33, wherein presence of the polymorphism 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 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 prostate. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 25 and 33, wherein increased or decreased levels in the GPCR 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 Tables 25 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 26 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 26 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 26 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR polypeptide not contacted with the compound, indicates that the candidate compound may be useful for the treatment of a skin disease or disorder. The GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 26 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 26 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 26 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 26 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 26 and 33; (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 GPCR 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 Tables 26 and 33, 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 polymorphism in a gene encoding a polypeptide listed in Tables 26 and 33, wherein presence of the polymorphism 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 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 skin disease or disorder. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 26 and 33, wherein increased or decreased levels in the GPCR 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 Tables 26 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 27 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 27 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 27 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 disruption in a nucleic acid molecule encoding a GPCR polypeptide substantially identical to a polypeptide listed in Tables 27 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 27 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 27 and 33, 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 may be useful for the treatment of a disease or disorder of the spleen. This method includes the steps of: (a) providing a GPCR polypeptide substantially identical to a polypeptide listed in Tables 27 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 27 and 33; (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 GPCR 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 Tables 27 and 33, 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 polymorphism in a gene encoding a polypeptide listed in Tables 27 and 33, wherein presence of the polymorphism 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 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 spleen. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 27 and 33, wherein increased or decreased levels in the GPCR 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 Tables 27 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 28 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 28 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 28 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 28 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 28 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 28 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 28 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 28 and 33; (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 GPCR 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 Tables 28 and 33, 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 polymorphism in a gene encoding a polypeptide listed in Tables 28 and 33, wherein presence of the polymorphism 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 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 stomach. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 28 and 33, wherein increased or decreased levels in the GPCR 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 Tables 28 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 29 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 29 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 29 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 29 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 29 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 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 GPCR polypeptide listed in Tables 29 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 29 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 29 and 33; (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 GPCR 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 Tables 29 and 33, 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 polymorphism in a gene encoding a polypeptide listed in Tables 29 and 33, wherein presence of the polymorphism 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 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 testes. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 29 and 33, wherein increased or decreased levels in the GPCR 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 determining 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 Tables 29 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 30 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 30 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 30 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 disruption in a nucleic acid molecule encoding a GPCR polypeptide substantially identical to a polypeptide listed in Tables 30 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 30 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide listed in Tables 30 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 30 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 30 and 33; (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 GPCR 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 Tables 30 and 33, 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 polymorphism in a gene encoding a polypeptide listed in Tables 30 and 33, wherein presence of the polymorphism 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 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 thymus. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 30 and 33, wherein increased or decreased levels in the GPCR 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 Tables 30 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 31 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 31 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 31 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 disruption in a nucleic acid molecule encoding a GPCR polypeptide substantially identical to a polypeptide listed in Tables 31 and 33; (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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 31 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 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 GPCR polypeptide listed in Tables 31 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 31 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 31 and 33; (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 GPCR 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 Tables 31 and 33, 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 polymorphism in a gene encoding a polypeptide listed in Tables 31 and 33, wherein presence of the polymorphism 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 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 thyroid. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 31 and 33, wherein increased or decreased levels in the GPCR 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 Tables 31 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 32 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 32 and 33.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 32 and 33; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 32 and 33; (b) contacting transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 32 and 33; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 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 nucleic acid molecule comprising a promoter from a gene encoding a GPCR polypeptide listed in Tables 32 and 33, 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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 32 and 33; (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 GPCR polypeptide substantially identical to a polypeptide listed in Tables 32 and 33; (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 GPCR 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 Tables 32 and 33, wherein presence of the mutation indicates that the patient may have an increased risk for developing a disease or disorder of the uterus.
  • 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 uterus. This method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in Tables 32 and 33, wherein presence of the polymorphism 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 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 uterus. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Tables 32 and 33, wherein increased or decreased levels in the GPCR 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 Tables 32 and 33, 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.
  • 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Table 32.
  • In another aspect, the invention features a cell from a non-human mammal having a mutation in a nucleic acid molecule encoding a GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 disruption in a nucleic acid molecule encoding a GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Table 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR 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 GPCR 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 GPCR 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 pancreas. Preferably the GPCR 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.
  • 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 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 pancreas.
  • 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 pancreas. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the GPCR biological activity, relative to normal levels, indicates that the patient has an increased risk for developing a disease or disorder of the pancreas.
  • 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 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.
  • 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Table I 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Table 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 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 bone and joints.
  • 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 bone and joints. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the GPCR 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.
  • 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Table 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 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 breast.
  • 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 breast. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the GPCR 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.
  • 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 GPCR polypeptide substantially identical to a polypeptide listed in Table I 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR 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 GPCR 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 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 mouse) overexpressing a nucleic acid molecule encoding a GPCR polypeptide substantially identical to a polypeptide listed in any one of Table 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR 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 GPCR 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 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 GPCR 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 GPCR 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 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 immune system.
  • 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 immune system. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the GPCR 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.
  • 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in Table 1; (b) contacting the GPCR polypeptide with the candidate compound; and (c) measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide substantially identical to a polypeptide listed in any one of Table 1; (b) contacting the transgenic non-human mammal with the candidate compound; and (c) measuring biological activity of the GPCR 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 GPCR 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 GPCR 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 GPCR 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 GPCR 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 determining 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 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 metabolic or nutritive 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 metabolic or nutritive disease or disorder. The method includes measuring biological activity of a GPCR polypeptide from the patient that is substantially identical to a polypeptide listed in Table 1, wherein increased or decreased levels in the GPCR 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.
  • In another aspect, the invention features a transgenic mouse expressing a transgene encoding a human GPCR 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 GPCR 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 GPCR 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 GPCR polypeptide listed in Table 1; and determining whether the candidate compound decreases the biological activity of the GPCR polypeptide, wherein a decrease in the biological activity of the GPCR 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 GPCR 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 transgenic 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 GPCR polypeptide in a gene listed in Table 1; and determining whether the candidate compound decreases the biological activity of the GPCR polypeptide. A decrease in the biological activity of the GPCR 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 GPCR 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 GPCR polynucleotide of Table 1. At least 50 different polynucleotides, each capable of hybridizing under high stringency conditions to a different human GPCR 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 GPCR polynucleotide listed on one of Tables 3-33, are present in the kit such that the kit includes polynucleotides that collectively hybridize to every GPCR polynucleotide listed on one of Tables 3-33.
  • The invention features another kit, this kit including a plurality of mice, each mouse having a mutation in a GPCR polynucleotide of Table 1, wherein at least 50 mice, each having a mutation in a different GPCR 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 GPCR polynucleotide of Table 1, wherein at least 50 different polynucleotides, each capable of hybridizing under high stringency conditions to a different mouse GPCR 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 GPCR polynucleotide. In this kit, mice having a mutation in each GPCR polynucleotide listed on one of Tables 3-33 are present in the kit.
  • In any of the foregoing kits, at least one of the GPCR polynucleotides is desirably a GPCR polynucleotide of Table 2.
  • In particular embodiment, the present invention provides methods of treating or preventing neurological and metabolic diseases and disorders, comprising administering to a patient a modulator of one or more G protein coupled receptors, including, e.g., GPR88, GPR 22, and the Super conserved Receptors Expressed in Brain (SREB) GPCRs. SREB GPCRs include GPR85 (SREB2), SREB3 (GPR173), and SREB1 (GPR27). In addition, the present invention provides related methods of diagnosing or detecting a neurological or metabolic disease or disorder, comprising measuring altered expression or activity of one or more G protein coupled receptors, or identifying a mutation in a one or more G protein coupled receptor genes, in a patient. The invention further provides related kits useful in the diagnosis and treatment of neurological and metabolic diseases and disorders.
  • In certain embodiments, the present invention includes a method of treating or preventing a neurological disease or disorder in a patient, said method comprising administering to said patient a first nucleic acid molecule encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558 or 484, or a variant or fragment thereof. In one embodiment, this method comprises administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558 or 484, or a variant or fragment thereof.
  • In a related embodiment, wherein said first nucleic acid molecule encodes a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, the above method further comprises administering a second nucleic acid molecule encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, or a variant or fragment thereof, wherein said first and second nucleic acid molecules encode different GPCR polypeptides. In one particular embodiment, the first and second nucleic acid molecules encode GPCR polypeptides having the amino acid sequences set forth in SEQ ID NO:488 and SEQ ID NO:552, respectively.
  • In another embodiment, the present invention includes a method of treating or preventing a neurological disease or disorder in a patient, said method comprising administering to said patient a first compound that modulates the biological activity or expression of a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484. In another embodiment, wherein said first nucleic acid molecule encodes a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, the method further comprises administering to said patient a second compound that modulates the biological activity or expression of a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second compounds modulate different GPCR polypeptides. In particular embodiments, said first or second compound is a nucleic acid molecule comprising a portion of the polynucleotide sequence set forth in any one of SEQ ID NOs:1046, 1014, 894, 1049, or 1012, or a complement thereof. In certain embodiments, the nucleic acid molecule may be a virus, plasmid, antisense RNA, ribozyme, or RNAi oligonucleotide. In other embodiments, the compound is an antibody that specifically binds a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, 243, 558, or 484. In yet another embodiment, the compound is a small molecule. In certain embodiments, said compound increases the biological activity or expression of a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, 243, 558, or 484. In other embodiments, said compound decreases the biological activity or expression of a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, 243, 558, or 484. In certain embodiments, two or more of such compounds are administered, wherein each binds a different polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243. In one embodiment, said first and second compounds modulate the biological activity or expression of GPCR polypeptides having the amino acid sequences set forth in SEQ ID NO:488 and SEQ ID NO:552, respectively.
  • In further related embodiments, the present invention includes methods for determining whether a patient has an increased risk for developing a neurological disease or disorder. In one embodiment, said method comprises determining the presence of a mutation or polymorphism in a first gene encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484 in a patient, wherein the presence of said mutation or polymorphism indicates that said patient has an increased risk for developing a neurological disease or disorder. In a related embodiment, wherein the first gene encodes a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, the method further comprises determining the presence of a mutation or polymorphism in a second gene encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second gene encode different GPCR polypeptides, and wherein the presence of mutations or polymorphisms in both genes indicates that said patient has an increased risk for developing a neurological disease or disorder.
  • In another embodiment, the method comprises measuring in said patient, or a biological sample obtained from said patient, the level of biological activity of a first GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484, wherein an altered level in said biological activity, relative to a normal control level, indicates that said patient has an increased risk for developing a neurological disease or disorder. In a related embodiment, wherein the first GPCR polypeptide has the amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, the method further comprises measuring in said patient, or a biological sample obtained from said patient, the level of biological activity of a second GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second GPCR polypeptides are different and wherein an altered level in biological activity of both the first and second GPCR polypeptides, relative to a normal control levels, indicates that said patient has an increased risk for developing a neurological disease or disorder.
  • In yet another embodiment, said method comprises measuring in said patient, or in a biological sample, e.g., cells, obtained from said patient, the level of expression of a first GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484, wherein an altered level in said expression, relative to a normal control level, indicates that said patient has an increased risk for developing a neurological disease or disorder. In a related embodiment, wherein the first GPCR polypeptide has the amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, the method further comprises measuring in said patient, or in a biological sample obtained from said patient, the expression of a second GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second GPCR polypeptide are different and wherein an altered level in expression of both GPCRs, relative to a normal control levels, indicates that said patient has an increased risk for developing a neurological disease or disorder. In one embodiment, expression is determined by measuring levels of said GPCR polypeptide. In particular embodiments, said expression is determined by measuring levels of RNA encoding said GPCR polypeptide.
  • The present invention also provides methods for identifying a compound for the treatment or prevention of a neurological disease or disorder, comprising: contacting a cell expressing a GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484 with a candidate compound; and measuring the biological activity or expression of said GPCR polypeptide expressed in said cell, wherein altered biological activity or expression of said GPCR polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound useful for the treatment of a neurological disease or disorder.
  • In a related embodiment, the present invention includes a method for identifying a compound for the treatment or prevention of a neurological disease or disorder, said method comprising: contacting a GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484 with a candidate compound; and determining whether said candidate compound binds to said GPCR polypeptide, wherein binding of said candidate compound to said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment or prevention of a neurological disease or disorder.
  • In a further related embodiment, the invention includes a method for identifying a compound for the treatment of a neurological disease or disorder, said method comprising administering a candidate compound to a transgenic animal expressing a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484; and determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein a alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a neurological disease or disorder. In one embodiment, said animal has a mutation in the endogenous gene that is orthologous to said transgene.
  • In yet a further embodiment, the present invention includes a method for identifying a compound for the treatment of a neurological disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic animal expressing in one of its neurological tissues a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484, said animal having a neurological disease or disorder; and determining whether said candidate compound treats said neurological disease or disorder.
  • In a related embodiment, the present invention provides a method for identifying a compound for the treatment of a neurological disease or disorder, said method comprising the steps of contacting a candidate compound with a cell from a transgenic animal expressing a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484; and determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein a alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a neurological disease or disorder.
  • In yet another embodiment, the present invention includes a method for identifying a compound for the treatment of a neurological disease or disorder, said method comprising administering a candidate compound to an animal comprising a mutation in a gene encoding a polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484; and determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein a alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a neurological disease or disorder.
  • Another embodiment of the present invention includes a method for identifying a compound for the treatment of a neurological disease or disorder, said method comprising the steps of administering a candidate compound to an animal comprising a mutation in a gene encoding a polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484, said animal having a neurological disease or disorder; and determining whether said candidate compound treats said neurological disease or disorder.
  • In a related embodiment, the present invention includes a method for identifying a compound for the treatment of a neurological disease or disorder, said method comprising the steps of contacting a candidate compound with a cell from an animal comprising a mutation in a gene encoding a polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484; and determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein a alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a neurological disease or disorder.
  • In a related embodiment, the invention further provides an animal model of a neurological disease or disorder, wherein said animal model is a non-human mammal comprising a mutation in a first gene encoding a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484, and wherein said non-human mammal exhibits one or more symptoms of a neurological disease or disorder. In another embodiment, wherein the first gene encodes a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, the mammal further comprises a mutation in a second gene encoding a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488 or 243, wherein said first and second genes are different.
  • In yet another related embodiment, the invention includes an animal model of a neurological disease or disorder, wherein said animal model is a non-human mammal comprising a first transgene encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484, and wherein said non-human mammal exhibits one or more symptoms of a neurological disease or disorder. In another embodiment, wherein the first transgene encodes a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:488 or 243, the mammal further comprises a second transgene encoding a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488 or 243, wherein said first and second genes are different.
  • In another embodiment, the present invention includes a cell isolated from a non-human mammal of the present invention.
  • In one embodiment, the present invention includes a kit for determining the presence of a neurological disease or disorder in a patient, wherein said kit comprises a first compound that specifically binds to a polynucleotide having the sequence set forth in any one of SEQ ID NOs:1014, 894, 1049, or 1012, or to a polypeptide having the sequence set forth in any one of SEQ ID NOs:488, 243, 558, or 484. In a related embodiment, wherein the first compound specifically binds to a polynucleotide having the sequence set forth in any one of SEQ ID NOs:1014 or 894 or to a polypeptide having the sequence set forth in any one of SEQ ID NOs:488 or 243, the kit further comprises a second compound that specifically binds to a polynucleotide having the sequence set forth in any on of SEQ ID NOs:1046, 1014, and 894 or to a polypeptide having the sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second compounds bind to different polypeptides or polynucleotides. In certain embodiments, the compound is labeled. The kit may further include one or more control samples.
  • In certain embodiments, the present invention includes a method of treating or preventing a metabolic disease or disorder in a patient, said method comprising administering to said patient a first nucleic acid molecule encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, or a variant or fragment thereof. In one embodiment, this method comprises administering to said patient an expression vector comprising a nucleic acid molecule operably linked to a promoter, said nucleic acid molecule encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, or a variant or fragment thereof. In a related embodiment, the method further comprises administering a second nucleic acid molecule encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, or a variant or fragment thereof, wherein said first and second nucleic acid molecules encode different GPCR polypeptides.
  • In related embodiments, the present invention includes a method of treating or preventing a metabolic disease or disorder in a patient, said method comprising administering to said patient a first compound that modulates the biological activity or expression of a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243. In another embodiment, the method further comprises administering to said patient a second compound that modulates the biological activity or expression of a GPCR polypeptide having the amino acid sequence set forth in any on of SEQ ID NOs:552, 488, or 243, wherein said first and second compounds modulate different GPCR polypeptides. In particular embodiments, said compound is a nucleic acid molecule comprising a portion of the polynucleotide sequence set forth in any one of SEQ ID NOs:1046, 1014, or 894, or a complement thereof. In certain embodiments, the nucleic acid molecule may be a virus, plasmid, antisense RNA, ribozyme, or RNAi oligonucleotide. In other embodiments, the compound is an antibody that specifically binds a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243. In yet another embodiment, the compound is a small molecule. In certain embodiments, said compound increases the biological activity or expression of a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243. In other embodiments, said compound decreases the biological activity or expression of a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243. In certain embodiments, two or more of such compounds are administered, wherein each binds a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243.
  • In further related embodiments, the present invention includes methods for determining whether a patient has an increased risk for developing a metabolic disease or disorder. In one embodiment, said method comprises determining the presence of a mutation or polymorphism in a first gene encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243 in a patient, wherein the presence of said mutation or polymorphism indicates that said patient has an increased risk for developing a metabolic disease or disorder. In a related embodiment, the method further comprises determining the presence of a mutation or polymorphism in a second gene encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second gene encode different GPCR polypeptides, and wherein the presence of mutations or polymorphisms in both genes indicates that said patient has an increased risk for developing a metabolic disease or disorder.
  • In another embodiment, the method comprises measuring in said patient, or a biological sample obtained from said patient, the level of biological activity of a first GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein an altered level in said biological activity, relative to a normal control level, indicates that said patient has an increased risk for developing a metabolic disease or disorder. In a related embodiment, the method further comprises measuring in said patient, or a biological sample obtained from said patient, the level of biological activity of a second GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second GPCR polypeptides are different and wherein an altered level in biological activity of both the first and second GPCR polypeptides, relative to a normal control levels, indicates that said patient has an increased risk for developing a metabolic disease or disorder.
  • In yet another embodiment, said method comprises measuring in said patient, or in a biological sample obtained from said patient, the level of expression of a first GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein an altered level in said expression, relative to a normal control level, indicates that said patient has an increased risk for developing a metabolic disease or disorder. In a related embodiment, the method further comprises measuring in said patient, or in a biological sample obtained from said patient, the expression of a second GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second GPCR polypeptide are different and wherein an altered level in expression of both GPCRs, relative to a normal control levels, indicates that said patient has an increased risk for developing a metabolic disease or disorder. In one embodiment, expression is determined by measuring levels of said GPCR polypeptide. In particular embodiments, said expression is determined by measuring levels of RNA encoding said GPCR polypeptide.
  • The present invention also provides methods for identifying a compound for the treatment or prevention of a metabolic disease or disorder, comprising: contacting a cell expressing a GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243 with a candidate compound; and measuring the biological activity or expression of said GPCR polypeptide expressed in said cell, wherein altered biological activity or expression of said GPCR polypeptide, relative to a cell not contacted with said compound, indicates that said candidate compound useful for the treatment of a metabolic disease or disorder.
  • In a related embodiment, the present invention includes a method for identifying a compound for the treatment or prevention of a metabolic disease or disorder, said method comprising: contacting a GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243 with a candidate compound; and determining whether said candidate compound binds to said GPCR polypeptide, wherein binding of said candidate compound to said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment or prevention of a metabolic disease or disorder.
  • In a further related embodiment, the invention includes a method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising administering a candidate compound to a transgenic animal expressing a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243; and determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein a alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a metabolic disease or disorder. In one embodiment, said animal has a mutation in the endogenous gene that is orthologous to said transgene.
  • In yet a further embodiment, the present invention includes a method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising the steps of administering a candidate compound to a transgenic animal expressing in one of its neurological tissues a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, said animal having a metabolic disease or disorder; and determining whether said candidate compound treats said metabolic disease or disorder.
  • In a related embodiment, the present invention provides a method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising the steps of contacting a candidate compound with a cell from a transgenic animal expressing a transgene encoding a human GPCR polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243; and determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein a alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a metabolic disease or disorder.
  • In yet another embodiment, the present invention includes a method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising administering a candidate compound to an animal comprising a mutation in a gene encoding a polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243; and determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein a alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a metabolic disease or disorder.
  • Another embodiment of the present invention includes a method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising the steps of administering a candidate compound to an animal comprising a mutation in a gene encoding a polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, said animal having a metabolic disease or disorder; and determining whether said candidate compound treats said metabolic disease or disorder.
  • In a related embodiment, the present invention includes a method for identifying a compound for the treatment of a metabolic disease or disorder, said method comprising the steps of contacting a candidate compound with a cell from an animal comprising a mutation in a gene encoding a polypeptide substantially identical to a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243; and determining whether said candidate compound alters the biological activity or expression of said GPCR polypeptide, wherein a alteration in the biological activity or expression of said GPCR polypeptide identifies said candidate compound as a compound useful for the treatment of a metabolic disease or disorder.
  • In a related embodiment, the invention further provides an animal model of a metabolic disease or disorder, wherein said animal model is a non-human mammal comprising a mutation in a first gene encoding a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, and wherein said non-human mammal exhibits one or more symptoms of a metabolic disease or disorder. In another embodiment, the mammal further comprises a mutation in a second gene encoding a polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second genes are different.
  • In yet another related embodiment, the invention includes an animal model of a metabolic disease or disorder, wherein said animal model is a non-human mammal comprising a transgene encoding a GPCR polypeptide having the amino acid sequence set forth in any one of SEQ ID NOs:552, 488, or 243, and wherein said non-human mammal exhibits one or more symptoms of a metabolic disease or disorder.
  • In another embodiment, the present invention includes a cell isolated from the non-human mammal of the present invention.
  • In one embodiment, the present invention includes a kit for determining the presence of a metabolic disease or disorder in a patient, wherein said kit comprises a first compound that specifically binds to a polynucleotide having the sequence set forth in any on of SEQ ID NOs:1046, 1014, and 894 or to a polypeptide having the sequence set forth in any one of SEQ ID NOs:552, 488, or 243. In a related embodiment, the kit further comprises a second compound that specifically binds to a polynucleotide having the sequence set forth in any on of SEQ ID NOs:1046, 1014, and 894 or to a polypeptide having the sequence set forth in any one of SEQ ID NOs:552, 488, or 243, wherein said first and second compounds bind to different polypeptides or polynucleotides. In certain embodiments, the compound is labeled. The kit may further include one or more control samples.
  • In certain embodiments of the methods, animals, cells, and kits of the present invention related to GPR8243 and SREBs, the neurological or metabolic disease or disorder is psychosis, schizophrenia, mania, bipolar disorder, obsessive compulsive disorders, autism spectrum disorders, attention-deficit hyperactivity disorders, dementia, mental retardation, other abnormal social behaviors, or other neurodevelopmental disorders. In certain embodiment, the metabolic disease or disorder is obesity, diabetes, metabolic syndrome, or anorexia.
  • In certain embodiments of the methods, animals, cells, and kits of the present invention related to GPR88, the neurological disease or disorder is a dopamine system-related and/or striatal function-related motor function disease or disorder or other neurological disease or disorder, such as, e.g., Parkinson's disease, Huntington's disease, motor skills disorder, restless legs syndrome, other movement disorders, psychosis, schizophrenia, mania, bipolar disorder, obsessive compulsive disorder, autism spectrum disorders, attention-deficit hyperactivity disorders, dementia, mental retardation, drug abuse and addiction, other abnormal social behaviors, or other neurodevelopmental disorders.
  • In certain embodiments of the methods, animals, cells, and kits of the present invention related to GPR22, the neurological disease or disorder is stress, post-traumatic stress disorder (PTSD), anxiety, panic attacks, or a mood or sleep disorder.
  • 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 2×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, N.Y., 1994, hereby incorporated 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 GPCR polypeptide that is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, pure. A substantially pure GPCR 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 GPCR 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 that 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 GPCR 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 occurring in several different sequence forms. A “mutation” is a form of a polymorphism in which the expression level, stability, function, or biological activity of the encoded protein is substantially altered.
  • By “GPCR related polypeptide” is meant a polypeptide having substantial identity to any of the polypeptides listed in Table 1, including polymorphic forms (e.g., sequences having one or more SNPs) and splice variants.
  • By “GPCR biological activity” is meant measurable effect or change in an organism or a cell resulting from the modulation of a GPCR 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 dominately 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; 7:502-508, 1997), luciferase (Welsh et al., Curr. Opin. Biotechnol. 8:617-622, 1997), lacZ (Spergel et al., Prog. Neurobiol. 63:673-686, 2001), aequorin (Deo et al., J. Anal. Chem. 369:258-266, 2001) and green fluorescent protein (Tsien, Annu. Rev. Biochem. 67:509-544, 1998).
  • “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 polydeoxyribonucleotide (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, Gln; 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 occurring 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 transconjugation.
  • 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 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, 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 polymorphism” 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 polymorphism being assayed. This common primer can be between 50 and 1500 bps from the polymorphic 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 polymorphism. 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.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a list of GPCR polynucleotides of the invention in human and mouse. Polynucleotides are divided into four classes, A, B, C, and F/S, according to conventional classification of the GPCR superfamily. The “No Class” group includes five polynucleotides that cannot be assigned to any of the above four classes. Within each class, polynucleotides are further grouped into small families based on ligand specificity or, in the case of orphan receptors, significant sequence homology (≧40%) within each family. Orphan receptors that cannot be grouped by this criterion are alphabetically listed at the end of each class. Whenever available, names are adopted from the official gene names of the NCBI LocusLink database. Orphan GPCRs are indicated with an asterisk. Abbreviations: H, human; M, mouse; FMLP, fMet-Leu-Phe; GNRH; gonadotropin-releasing hormone; PAF, platelet-activating factor; INSL3, insulin-like 3; SPC, sphingosylphosphorylcholine; LPC, lysophosphatidylcholine; TRH, thyrotropin-releasing hormone; LGR, leucine-rich repeat-containing G protein-coupled receptor; SREB, super conserved receptor expressed in brain; GIP, gastric inhibitory polypeptide; GHRH, growild typeh hormone-releasing hormone; PACAP, pituitary adenylate cyclase activating polypeptide; DAF, decay accelerating factor; GPRC5, G protein-coupled receptor family C group 5.
  • FIG. 2 is a series of phylogenetic trees of human GPCRs. Lines corresponding to individual polynucleotides are colored black for those with known ligands, red for orphan genes, and blue for genes with 7 trans-membrane domains but no homology to known GPCRs. The Class A tree was split into two parts due to size considerations (arrow line indicates the connection). Families are defined as described in FIG. 1. Clusters of GPCRs with significant predictive value as to ligands are highlighted in purple on these bootstrap consensus trees (bootstrap values not shown). The ruler at the bottom of each tree indicates the horizontal distance equal to 10% sequence divergence.
  • FIG. 3 is a photograph showing the expression profiles of nine GPCRs as identified by RT-PCR.
  • FIG. 4 is schematic summary of tissue expression in 100 GPCR polynucleotides. Polynucleotides were analyzed individually by RT-PCR, as shown in FIG. 3, and the intensity of the observed bands determined by scanning. Each gene is represented by a single row of colored boxes, with four different expression levels: no expression—blue; low expression—purple; moderate expression—dark red; strong expression—pure red. Polynucleotides and tissues, as well as groups of expression patterns, are indicated.
  • FIGS. 5 a-5 h are representative in situ hybridization photomicrographs of GPCR expression in the mouse brain. FIG. 5 a: GPR63 in the Ammons horn (CA) regions of the hippocampus. FIG. 5 b: PGR7 in the habenula. FIG. 5 c: GRCA in the cortex and thalamus. FIG. 5 d: GPR63 in the Purkinje cells of the cerebellum. FIG. 5 e: GPR37 in the frontal cortex. FIG. 5 f: GPR26 in the inferior olive. FIG. 5 g: GPR50 in the cells lining the third ventricle. FIG. 5 h: PGR15 in the preoptic region of the hypothalamus. Vertical lines on sagittal mouse brain drawing represent approximate coronal plane of photomicrographs. Scale bars=500 μm.
  • FIGS. 6 a-6 b. Home Cage Activity data for GPR85. FIG. 6A. illustrates the average 24 hour activity of GPR85 wild type and knock out female mice. FIG. 6B illustrates the average 24 hour activity of GPR85 wild type and knock out male mice.
  • FIGS. 7 a-7 b. Temperature differences between GPR85 knock out and wild type mice. FIG. 7A. SIH results showing an increased body temperature change for knock out compared to wild type mice. FIG. 7B. Baseline core body temperature difference between wild type and knock out mice.
  • FIG. 8. Percentage freezing in the conditioned fear test. GPR85 knock out mice displayed significantly more freezing responses during the context test.
  • FIGS. 9 a-9 b. Acute effects of ethanol-induced hypothermia. FIG. 9A. Initial sensitivity to the hypothermic effects of ethanol as measured by the difference before and 30 minutes after an i.p injection of 2.5 g/kg ethanol on two consecutive treatment days. GPR85 knock out mice display a decreased initial sensitivity to the effects of ethanol. FIG. 9B. Tolerance to the hypothermic effects of ethanol as shown by the difference in the change of core body temperature for day 1 and day 2.
  • FIG. 10 is a graph demonstrating that mice in which both GPR85 and SREB3 have been knocked out (DKO) are hyperactive as assessed in the open field activity test. Data plotted are in 4-min bins. Compared to wild type (WT) mice, the DKO mice exhibit increased locomotor activity as measured by the total distance traveled in the chamber (p<0.05, repeated measures ANOVA, n=12-14 per group), whereas the SREB3 and GPR85 single knock-outs (Kos) do not behave differently from WT.
  • FIGS. 11 a-11 b are graphs demonstrating that DKO mice have reduced prepulse inhibition (PPI). The startle responses to 120 dB noise alone are not significantly altered in any of the KO strains (FIG. 11 a). There is significant reduction of PPI (FIG. 11 b) in DKO mice at all prepulse levels (**p<0.01, ***p<0.001, n=19-22 per group, Student's t-test). There is also a partial reduction of PPI in GPR85 KO but not SREB3 KO.
  • FIG. 12 is a graph demonstrating that DKO mice are less anxious or have less obsessive behavior in the marble burying test. There is a significant reduction of number of marbles buried by DKO mice (***p<0.001, n=19-22 per group, Student's t-test) but not GPR85 KO or SREB3 KO.
  • FIG. 13 is a graph showing that DKO mice are impaired in nest building. At all time points examined after a piece of nesting material is given, the DKO mice show significant impairment in building the nest (**p<0.01, ***p<0.001, n=7-10 per group, Mann-Whitney U test). GPR85 KO mice also show significant impairment at 1 h and 2 h time points (*p<0.05, **p<0.01), while SREB3 KO mice have no significant impairment.
  • FIGS. 14 a and 14 b are graphs demonstrating that DKO mice have reduced aggressive behavior in the resident-intruder test. Only WT and DKO, but not GPR85 KO or SREB3 KO, were tested. The total numbers of all social interactive behavior exhibited by the WT or DKO resident mice, including sniffing, tail chasing and attacking, do not differ significantly by genotype (FIG. 14 a). There is a significant reduction of aggressive behavior, i.e. attacking the intruder mice, in the DKO mice (**p<0.01, n=16DKO, 21WT, Student's t-test, FIG. 14 b).
  • FIGS. 15 a and 15 b are graphs demonstrating that aged GPR85 KO mice are also impaired in nest building. When tested at 16-18 months of age, both male (FIG. 15 a) and female (FIG. 15 b) GPR85 KO mice show significant impairment in building the nest at all time points examined (*p<0.05, **p<0.01, ***p<0.001, n=6-9 per group, Mann-Whitney U test).
  • FIGS. 16 a and 16 b are graphs that demonstrate that older GPR85 KO mice also have reduced prepulse inhibition (PPI). The same animals are tested at young (3 months, FIG. 16 a) and old (17 months, FIG. 16 b) ages. There is a significant reduction of PPI in old GPR85 KO mice (*p<0.05, # p=0.066, n=6-9 per group, Student's t-test).
  • FIGS. 17 a-17 d are graphs depicting GPR85 KO mice body weight and body length. Growth curves were generated by measuring the animal's weight and length every one or two weeks. Both male and female KO mice have lower body weight and length than WT, with more significant genotype difference in female mice. P values at 70 weeks are: female weight p<0.0001 (FIG. 17 a), male weight p=0.12 (FIG. 17 b), female length p<0.0001 (FIG. 17 c), male length p<0.05 (FIG. 17 d) (n=8-10 per group, Student's t-test).
  • FIGS. 18 a and 18 b are graphs demonstrating that GPR85 KO mice have normal baseline food intake. There is no significant difference in the amount of daily food intake between genotypes in either male (FIG. 18 b) or female (FIG. 18 a) mice (n=8-10 per group, Student's t-test).
  • FIGS. 19 a and 19 b are graphs demonstrating that GPR85 KO mice eat less after a fasting challenge. Mice are subjected to a 24-hr fasting and then re-feeding. The amount of food eaten and the animal's body weight are measured at 1 h, 4 h and 24 h after re-feeding. Daily food intake is also measured for Days 2-5. Both male (FIG. 19 a) and female (FIG. 19 b) KO mice have significantly less cumulative food intake during re-feeding than WT mice (*p<0.05, **p<0.01, n=8-10 per group, Student's t-test).
  • FIGS. 20 a and 20 b are graphs showing that GPR85 KO mice are slow to recover body weight after a fasting challenge. Body weight changes are monitored in the same experiment as in FIG. 19. Both male and female KO mice lost the same amount of weight as the WT mice after the fasting (FIGS. 20 a and 20 b, respectively). However, during re-feeding, both male and female KO mice are significantly slower in regaining their body weight than WT mice (*p<0.05, **p<0.01, n=8-10 per group, Student's t-test).
  • FIG. 21 is a graph showing that GPR85 KO mice have lower baseline body temperature. Baseline body temperature is measured by a rectal probe on singly housed, resting mice. Both male and female KO mice have significantly lower body temperature than WT mice (p<0.05, n=9-11 per group, Student's t-test).
  • FIGS. 22 a-22 d are graphs demonstrating that female GPR85 KO mice have lower percentage of white fat. DEXA analysis shows that KO mice have significantly lower total fat mass than WT mice (p<0.05, n=10 per group, Student's t-test, FIG. 22 a). KO mice have significantly lower amount of white fat (p<0.01, FIG. 21 b) but normal amount of brown fat (FIG. 21 c). The percentage of white fat versus the whole body weight is also significantly lower in KO mice (p<0.01) by ˜33% (FIG. 22 d).
  • FIG. 23 provides graphs showing that GPR85 KO mice have slightly reduced leptin and insulin levels. There is a trend of reduction of baseline plasma leptin and insulin levels in both male and female KO mice (n=7-10 per group, top four panels), but these differences are not statistically significant. There is no difference in IGF-1 level between genotypes (bottom two panels).
  • FIGS. 24 a-24 d demonstrate that aged male GPR85 KO mice have improved glucose tolerance. Old (16 months) male GPR85 KO mice have significantly lower fed and fasting glucose levels compared to WT mice (FIGS. 24 a and 24 b, *p<0.05, **p<0.01, n=7-10 per group, Student's t-test). These mice are given an insulin challenge or a glucose challenge. In the insulin challenge test (FIG. 24 c), mice are fasted for 4 hours and then injected with 0.75 U/kg insulin via i.p., and blood glucose levels are measured at different time points afterwards. KO mice have significantly lower glucose levels and are slower in recovery (*p<0.05, **p<0.01). In the glucose challenge test (FIG. 24 d), mice are injected with 2 g/kg glucose via i.p., and blood glucose levels are measured at different time points afterwards. KO mice are faster in clearing glucose than WT at 1 hr post injection (p<0.05).
  • FIGS. 25 a and 25 b are graphs showing that DKO mice have greatly reduced body weight and body length. Growth curves are generated by measuring the animal's weight and length every two or four weeks. Both male and female DKO mice have significantly lower body weight and length than WT, with more significant genotype difference in male mice (n=8-10 per group, Student's t-test). Male DKO mice weigh 27% less than WT (p<0.0001, FIG. 25 a). Female DKO mice weigh 18% less than WT (p<0.01, FIG. 25 b).
  • FIG. 26 provides graphs showing that DKO mice eat more food per gram body weight. Both male and female DKO mice have lower baseline body weight than WT (upper panels, *p<0.05, ***p<0.001, Student's t-test, n=6-10 per group, ages 3-5 months). When normalized to their body weights, both male and female DKO mice eat more food per gram body weight (lower panels, *p<0.05, ***p<0.001).
  • FIG. 27 is a graph demonstrating that GPR88 knock-out (KO) mice are impaired in motor coordination as assessed by the rotarod test. Each mouse was tested for 4 trials per day, and the latency to fall from the rotating rod with accelerating rotating speed was averaged across the 4 trials. The KO mice (n=16) had significantly shorter latency compared to wild type (WT) mice (n=18) in each of the four testing days (p<0.01 for day 1, p<0.001 for days 2-4, Student's t-test).
  • FIGS. 28 a-28 d are graphs demonstrating that GPR88 KO mice are hyperactive in the open field activity test. Mice were placed in the novel chamber and their locomotor activities were monitored for 20 min. Data plotted are in 4-min bins. Compared to WT mice (n=18), the KO mice (n=18) had increased horizontal activity (p<0.05, repeated measures ANOVA, FIG. 28 a), total distance traveled in the chamber (p<0.05, FIG. 28 b), vertical/rearing activity (p<0.001, FIG. 28 c) and stereotypy behavior (p<0.05, FIG. 28 d).
  • FIG. 29 is a graph demonstrating that GPR88 KO mice are hypersensitive to amphetamine-induced hyperactivity. Mice were injected with amphetamine (2.5 mg/kg) via i.p. The mice were placed in the activity chambers 30 minutes after amphetamine injection, and their locomotor activities were monitored for 20 min. Compared to baseline locomotor activity in the absence of drugs, both WT and KO mice had significantly higher activity after amphetamine administration (p<0.001 respectively). However, the activity level of KO mice (n=18) was much higher than that of the WT mice (n=18) (p<0.001 for the first 4-min block, p<0.05 for the second 4-min block, p<0.05 during the whole 20-min period). There was a strong genotype×treatment interaction for the first 4-min block (F(3,68)=10.5, p<0.01, two-way ANOVA).
  • FIGS. 30 a and 30 b are graphs demonstrating that GPR88 KO mice tend to be more sensitive to amphetamine-induced reduction of prepulse inhibition (PPI). GPR88 KO (n=20) and WT (n=21) mice in the inbred 129sv background were tested for baseline PPI, and there was no significant difference between genotypes (p>0.3, repeated measures ANOVA). Several weeks later, the mice were injected with amphetamine (2.5 mg/kg) via i.p. and tested for PPI 30 minutes later. The startle responses to the 120 dB stimulus of both WT and KO were significantly decreased after amphetamine treatment, and there was no significant difference between genotypes (p>0.5, FIG. 30 a). There was significant reduction of PPI in both WT and KO after amphetamine treatment (p<0.001 for both, FIG. 30 b). There was a trend of more reduction of PPI in KO than WT (p=0.091, repeated measures ANOVA).
  • FIGS. 31 a and 31 b are graphs demonstrating that GPR22 knock-out (KO) mice are hypoactive and more anxious in the open field activity test. Mice were placed in the novel chamber and their locomotor activities were monitored for 20 min. Data plotted are in 4-min bins. Compared to wild type (WT) mice (n=23), the KO mice (n=27) traveled less distance during the testing period (p<0.05, repeated measures ANOVA) (FIG. 31 a), and spent less time in the center arena of the chamber (p<0.05, Student's t-test) (FIG. 31 b).
  • FIG. 32 is a graph demonstrating that GPR22 KO mice are more anxious than WT controls in the light-dark box test. In this test, less number of transitions between the light and dark compartments and more time spent in the dark compartment are two indicators for increased anxiety in animals. Compared to WT mice (n=21), the KO mice (n=26) had less number of transitions between the light and dark compartments (p<0.05, Student's t-test), and spent less time in the light compartment (p<0.05).
  • FIG. 33 is a graph demonstrating that GPR22 KO mice are hyperactive at night in their home cages. Data plotted are in 1-hr bins. Compared to WT mice (n=23), the KO mice (n=23) had significantly higher locomotor activity levels during the night time (p<0.01, repeated measures ANOVA). During the daytime, locomotor activity levels were not significantly different between genotypes.
  • DETAILED DESCRIPTION OF THE INVENTION
  • G protein coupled receptors (GPCRs) include receptors for neurotransmitters, light, odors, hormones, and molecules used for communication in the immune system. GPCRs are by far the largest family of receptors known. It is believed that there are as many as 1,000 different GPCRs for odor recognition alone. The present invention is based, in part, upon the identification and characterization of novel human and mouse GPCRs.
  • The present invention is based, in part, on the identification of GPCRs that are expressed in the brain and associated with neurological and/or metabolic diseases and disorders, wherein said GPCRs are GPR88, GPR22, or belong to a family of polypeptides called SREBs (Super-Conserved Receptors Expressed in Brain), and have a polypeptide sequence set forth in any one of SEQ ID NOs: 552, 488, 243, 558, and 484. These sequences correspond to SREBs termed GPR85 (SREB2), GPR27 (SREB1), and GPR173 (SREB3), GPR88, and GPR22, respectively. The polynucleotide sequences of GPR85, SREB1, SREB3, GPR88, and GPR22 are provided in SEQ ID NO:s 1046, 1014, 894, 1049, and 1012, respectively. The sequences of the mouse polypeptide and polynucleotide homologs are provided in SEQ ID NOs:553 and 1337 (mouse GPR85 polypeptide and polynucleotide), SEQ ID NOs:489 and 1305 (mouse SREB1 polypeptide and polynucleotide), SEQ ID NOs:244 and 245 (mouse SREB3 polypeptide and polynucleotide), SEQ ID NOs:559 and 1340 (mouse GPR88 polypeptide and polynucleotide), and SEQ ID NOs:485 and 1303 (mouse GPR22 polypeptide and polynucleotide. All of these sequences are included within the full scope of the present invention.
  • The SREB family of GPCRs is extraordinarily conserved among vertebrate species. The SREB family consists of at least three members, termed SREB1, SREB2, and SREB3. SREB members share 52-63% amino acid identity with each other and show some similarity to previously known rhodopsin-like GPCRs. Amino acid sequence identity between human and rat orthologues is 97% for SREB1 and 99% for SREB3, while the SREB2 sequence is surprisingly completely identical between the species. Furthermore, amino acid sequence of zebrafish SREB2 and SREB3 are 94 and 78% identical to mammal orthologues, respectively. Northern blot analysis revealed that SREB members are predominantly expressed in the brain regions and genital organs. Radiation hybrid analysis localized SREB1, SREB2, and SREB3 genes to different human chromosomes, namely 3p21-p14, 7q31 and Xp11, respectively. The high sequence conservation and abundant expression in the central nervous system suggest that SREBs play fundamental roles in the nervous system.
  • As described in US Patent Application Publication No. US 2006/0134109, SREB polynucleotides and/or polypeptides are expressed in a variety of neurological tissues, including, hypothalamus, amygdalae, pituitary, female brain, male brain, brainstem, cerebellum, cortex, frontal cortex, hippocampus, striatum, and thalamus. According to the present invention, it has now been found that disruption of two or more SREBs, e.g., GPR85 and SREB3, in mice leads to increased neurological abnormalities, thereby demonstrating that SREBs play a fundamental role in these biological processes underlying these neurological conditions. In addition, disruption of GPR85, alone or in combination with a disruption in a second SREB, resulted in lower body weight and improved glucose tolerance, suggesting that SREBs also play a role in metabolic diseases and disorder, such as obesity and diabetes. These results further suggest that the SREBs may play overlapping or redundant roles in the nervous and metabolic systems and that modulating the activity of expression of two or more SREBs may be used to treat associated neurological and metabolic diseases and disorders.
  • Accordingly, the present invention includes methods of modulating the biological activity or expression of one or more SREBs, which are useful in treating neurological and metabolic diseases and disorders. The present invention provides modulators of one or more SREBs, pharmaceutical compositions comprising modulators of one or more SREBs, and methods of use thereof to treat or prevent neurological and metabolic diseases. In addition, given the association between SREBs and neurological and metabolic diseases and disorders, the present invention further includes methods of diagnosing or detecting neurological and metabolic diseases or disorders based upon detecting mutations in one or more SREB genes, or alterations in the biological activity or expression of one or more SREBs as compared to normal.
  • In various embodiments, methods and compounds of the present invention may be used to modulate one of the three SREBs described herein, while in other embodiments, methods and compounds of the present invention are used to modulate two more, e.g., two or three, of the SREBs. These methods may employ two or more different modulators, each targeting one or more different SREBs. However, given the high degree of sequence similarity between the SREBs, the present invention also contemplates using one modulator having the ability to modulate two or more SREBs. For example, such a modulator may be an antibody that binds to a conserved extracellular region of SREB1 and SREB2, SREB1 and SREB3, SREB2 and SREB3, or SREB1, SREB2, and SREB3.
  • The present invention is based, in part, on the identification that GPR88 is expressed in the brain and associated with neurological diseases and disorders. As described in US Patent Application Publication No. US 2006/0134109, GPR88 polynucleotides and/or polypeptides are expressed in a variety of neurological tissues, including, hypothalamus, amygdale, female brain, male brain, brainstem, cortex, frontal cortex, hippocampus, striatum, and thalamus. According to the present invention, it has now been found that GPR88 is anatomically and functionally involved with the dopamine system and striatal function, thereby suggesting that deregulation of GPR88 expression or activity is associated with a variety of dopamine system- or striatal function-related motor function disease or disorder or other neurological disease or disorder, such as, e.g., Parkinson's disease, Huntington's disease, motor skills disorder, restless legs syndrome, other movement disorders, psychosis, schizophrenia, mania, bipolar disorder, obsessive compulsive disorder, autism spectrum disorders, attention-deficit hyperactivity disorders, dementia, mental retardation, drug abuse and addiction, other abnormal social behaviors, or other neurodevelopmental disease or disorder.
  • Accordingly, the present invention includes methods of modulating the biological activity or expression of GPR88, which are useful in treating neurological diseases and disorders, including dopamine system or striatal function-related motor function disease or disorder or other neurological disease or disorder, such as, e.g., Parkinson's disease, Huntington's disease, motor skills disorder, restless legs syndrome, other movement disorders, psychosis, schizophrenia, mania, bipolar disorder, obsessive compulsive disorder, autism spectrum disorders, attention-deficit hyperactivity disorders, dementia, mental retardation, drug abuse and addiction, other abnormal social behaviors, or other neurodevelopmental disease or disorder. The present invention provides modulators of GPR88, pharmaceutical compositions comprising modulators of GPR88, and methods of use thereof to treat or prevent neurological diseases. In addition, given the association between GPR88 and neurological diseases and disorders, the present invention further includes methods of diagnosing or detecting neurological diseases or disorders based upon detecting mutations in the GPR88 gene, or alterations in the biological activity or expression of GPR88 as compared to normal.
  • The present invention is based, in part, on the identification that GPR22 is expressed in the brain and associated with neurological diseases and disorders, including stress, post-traumatic stress disorder (PTSD), anxiety, panic attacks, or a mood or sleep disorder. As described in US Patent Application Publication No. US 2006/0134109, GPR22 polynucleotides and/or polypeptides are expressed in a variety of neurological tissues, including, hypothalamus, amygdala, pituitary, female brain, male brain, brainstem, cerebellum, cortex, frontal cortex, hippocampus, striatum, and thalamus. According to the present invention, it has now been found that disruption of GPR22 in mice leads to increased anxiety and stress, thereby demonstrating that GPR22 plays a fundamental role in the biological processes underlying these neurological conditions.
  • Accordingly, the present invention includes methods of modulating the biological activity or expression of GPR22, which are useful in treating neurological diseases and disorders, including stress, post-traumatic stress disorder (PTSD), anxiety, panic attacks, and mood or sleep disorders. The present invention provides modulators of GPR22, pharmaceutical compositions comprising modulators of GPR22, and methods of use thereof to treat or prevent neurological diseases. In addition, given the association between GPR22 and neurological diseases and disorders, the present invention further includes methods of diagnosing or detecting neurological diseases or disorders based upon detecting mutations in the GPR22 gene, or alterations in the biological activity or expression of GPR22 as compared to normal.
  • Methods of Treating and Preventing Neurological and Metabolic Diseases and Disorders
  • The present invention provides methods of treating or preventing a disease or disorder by modulating the activity or expression of a GPCR normally expressed in a tissue associated with the disease or disorder, including those tissues and associated diseases an disorders described herein.
  • In certain embodiment, the present invention includes methods of modulating the biological activity or expression of one or more SREBs, which methods may be used to treat or prevent a disease or disorder, including any one of those described herein. In particular embodiments, the neurological disease or disorder is psychosis, schizophrenia, mania, bipolar disorder, obsessive compulsive disorders, autism spectrum disorders, attention-deficit hyperactivity disorders, dementia, mental retardation, other abnormal social behaviors, or other neurodevelopmental disorders. In certain embodiments, the metabolic disease is obesity, diabetes, metabolic syndrome, or anorexia. In particular embodiments, these methods comprise modulating the biological activity or expression of two or more SREBs. In one embodiment, the methods comprise modulating the biological activity of GRCR85 and SREB1, or GPCR85 and SREB3.
  • The present invention also includes methods of modulating the biological activity or expression of GPR88, which methods may be used to treat or prevent a neurological condition, including any of those described in U.S. Patent Application Publication No. US2006/0134109. In particular embodiments, the neurological disease or disorder is a dopamine system- or striatal function-related motor function disease or disorder or other neurological disease or disorder, such as, e.g., Parkinson's disease, Huntington's disease, motor skills disorder, restless legs syndrome, other movement disorders, psychosis, schizophrenia, mania, bipolar disorder, obsessive compulsive disorder, autism spectrum disorders, attention-deficit hyperactivity disorders, dementia, mental retardation, drug abuse and addiction, other abnormal social behaviors, or other neurodevelopmental disease or disorder.
  • The present invention includes methods of modulating the biological activity or expression of GPR22, which methods may be used to treat or prevent a neurological condition. In particular embodiments, the neurological disease or disorder is stress, post-traumatic stress disorder (PTSD), anxiety, panic attacks, or a mood or sleep disorder.
  • In various embodiments, methods or modulating the biological activity or expression of a GPCR, e.g., one or more SREBs, GPR88, or GPR22, include either increasing the activity or expression of a GPCR or decreasing the activity or expression of a GPCR. This may be accomplished genetically, e.g., by introducing a GPCR transgene into a cell or animal or by mutating or disrupting genes encoding A GPCR in a cell or animal. This may also be accomplished using one or more compounds that bind to GPCR polypeptides or polynucleotides, or bind to another molecule that regulates the expression or activity or a GPCR, e.g., compounds that bind to a GPCR ligand or a transcriptional repressor that binds the promoter of a GPCR gene. Accordingly, the methods of the present invention may directly affect the activity or expression of a GPCR, or they may indirectly affect the activity or expression of a GPCR. In particular embodiments, wherein the activity of more than one SREB is modulated, these methods are practiced using more than one agent, each which modulates a particular SEB being modulated.
  • Methods that involve increasing the expression or activity of one or more GPCRs are particularly useful in treating or preventing disease states or conditions characterized by insufficient GPCR signaling (e.g., as a result of insufficient activity of one or more GPCR ligands). Methods that involve decreasing the expression or activity of one or more GPCRs are particularly useful in treating or preventing disease states or conditions characterized by excessive GPCR signaling. These methods may involve administering a compound that modulates one or more GPCRs, wherein the compound is either an agonist or antagonist of one or more GPCRs to a cell or patient.
  • In one embodiment, the present invention includes a method of treating or preventing a neurological or metabolic disease or disorder in a mammal, comprising administering one or more polynucleotides that encode a GPCR, or a functional variant or fragment thereof, to said mammal, wherein said polynucleotides are expressed in said mammal. In certain embodiments, the polynucleotide is an expression vector, and in other embodiments, the polynucleotide is a transgene. In particular embodiments, a neurological or metabolic disease is treated or prevented by administering one or more polynucleotides that encode a SREB. In particular embodiments, a neurological or metabolic disease is treated or prevented by administering two or more polynucleotides that encode polypeptides selected from SREB1, SREB2, and SREB3. In other embodiments, a neurological disease is treated or prevented by administered a polynucleotide that encodes GPR88 or GPR22.
  • In another embodiment, the present invention includes a method of treating or preventing a neurological or metabolic disease or disorder in a mammal, comprising administering one or more GPCR polypeptides, or a functional variant or fragment thereof, to said mammal. In particular embodiments, a neurological or metabolic disease is treated or prevented by administering one or more SREB polypeptides. In particular embodiments, a neurological or metabolic disease is treated or prevented by administering two or more polypeptides selected from SREB1, SREB2, and SREB3. In other embodiments, a neurological disease is treated or prevented by administered a GPR88 or GPR22 polypeptide.
  • In one embodiment, the present invention includes a method of treating or preventing a neurological or metabolic disease or disorder in a mammal, comprising administering one or more polynucleotides comprising a sequence identical to a region of a SREB polynucleotide sequence set forth in any one of SEQ ID NOs:2, 4, or 6 or a complement thereof, to said mammal, wherein said polynucleotide inhibits expression of one or more SREBs. In certain embodiments, the polynucleotide is an expression vector, and in particular embodiments, the polynucleotide is an antisense RNA, an RNAi molecule, or a ribozyme.
  • In one embodiment, the present invention includes a method of treating or preventing a neurological disease or disorder in a mammal, comprising administering a polynucleotide comprising a sequence identical to a region of the GPR88 polynucleotide sequence set forth in SEQ ID NO:2 or a complement thereof, to said mammal, wherein said polynucleotide inhibits expression of GPR88. In certain embodiments, the polynucleotide is an expression vector, and in particular embodiments, the polynucleotide is an antisense RNA, an RNAi molecule, or a ribozyme.
  • In one embodiment, the present invention includes a method of treating or preventing a neurological disease or disorder in a mammal, comprising administering a polynucleotide comprising a sequence identical to a region of the GPR22 polynucleotide sequence set forth in SEQ ID NO:2 or a complement thereof, to said mammal, wherein said polynucleotide inhibits expression of GPR22. In certain embodiments, the polynucleotide is an expression vector, and in particular embodiments, the polynucleotide is an antisense RNA, an RNAi molecule, or a ribozyme.
  • In another embodiment, the present invention includes a method of treating or preventing a neurological or metabolic disease or disorder in a mammal, comprising administering one or more antibodies that specifically bind to a SREB polypeptide having the sequence set forth in any one of SEQ ID NOs: 1, 3, or 5 to said mammal. In one embodiment, the antibodies inhibit a biological activity of a SREB, while in another embodiment, the antibodies increase a biological activity of a SREB.
  • In another embodiment, the present invention includes a method of treating or preventing a neurological disease or disorder in a mammal, comprising administering an antibody that specifically binds to the GPR88 polypeptide having the sequence set forth in SEQ ID NO:1 to said mammal. In one embodiment, the antibody inhibits a biological activity of GPR88, while in another embodiment, the antibody increases a biological activity of GPR88.
  • In another embodiment, the present invention includes a method of treating or preventing a neurological disease or disorder in a mammal, comprising administering an antibody that specifically binds to the GPR22 polypeptide having the sequence set forth in SEQ ID NO:1 to said mammal. In one embodiment, the antibody inhibits a biological activity of GPR22, while in another embodiment, the antibody increases a biological activity of GPR22.
  • The present invention further includes a method of treating or preventing a neurological or metabolic disease or disorder in a mammal, comprising administering one or more small molecules that specifically binds to a SREB polypeptide having the sequence set forth in any one of SEQ ID NOs: 1, 3, or 5 to said mammal. In one embodiment, the small molecule inhibits a biological activity of a SREB, while in another embodiment, the small molecule increases a biological activity of a SREB.
  • The present invention further includes a method of treating or preventing a neurological disease or disorder in a mammal, comprising administering a small molecule that specifically binds to the GPR88 polypeptide having the sequence set forth in SEQ ID NO:1 to said mammal. In one embodiment, the small molecule inhibits a biological activity of GPR88, while in another embodiment, the small molecule increases a biological activity of GPR88.
  • The present invention further includes a method of treating or preventing a neurological disease or disorder in a mammal, comprising administering a small molecule that specifically binds to the GPR22 polypeptide having the sequence set forth in SEQ ID NO:1 to said mammal. In one embodiment, the small molecule inhibits a biological activity of GPR22, while in another embodiment, the small molecule increases a biological activity of GPR22.
  • These methods may be readily adapted for use of any compound that modulates a biological activity or expression of a GPCR, including those specifically described herein. In certain embodiments, two or more compounds that modulate a GPCR, e.g., an SREB, are administered simultaneously or sequentially. These two or more compounds may modulate the same of different GPCRs, e.g., SREBs.
  • The methods of the present invention may be used to treat or prevent a variety of neurological or metabolic diseases and disorders in an animal. Thus, the present invention provide methods of treating or preventing a neurological or metabolic disease or disorder in an animal, comprising administering to the animal one or more compounds that modulate one or more GPCRs' biological activity or expression. In various embodiments, the compounds increase the expression or activity of one or more GPCRs, while in other embodiments, they decrease the expression or activity of one or more GPCRs. In particular embodiments, the animal is a mammal, and in one embodiment, the animal is a human. The animal may be diagnosed with or considered at risk of developing a neurological or metabolic disease or disorder. Neurological or metabolic diseases and disorders that may be treated or prevented include, but are not limited to, those described herein.
  • Compounds of the invention may be administered in a pharmaceutical composition. Pharmaceutical compositions of the present invention comprise one or more compounds that modulate the expression or activity of one or more GPCrs and a pharmaceutically-acceptable diluent, carrier, or excipient. Pharmaceutical compositions may be administered in unit dosage form.
  • Any appropriate route of administration may be employed, for example, parenteral, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraarticular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, or oral administration. Examples of specific routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer such compositions to patients. Methods well known in the art for making pharmaceutical compositions and formulations are found in, for example, Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A R., 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 napthalenes. 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 compounds 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.
  • Therapeutic formulations may be 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. 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, N.J.) or phosphate buffered saline (PBS).
  • The composition should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should 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 absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, 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 incorporating 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 preferred 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. For the purpose of oral therapeutic administration, the active compound can be incorporated 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 corn 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 may be 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 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 acid.
  • Liposomal suspensions (including liposomes targeted to specific cell types) can also be used as pharmaceutically acceptable carriers. A variety of liposomal formulations suitable for delivering a compound to an animal have been described and demonstrated to be effective in delivering a variety of compound, including, e.g., small molecules, nucleic acids, and polypeptides.
  • It may be 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 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 μg/kg to 100 mg/kg or more, depending on the factors mentioned above. 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 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 that exhibit large therapeutic indices are preferred. 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.
  • Data obtained from 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 compounds that modulate expression or activity. A compound 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.
  • Appropriate doses of a small molecule also 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.
  • The present invention also encompasses a method of agonizing (stimulating) or antagonizing a GPCR's natural binding partner's associated activity in a mammal, comprising administering to said mammal one or more agonists or antagonists to a GPCR 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 a GPCR comprising administering the agonist or antagonist to a mammal in an amount sufficient to agonize or antagonize one or more GPCR-associated functions.
  • In one embodiment, the present invention provides a method for monitoring the effectiveness of treatment of a subject with a compound (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) including the steps of (i) obtaining a pre-administration biological sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a GPCR polypeptide, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration biological samples from the subject; (iv) detecting the level of expression or activity of a GPCR polypeptide, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of a GPCR 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 compound to the subject accordingly. For example, increased administration of the compound may be desirable to increase the expression or activity of a GPCR polypeptide to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the compound may be desirable to decrease expression or activity of a GPCR polypeptide to lower levels than detected.
  • GPCR Expression Profiles: Related Diseases and Disorders
  • Expression profiles for GPCRs of the present invention were determined with human and mice tissues using RT-PCR and tissue in situ hybridization methods. Modulators of GPCR expression and/or activity, which include GPCR polypeptides and polynucleotides themselves, may be used to treat or prevent diseases and disorders associated with a tissue in which the GPCR is expressed. The findings are summarized below.
  • Methods
  • RT-PCR
  • Tissue harvesting: 8-10 week old male or female 129S1/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, intron/exon spanning PCR primers for several genes (ApoAl, Nurr1, Actin, G3PDH and Blue opsin) were used in RT-PCRs, performed in the presence or absence of RT, with 200 ng of input cDNA.
  • RT reactions: 5 μg of each RNA sample was reverse transcribed with random primers (Roche) in a 40 μl reaction with 40 U MMLV-RT (Roche) and 20 U 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 25 μl reactions with 2 ng, 20 ng or 200 ng of input cDNA, in the presence of 1.25 U of AmpliTaq Gold Polymerase (Applied Biosystems) and 0.25 uM 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 and confirmed by sequencing the bands obtained from RT-PCR.
  • In Situ Hybridization
  • Tissue dissection and sectioning: 8-10 week old male 129SI/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 corresponding gene and promoter sequences. Transcription reactions were performed using Ambion Maxiscript kits. PCR generated templates (500 ng) were added to 100 μCi of dried down 33P-UTP (Perkin Elmer) in 10 μl reactions.
  • Hybridization: Prehybridization and hybridization reactions were performed as previously described, with modifications. Briefly, 33P labeled riboprobes (˜5×106 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 0.1×SSC at 70° C. for 30 min. 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 corresponding 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 MetaMorph software (both Meridian Instruments).
  • Expression Profile Results
  • We have determined the expression pattern for GPCRs, providing functional information for these receptors (Table 1). In addition, we have identified several new GPCRs (Table 2). The GPCR polypeptides and polynucleotides may be relevant for the treatment or diagnosis of various disease or disorders, particularly behavioral disorders. In addition to the wild-type GPCR polypeptide, polymorphic, splice variant, mutagenized, and recombinant forms of a GPCR polypeptide may also be targets for treatment or diagnosis of diseases and disorders or for assaying for therapeutic compounds.
  • TABLE 1
    GPCRs
    Human
    Poly-
    peptide Human Mouse Mouse
    SEQ Polynucleotide Polypeptide Polynucleotide
    Gene Name ID NO: SEQ ID NO: SEQ ID NO: SEQ ID NO:
    KIAA1828 1 2 3 4
    PGR10 5 6 7 8
    PGR11 9 10 11 12
    PGR12 13 14 15 16
    PGR13 17 18 19 20
    PGR14 21 22 23 24
    PGR15 25 26 27 28
    PGR17 29 30 31 32
    PGR2 33 34 35 36
    PGR20 37 38 39 40
    PGR22 41 42 43 44
    PGR25 45 46 47 48
    PGR26 49 50 51 52
    PGR3 53 54 55 56
    PGR5 57 58 59 60
    PGR1 61 62 63 836
    PGR16 64 65 66 837
    PGR18 67 68 69 838
    PGR19 70 71 72 839
    PGR21 73 74 75 840
    PGR23 76 77 78 841
    PGR24A 79 80
    PGR24P 1551 1552
    PGR27 81 82 83 842
    PGR28 84 85 86 843
    PGR4 87 88 89 844
    PGR6 90 91
    PGR7 92 93 94 845
    PGR9 95 96
    AGR9 97 846 98 99
    BAI1 100 847 101 102
    BAI2 103 848 104 105
    BAI3 106 849 107 108
    DJ287G14 109 850 110 111
    DRD1 112 851 113 114
    DRD5 115 852 116 117
    EBI2 118 853 119 120
    FLJ14454 121 854 122 123
    GHSR 124 855 125 126
    GIPR 127 856 128 129
    GLP2R 130 857 131 132
    GPR101 133 858 134 135
    GPR103 136 859 137 138
    GPR17 139 860 140 141
    GPR20 142 861 143 144
    GPR21 145 862 146 147
    GPR23 148 863 149 150
    GPR25 151 864 152 153
    GPR26 154 865 155 156
    GPR37L1 157 866 158 159
    GPR39 160 867 161 162
    GPR4 163 868 164 165
    GPR48 166 869 167 168
    GPR51 169 870 170 171
    GPR58 172 871 173 174
    GPR62 175 872 176 177
    GPR64 178 873 179 180
    GPR68 181 874 182 183
    GPR82 184 875 185 186
    GPR92 187 876 188 189
    GRM2 190 877 191 192
    GRM4 193 878 194 195
    GRM5 196 879 197 198
    GRM6 199 880 200 201
    GRM7 202 881 203 204
    HCRTR1 205 882 206 207
    HCRTR2 208 883 209 210
    KIAA0758 211 884 212 213
    LEC1 214 885 215 216
    LEC2 217 886 218 219
    LEC3 220 887 221 222
    LGR6 223 888 224 225
    LGR7 226 889 227 228
    MTNR1B 229 890 230 231
    NPFF1R 232 891 233 234
    RE2 237 892 238 239
    SCTR 240 893 241 242
    SREB3 243 894 244 245
    TAR2 246 247
    TAR3 248 895 249 250
    TM7SF1L2 251 896 252 253
    ADCYAP1R1 254 897 255 1188
    ADMR 256 898 257 1189
    ADORA1 258 899 259 1190
    ADORA2A 260 900 261 1191
    ADORA2B 262 901 263 1192
    ADORA3 264 902 265 1193
    ADRA1A 266 903 267 1194
    ADRA1B 268 904 269 1195
    ADRA1D 270 905 271 1196
    ADRA2A 272 906 273 1197
    ADRA2B 274 907 275 1198
    ADRA2C 276 908 277 1199
    ADRB1 278 909 279 1200
    ADRB2 280 910 281 1201
    ADRB3 282 911 283 1202
    AGTR1 284 912 285 1203
    AGTR2 286 913 287 1204
    AGTRL1 288 914 289 1205
    AVPR1A 290 915 291 1206
    AVPR1B 292 916 293 1207
    AVPR2 294 917 295 1208
    BDKRB1 296 918 297 1209
    BDKRB2 298 919 299 1210
    BLR1 300 920 301 1211
    BRS3 302 921 303 1212
    C3AR1 304 922 305 1213
    C5R1 306 923 307 1214
    CALCR 308 924 309 1215
    CALCRL 310 925 311 1216
    CASR 312 926 313 1217
    CCBP2 314 927 315 1218
    CCKAR 316 928 317 1219
    CCKBR 318 929 319 1220
    CCR1 320 930 321 1221
    CCR2 322 931 323 1222
    CCR3 324 932 325 1223
    CCR4 326 933 327 1224
    CCR5 328 934 329 1225
    CCR6 330 935 331 1226
    CCR7 332 936 333 1227
    CCR8 334 937 335 1228
    CCR9 336 938 337 1229
    CCRL1 338 939 339 1230
    CCXCR1 340 940 341 1231
    CD97 342 941 343 1232
    CELSR1 344 942 345 1233
    CELSR2 346 943 347 1234
    CELSR3 348 944 349 1235
    CHRM1 350 945 351 1236
    CHRM2 352 946 353 1237
    CHRM3 354 947 355 1238
    CHRM4 356 948 357 1239
    CHRM5 358 949 359 1240
    CMKLR1 360 950 361 1241
    CNR1 362 951 363 1242
    CNR2 364 952 365 1243
    CRHR1 366 953 367 1244
    CRHR2 368 954 369 1245
    CX3CR1 370 955 371 1246
    CXCR4 372 956 373 1247
    CXCR6 374 957 375 1248
    CYSLT1 376 958 377 1249
    CYSLT2 378 959 379 1250
    DRD2 380 960 381 1251
    DRD3 382 961 383 1252
    DRD4 384 962 385 1253
    EDG1 386 963 387 1254
    EDG2 388 964 389 1255
    EDG3 390 965 391 1256
    EDG4 392 966 393 1257
    EDG5 394 967 395 1258
    EDG6 396 968 397 1259
    EDG7 398 969 399 1260
    EDG8 400 970 401 1261
    EDNRA 402 971 403 1262
    EDNRB 404 972 405 1263
    EMR1 406 973 407 1264
    ETL 408 974 409 1265
    F2R 410 975 411 1266
    F2RL1 412 976 413 1267
    F2RL2 414 977 415 1268
    F2RL3 416 978 417 1269
    FKSG79 418 979 419 1270
    FPR1 420 980 421 1271
    FSHR 422 981 423 1272
    FY 424 982 425 1273
    FZD10 426 983 427 1274
    FZD2 428 984 429 1275
    FZD3 430 985 431 1276
    FZD4 432 986 433 1277
    FZD5 434 987 435 1278
    FZD6 436 988 437 1279
    FZD7 438 989 439 1280
    FZD8 440 990 441 1281
    FZD9 442 991 443 1282
    G2A 444 992 445 1283
    GABBR1 446 993 447 1284
    GALR1 448 994 449 1285
    GALR2 450 995 451 1286
    GALR3 452 996 453 1287
    GCGR 454 997 455 1288
    GHRHR 456 998 457 1289
    GLP1R 458 999 459 1290
    GNRHR 460 1000 461 1291
    GPCR150 462 1001 463 1292
    GPR1 464 1002 465 1293
    GPR10 466 1003 467 1294
    GPR102 468 1004
    GPR105 470 1005 471 1296
    GPR12 472 1006 473 1297
    GPR14 474 1007 475 1298
    GPR15 476 1008 477 1299
    GPR18 478 1009 479 1300
    GPR19 480 1010 481 1301
    GPR2 482 1011 483 1302
    GPR22 484 1012 485 1303
    GPR24 486 1013 487 1304
    GPR27 488 1014 489 1305
    GPR3 490 1015 491 1306
    GPR30 492 1016 493 1307
    GPR34 494 1017 495 1308
    GPR35 496 1018 497 1309
    GPR37 498 1019 499 1310
    GPR40 500 1020 501 1311
    GPR41 502 1021 503 1312
    GPR43 504 1022 505 1313
    GPR44 506 1023 507 1314
    GPR45 508 1024 509 1315
    GPR49 510 1025 511 1316
    GPR50 512 1026 513 1317
    GPR54 514 1027 515 1318
    GPR55 516 1028 517 1319
    GPR56 518 1029 519 1320
    GPR57 520 1030 521 1321
    GPR6 522 1031 523 1322
    GPR61 524 1032 525 1323
    GPR63 526 1033 527 1324
    GPR65 528 1034 529 1325
    GPR66 530 1035 531 1326
    GPR7 532 1036 533 1327
    GPR73 534 1037 535 1328
    GPR73L1 536 1038 537 1329
    GPR74 538 1039 539 1330
    GPR75 540 1040 541 1331
    GPR77 542 1041 543 1332
    GPR80 544 1042 545 1333
    GPR81 546 1043 547 1334
    GPR83 548 1044 549 1335
    GPR84 550 1045 551 1336
    GPR85 552 1046 553 1337
    GPR86 554 1047 555 1338
    GPR87 556 1048 557 1339
    GPR88 558 1049 559 1340
    GPR9 560 1050 561 1341
    GPR91 562 1051 563 1342
    GPRC5B 564 1052 565 1343
    GPRC5C 566 1053 567 1344
    GPRC5D 568 1054 569 1345
    GPRC6A 570 1055 571 1346
    GRCA 572 1056 573 1347
    GRM1 574 1057 575 1348
    GRM3 576 1058 577 1349
    GRM8 578 1059 579 1350
    GRPR 580 1060 581 1351
    H963 582 1061 583 1352
    HGPCR11 584 1062 585 1353
    HGPCR19 586 1063 587 1354
    HGPCR2 588 1064 589 1355
    HM74 590 1065 591 1356
    HRH1 592 1066 593 1357
    HRH2 594 1067 595 1358
    HRH3 596 1068 597 1359
    HRH4 598 1069 599 1360
    HTR1A 600 1070 601 1361
    HTR1B 602 1071 603 1362
    HTR1D 604 1072 605 1363
    HTR1F 606 1073 607 1364
    HTR2A 608 1074 609 1365
    HTR2B 610 1075 611 1366
    HTR2C 612 1076 613 1367
    HTR4 614 1077 615 1368
    HTR5A 616 1078 617 1369
    HTR6 618 1079 619 1370
    HTR7 620 1080 621 1371
    HUMNPIIY20 622 1081 623 1372
    IL8RA 624 1082 625 1373
    IL8RB 626 1083 627 1374
    LGR8 628 1084 629 1375
    LHCGR 630 1085 631 1376
    LTB4R 632 1086 633 1377
    LTB4R2 634 1087 635 1378
    MAS1 636 1088 637 1379
    MC1R 638 1089 639 1380
    MC2R 640 1090 641 1381
    MC3R 642 1091 643 1382
    MC4R 644 1092 645 1383
    MC5R 646 1093 647 1384
    MRGD 648 1094 649 1385
    MRGE 650 1095 651 1386
    MRGF 652 1096 653 1387
    MTNR1A 654 1097 655 1388
    N8(MRGG) 656 1098 657 1389
    NMBR 658 1099 659 1390
    NMU2R 660 1100 661 1391
    NPY1R 662 1101 663 1392
    NPY2R 664 1102 665 1393
    NPY5R 666 1103 667 1394
    NPY6R 668 1104 669 1395
    NTSR1 670 1105 671 1396
    NTSR2 672 1106 673 1397
    OA1 674 1107 675 1398
    OPN1MW 676 1108 677 1399
    OPN1SW 678 1109 679 1400
    OPN3 680 1110 681 1401
    OPN4 682 1111 683 1402
    OPRD1 684 1112 685 1403
    OPRK1 686 1113 687 1404
    OPRL1 688 1114 689 1405
    OPRM1 690 1115 691 1406
    OXTR 692 1116 693 1407
    P2RY1 694 1117 695 1408
    P2RY12 696 1118 697 1409
    P2RY2 698 1119 699 1410
    P2RY4 700 1120 701 1411
    P2RY6 702 1121 703 1412
    P2Y10 704 1122 705 1413
    P2Y5 706 1123 707 1414
    PGR8 708 1124 709 1415
    PNR 710 1125 711 1416
    PPYR1 712 1126 713 1417
    PTAFR 714 1127 715 1418
    PTGDR 716 1128 717 1419
    PTGER1 718 1129 719 1420
    PTGER2 720 1130 721 1421
    PTGER3 722 1131 723 1422
    PTGER4 724 1132 725 1423
    PTGFR 726 1133 727 1424
    PTGIR 728 1134 729 1425
    PTHR1 730 1135 731 1426
    PTHR2 732 1136 733 1427
    RAI3 734 1137 735 1428
    RDC1 736 1138 737 1429
    RGR 738 1139 739 1430
    RHO 740 1140 741 1431
    RRH 742 1141 743 1432
    SALPR 744 1142 745 1433
    SMOH 746 1143 747 1434
    SSTR1 748 1144 749 1435
    SSTR2 750 1145 751 1436
    SSTR3 752 1146 753 1437
    SSTR4 754 1147 755 1438
    SSTR5 756 1148 757 1439
    TACR1 758 1149 759 1440
    TACR2 760 1150 761 1441
    TACR3 762 1151 763 1442
    TAR1 764 1152 765 1443
    TAR4 766 1153 767 1444
    TBXA2R 768 1154 769 1445
    TEM5 770 1155 771 1446
    TM7SF1 772 1156 773 1447
    TM7SF1L1 774 1157 775 1448
    TM7SF3 776 1158 777 1449
    TPRA40 778 1159 779 1450
    TRHR 780 1160 781 1451
    TSHR 782 1161 783 1452
    VIPR1 784 1162 785 1453
    VIPR2 786 1163 787 1454
    VLGR1 788 1164 789 1455
    CCRL2 790 1165 1554 1553
    EMR2 791 1166
    EMR3 792 1167
    FPRL1 793 1168
    FPRL2 794 1169
    FZD1 795 1170 1545 1546
    GNRHR2 796 1171
    GPR31 797 1172 1547 1548
    GPR32 798 1173
    GPR38 799 1174
    GPR52 800 1175
    GPR78 801 1176
    GPR8 802 1177
    HTR1E 803 1178
    MRG 804 1179
    MRGX1 805 1180
    MRGX2 806 1181
    MRGX3 807 1182
    MRGX4 808 1183
    OPN1LW 809 1184 1549 1550
    P2RY11 810 1185
    SLT 811 1186
    TG1019 812 1187
    CMKBR1L1 813 1456
    CMKBR1L2 814 1457
    FPR-RS1 815 1458
    FPR-RS2 816 1459
    FPR-RS3 817 1460
    FPR-RS4 818 1461
    GPR33 819 1462
    GPR90 820 1463
    HTR5B 821 1464
    MrgA1 822 1465
    MrgA2 823 1466
    MrgA3 824 1467
    MrgA4 825 1468
    MrgA5 826 1469
    MrgA6 827 1470
    MrgA7 828 1471
    MrgA8 829 1472
    MrgB1 830 1473
    MrgB2 831 1474
    MrgB3 832 1475
    MrgB4 833 1476
    MrgB5 834 1477
    TRHR2 835 1478
    F2RL 1479 1480
    TA10 1481 1482
    TA11 1483 1484
    TA12 1485 1486
    TA14 1487 1488
    TA15 1489 1490
    HM74A 1555 1556
    PGR15L 1491 1492
    TA7 1493 1494
    TA8 1495 1496
    P2Y3L 1497 1498 1499 1500
    TCP10C 1501 1502
    GPR103L 1503 1504
    OR51E1 1505 1515 1525 1535
    OR4N4 1506 1516 1526 1536
    OR51Q1 1507 1517 1527 1537
    OR51E2 1508 1518 1528 1538
    OR8B3 1509 1519 1529 1539
    OR7D2 1510 1520 1530 1540
    OR2A7 1511 1521 1531 1541
    OR7E102 1512 1522 1532 1542
    OR2A1 1513 1523 1533 1543
    OR2I2 1514 1524 1534 1544
  • TABLE 2
    GPCRs
    Human
    Human Poly- Mouse Mouse
    Polypeptide nucleotide Polypeptide Polynucleotide
    Gene Name SEQ ID NO: SEQ ID NO: SEQ ID NO: SEQ ID NO:
    KIAA1828 1 2 3 4
    PGR10 5 6 7 8
    PGR11 9 10 11 12
    PGR12 13 14 15 16
    PGR13 17 18 19 20
    PGR14 21 22 23 24
    PGR15 25 26 27 28
    PGR17 29 30 31 32
    PGR2 33 34 35 36
    PGR20 37 38 39 40
    PGR22 41 42 43 44
    PGR25 45 46 47 48
    PGR26 49 50 51 52
    PGR3 53 54 55 56
    PGR5 57 58 59 60
    PGR1 61 62 63 836
    PGR16 64 65 66 837
    PGR18 67 68 69 838
    PGR19 70 71 72 839
    PGR21 73 74 75 840
    PGR23 76 77 78 841
    PGR24A 79 80
    PGR24P 1551 1552
    PGR27 81 82 83 842
    PGR28 84 85 86 843
    PGR4 87 88 89 844
    PGR6 90 91
    PGR7 92 93 94 845
    PGR9 95 96
    AGR9 97 846 98 99
    BAI1 100 847 101 102
    BAI2 103 848 104 105
    BAI3 106 849 107 108
    DJ287G14 109 850 110 111
    DRD1 112 851 113 114
    DRD5 115 852 116 117
    EBI2 118 853 119 120
    FLJ14454 121 854 122 123
    GHSR 124 855 125 126
    GIPR 127 856 128 129
    GLP2R 130 857 131 132
    GPR101 133 858 134 135
    GPR103 136 859 137 138
    GPR17 139 860 140 141
    GPR20 142 861 143 144
    GPR21 145 862 146 147
    GPR23 148 863 149 150
    GPR25 151 864 152 153
    GPR26 154 865 155 156
    GPR37L1 157 866 158 159
    GPR39 160 867 161 162
    GPR4 163 868 164 165
    GPR48 166 869 167 168
    GPR51 169 870 170 171
    GPR58 172 871 173 174
    GPR62 175 872 176 177
    GPR64 178 873 179 180
    GPR68 181 874 182 183
    GPR82 184 875 185 186
    GPR92 187 876 188 189
    GRM2 190 877 191 192
    GRM4 193 878 194 195
    GRM5 196 879 197 198
    GRM6 199 880 200 201
    GRM7 202 881 203 204
    HCRTR1 205 882 206 207
    HCRTR2 208 883 209 210
    KIAA0758 211 884 212 213
    LEC1 214 885 215 216
    LEC2 217 886 218 219
    LEC3 220 887 221 222
    LGR6 223 888 224 225
    LGR7 226 889 227 228
    MTNR1B 229 890 230 231
    NPFF1R 232 891 233 234
    PGR15L 1491 1492
    RE2 237 892 238 239
    SCTR 240 893 241 242
    SREB3 243 894 244 245
    TAR2 246 247
    TAR3 248 895 249 250
    TM7SF1L2 251 896 252 253
  • Nervous System Tissues
  • Hypothalamus. GPCRs 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 polymorphs 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
    GPCRs Expressed in the Hypothalamus
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRA1A
    ADRA1D
    ADRA2A
    ADRA2B
    ADRA2C
    ADRB1
    ADRB2
    AGR9
    AGTR1
    AGTR2
    AGTRL1
    AVPR1A
    AVPR2
    BAI1
    BAI2
    BAI3
    BDKRB1
    BDKRB2
    BLR1
    BRS3
    C3AR1
    C5R1
    CALCR
    CALCRL
    CASR
    CCBP2
    CCKAR
    CCKBR
    CCR1
    CCR2
    CCR4
    CCR5
    CCR6
    CCR8
    CCR9
    CCRL1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKBR1L2
    CMKLR1
    CNR1
    CNR2
    CRHR1
    CRHR2
    CX3CR1
    CXCR4
    CXCR6
    CYSLT1
    DJ287G14
    DRD1
    DRD2
    DRD3
    DRD4
    DRD5
    EBI2
    EDG1
    EDG2
    EDG3
    EDG4
    EDG5
    EDG7
    EDG8
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL1
    F2RL2
    F2RL3
    FKSG79
    FPR1
    FPR-RS2
    FY
    FZD1
    FZD10
    FZD2
    FZD3
    FZD4
    FZD5
    FZD6
    FZD7
    FZD8
    G2A
    GABBR1
    GALR1
    GALR2
    GALR3
    GHSR
    GIPR
    GLP1R
    GLP2R
    GNRHR
    GPCR150
    GPR1
    GPR10
    GPR101
    GPR103
    GPR105
    GPR12
    GPR14
    GPR15
    GPR17
    GPR18
    GPR19
    GPR2
    GPR20
    GPR21
    GPR22
    GPR23
    GPR24
    GPR26
    GPR27
    GPR30
    GPR31
    GPR34
    GPR35
    GPR37
    GPR37L1
    GPR4
    GPR43
    GPR44
    GPR45
    GPR48
    GPR49
    GPR50
    GPR51
    GPR54
    GPR55
    GPR56
    GPR6
    GPR61
    GPR62
    GPR63
    GPR64
    GPR65
    GPR66
    GPR68
    GPR7
    GPR73
    GPR73L1
    GPR74
    GPR75
    GPR77
    GPR80
    GPR81
    GPR82
    GPR83
    GPR84
    GPR85
    GPR86
    GPR87
    GPR88
    GPR90
    GPR92
    GPRC5B
    GPRC5C
    GPRC5D
    GRCA
    GRM1
    GRM2
    GRM3
    GRM4
    GRM5
    GRM7
    GRM8
    GRPR
    H963
    HCRTR1
    HCRTR2
    HGPCR11
    HGPCR2
    HM74
    HRH1
    HRH2
    HRH3
    HTR1A
    HTR1B
    HTR1D
    HTR1F
    HTR2A
    HTR2B
    HTR2C
    HTR4
    HTR5A
    HTR6
    HTR7
    HUMNPIIY20
    IL8RA
    KIAA0758
    KIAA1828
    LEC1
    LEC2
    LEC3
    LGR6
    LGR7
    LGR8
    LHCGR
    LTB4R
    LTB4R2
    MAS1
    MC2R
    MC3R
    MC4R
    MC5R
    MRG
    MRGE
    MRGF
    MTNR1A
    NMBR
    NMU2R
    NPFF1R
    NPY1R
    NPY2R
    NPY5R
    NPY6R
    NTSR1
    NTSR2
    OA1
    OPN1MW
    OPN1SW
    OPN3
    OPRD1
    OPRK1
    OPRL1
    OPRM1
    OXTR
    P2RY1
    P2RY12
    P2RY2
    P2RY4
    P2RY6
    P2Y10
    P2Y5
    PGR1
    PGR10
    PGR11
    PGR12
    PGR13
    PGR14
    PGR15
    PGR16
    PGR17
    PGR18
    PGR20
    PGR21
    PGR22
    PGR23
    PGR25
    PGR26
    PGR27
    PGR28
    PGR3
    PGR4
    PGR5
    PGR7
    PGR8
    PTAFR
    PTGDR
    PTGER1
    PTGER2
    PTGER3
    PTGER4
    PTGFR
    PTHR1
    PTHR2
    RAI3
    RDC1
    RE2
    RHO
    RRH
    SALPR
    SCTR
    SMOH
    SREB3
    SSTR1
    SSTR2
    SSTR3
    SSTR4
    SSTR5
    TACR1
    TACR3
    TBXA2R
    TEM5
    TM7SF1
    TM7SF1L1
    TM7SF1L2
    TM7SF3
    TPRA40
    TRHR
    TRHR2
    VIPR2
    VLGR1
  • Amygdala. GPCRs 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 GPCR in the amydala. These polypeptides, or polymorphs 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
    GPCRs Expressed in the Amygdala
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRA1A
    ADRA1D
    ADRA2A
    ADRA2C
    ADRB1
    ADRB2
    AGR9
    AGTR1
    AGTR2
    AGTRL1
    BAI1
    BAI2
    BAI3
    BRS3
    C5R1
    CALCRL
    CASR
    CCBP2
    CCKBR
    CCR5
    CCR6
    CCR9
    CCRL1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKBR1L2
    CMKLR1
    CNR1
    CRHR1
    CRHR2
    CX3CR1
    CXCR6
    DJ287G14
    DRD1
    DRD2
    DRD5
    EBI2
    EDG1
    EDG2
    EDG4
    EDG5
    EDG7
    EDG8
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL2
    FPR1
    FPR-RS2
    FY
    FZD1
    FZD10
    FZD2
    FZD3
    FZD4
    FZD5
    FZD6
    FZD7
    GABBR1
    GALR1
    GALR2
    GIPR
    GLP1R
    GPCR150
    GPR1
    GPR10
    GPR101
    GPR103
    GPR105
    GPR12
    GPR14
    GPR15
    GPR17
    GPR19
    GPR2
    GPR21
    GPR22
    GPR23
    GPR24
    GPR26
    GPR27
    GPR3
    GPR30
    GPR34
    GPR37
    GPR37L1
    GPR4
    GPR45
    GPR48
    GPR50
    GPR51
    GPR54
    GPR55
    GPR56
    GPR6
    GPR61
    GPR62
    GPR63
    GPR64
    GPR66
    GPR7
    GPR73L1
    GPR75
    GPR77
    GPR80
    GPR81
    GPR82
    GPR83
    GPR84
    GPR85
    GPR86
    GPR87
    GPR88
    GPR9
    GPR92
    GPRC5B
    GPRC5C
    GRCA
    GRM1
    GRM2
    GRM3
    GRM4
    GRM5
    GRM7
    GRM8
    GRPR
    H963
    HCRTR1
    HCRTR2
    HRH1
    HRH2
    HRH3
    HTR1A
    HTR1B
    HTR1D
    HTR1F
    HTR2A
    HTR2B
    HTR2C
    HTR4
    HTR5A
    HTR7
    HUMNPIIY20
    KIAA0758
    KIAA1828
    LEC1
    LEC2
    LEC3
    LGR7
    LHCGR
    LTB4R
    MAS1
    MC2R
    MC3R
    MC4R
    MC5R
    MRG
    MRGE
    MRGF
    NMBR
    NMU2R
    NPFF1R
    NPY2R
    NPY5R
    NTSR1
    NTSR2
    OPN1MW
    OPN3
    OPRD1
    OPRK1
    OPRL1
    OPRM1
    OXTR
    P2RY1
    P2RY12
    P2RY2
    P2RY6
    P2Y5
    PGR1
    PGR10
    PGR11
    PGR13
    PGR14
    PGR15
    PGR18
    PGR20
    PGR21
    PGR22
    PGR25
    PGR28
    PGR3
    PGR7
    PTAFR
    PTGDR
    PTGER1
    PTGER2
    PTGER3
    PTGER4
    PTHR1
    PTHR2
    RAI3
    RDC1
    RE2
    SALPR
    SCTR
    SMOH
    SREB3
    SSTR1
    SSTR2
    SSTR3
    SSTR4
    SSTR5
    TACR1
    TACR2
    TACR3
    TEM5
    TM7SF1
    TM7SF1L1
    TM7SF1L2
    TM7SF3
    TPRA40
    TRHR
    TRHR2
  • Pituitary. GPCRs 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 GPCR in the pituitary. These polypeptides, or polymorphs 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 5
    GPCRs Expressed in the Pituitary
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRB1
    ADRB2
    AGTR1
    AGTRL1
    AVPR1B
    BAI2
    BAI3
    BDKRB1
    BDKRB2
    C3AR1
    C5R1
    CALCRL
    CASR
    CCKBR
    CCR1
    CCR2
    CCR4
    CCR5
    CCR6
    CCR7
    CCR8
    CCRL1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKBR1L2
    CMKLR1
    CNR1
    CNR2
    CRHR1
    CX3CR1
    CXCR4
    CXCR6
    CYSLT1
    CYSLT2
    DJ287G14
    DRD1
    DRD2
    DRD3
    DRD4
    EBI2
    EDG1
    EDG2
    EDG3
    EDG4
    EDG5
    EDG6
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL1
    F2RL2
    F2RL3
    FKSG79
    FPR1
    FPR-RS2
    FSHR
    FY
    FZD1
    FZD10
    FZD2
    FZD3
    FZD4
    FZD5
    FZD6
    G2A
    GABBR1
    GALR1
    GALR3
    GHRHR
    GHSR
    GLP1R
    GNRHR
    GPCR150
    GPR10
    GPR105
    GPR12
    GPR18
    GPR19
    GPR20
    GPR21
    GPR22
    GPR23
    GPR24
    GPR27
    GPR30
    GPR31
    GPR34
    GPR35
    GPR37L1
    GPR39
    GPR4
    GPR43
    GPR45
    GPR48
    GPR49
    GPR50
    GPR51
    GPR54
    GPR56
    GPR6
    GPR62
    GPR63
    GPR65
    GPR66
    GPR68
    GPR7
    GPR73
    GPR73L1
    GPR74
    GPR75
    GPR81
    GPR82
    GPR84
    GPR85
    GPR86
    GPR87
    GPR9
    GPR92
    GPRC5B
    GPRC5C
    GRCA
    GRM5
    GRM6
    GRPR
    H963
    HCRTR1
    HGPCR11
    HM74
    HRH1
    HRH2
    HRH3
    HTR1D
    HTR1F
    HTR2A
    HTR2B
    HTR4
    IL8RA
    KIAA0758
    KIAA1828
    LEC1
    LEC2
    LEC3
    LGR6
    LHCGR
    LTB4R
    MAS1
    MC1R
    MC3R
    MC4R
    MRG
    MrgA1
    MrgG
    NMU2R
    NTSR2
    OPRL1
    OPRM1
    OXTR
    P2RY1
    P2RY12
    P2RY2
    P2RY6
    P2Y10
    P2Y5
    PGR1
    PGR10
    PGR12
    PGR13
    PGR15
    PGR16
    PGR19
    PGR21
    PGR22
    PGR25
    PGR26
    PGR27
    PGR28
    PGR3
    PGR4
    PGR7
    PGR8
    PTAFR
    PTGDR
    PTGER2
    PTGER3
    PTGER4
    PTGFR
    RAI3
    RDC1
    RE2
    RHO
    SALPR
    SMOH
    SREB3
    SSTR1
    SSTR2
    SSTR3
    SSTR4
    SSTR5
    TEM5
    TM7SF1
    TM7SF1L1
    TM7SF1L2
    TM7SF3
    TPRA40
    TRHR
    TRHR2
    TSHR
    VIPR2
    VLGR1
  • Brain. GPCRs expressed in the female brain are listed in Table 6, and GPCRs 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 polymorphs 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
    GPCRs Expressed in the Female Brain
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRA1A
    ADRA1D
    ADRA2A
    ADRA2B
    ADRB1
    ADRB2
    AGR9
    AGTR2
    AGTRL1
    AVPR2
    BAI1
    BAI2
    BAI3
    BDKRB1
    BLR1
    BRS3
    C3AR1
    C5R1
    CALCR
    CALCRL
    CASR
    CCBP2
    CCKAR
    CCKBR
    CCR1
    CCR2
    CCR5
    CCR6
    CCR8
    CCRL1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKLR1
    CNR1
    CNR2
    CRHR1
    CRHR2
    CX3CR1
    CXCR4
    CXCR6
    CYSLT1
    DJ287G14
    DRD1
    DRD2
    DRD3
    DRD4
    DRD5
    EBI2
    EDG1
    EDG2
    EDG3
    EDG4
    EDG5
    EDG6
    EDG7
    EDG8
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL1
    F2RL2
    F2RL3
    FKSG79
    FPR1
    FPR-RS2
    FY
    FZD1
    FZD10
    FZD2
    FZD3
    FZD4
    FZD5
    FZD6
    FZD7
    FZD8
    GABBR1
    GALR1
    GALR2
    GHSR
    GIPR
    GLP1R
    GLP2R
    GPCR150
    GPR1
    GPR10
    GPR101
    GPR103
    GPR105
    GPR12
    GPR14
    GPR15
    GPR17
    GPR18
    GPR19
    GPR20
    GPR21
    GPR22
    GPR23
    GPR24
    GPR26
    GPR27
    GPR3
    GPR30
    GPR34
    GPR35
    GPR37
    GPR37L1
    GPR4
    GPR43
    GPR45
    GPR48
    GPR49
    GPR50
    GPR51
    GPR54
    GPR55
    GPR56
    GPR57
    GPR6
    GPR61
    GPR62
    GPR63
    GPR64
    GPR65
    GPR66
    GPR68
    GPR7
    GPR73
    GPR73L1
    GPR75
    GPR77
    GPR80
    GPR81
    GPR82
    GPR83
    GPR84
    GPR85
    GPR86
    GPR88
    GPR92
    GPRC5B
    GPRC5C
    GPRC5D
    GRCA
    GRM1
    GRM2
    GRM3
    GRM4
    GRM5
    GRM6
    GRM7
    GRM8
    GRPR
    H963
    HCRTR1
    HCRTR2
    HGPCR11
    HGPCR2
    HRH1
    HRH2
    HRH3
    HTR1A
    HTR1B
    HTR1D
    HTR1F
    HTR2A
    HTR2B
    HTR2C
    HTR4
    HTR5A
    HTR6
    HTR7
    HUMNPIIY20
    KIAA0758
    KIAA1828
    LEC1
    LEC2
    LEC3
    LGR6
    LGR7
    LGR8
    LTB4R2
    MAS1
    MC3R
    MC4R
    MC5R
    MRG
    MrgA1
    MRGE
    MRGF
    MrgG
    MTNR1A
    NMBR
    NMU2R
    NPFF1R
    NPY1R
    NPY5R
    NTSR1
    NTSR2
    OA1
    OPN1MW
    OPN1SW
    OPN3
    OPRD1
    OPRK1
    OPRL1
    OPRM1
    OXTR
    P2RY1
    P2RY12
    P2RY6
    P2Y10
    P2Y5
    PGR1
    PGR10
    PGR11
    PGR12
    PGR13
    PGR14
    PGR15
    PGR18
    PGR20
    PGR21
    PGR22
    PGR25
    PGR27
    PGR28
    PGR3
    PGR5
    PGR7
    PGR8
    PTAFR
    PTGDR
    PTGER1
    PTGER2
    PTGER3
    PTGER4
    PTGFR
    PTHR1
    PTHR2
    RAI3
    RDC1
    RE2
    RRH
    SCTR
    SMOH
    SREB3
    SSTR1
    SSTR2
    SSTR3
    SSTR4
    SSTR5
    TACR1
    TACR3
    TBXA2R
    TEM5
    TM7SF1
    TM7SF1L1
    TM7SF1L2
    TM7SF3
    TPRA40
    TRHR
    TRHR2
    TSHR
    VIPR1
    VIPR2
    VLGR1
  • TABLE 7
    GPCRs Expressed in the Male Brain
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRA1A
    ADRA1D
    ADRA2A
    ADRA2B
    ADRA2C
    ADRB1
    ADRB2
    AGR9
    AGTR1
    AGTR2
    AGTRL1
    AVPR2
    BAI1
    BAI2
    BAI3
    BDKRB1
    BDKRB2
    BRS3
    C3AR1
    C5R1
    CALCR
    CALCRL
    CASR
    CCBP2
    CCKAR
    CCKBR
    CCR1
    CCR4
    CCR5
    CCR6
    CCR7
    CCR8
    CCRL1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKLR1
    CNR1
    CRHR1
    CRHR2
    CX3CR1
    CXCR4
    CXCR6
    CYSLT1
    DJ287G14
    DRD1
    DRD2
    DRD3
    DRD4
    DRD5
    EBI2
    EDG1
    EDG2
    EDG3
    EDG4
    EDG5
    EDG6
    EDG7
    EDG8
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL1
    F2RL2
    F2RL3
    FKSG79
    FPR-RS2
    FY
    FZD1
    FZD10
    FZD2
    FZD3
    FZD4
    FZD5
    FZD6
    FZD7
    FZD8
    G2A
    GABBR1
    GALR1
    GALR2
    GCGR
    GIPR
    GLP1R
    GLP2R
    GPCR150
    GPR1
    GPR10
    GPR101
    GPR103
    GPR105
    GPR12
    GPR14
    GPR15
    GPR17
    GPR18
    GPR19
    GPR21
    GPR22
    GPR23
    GPR24
    GPR26
    GPR27
    GPR3
    GPR30
    GPR34
    GPR35
    GPR37
    GPR37L1
    GPR4
    GPR43
    GPR44
    GPR45
    GPR48
    GPR49
    GPR50
    GPR51
    GPR54
    GPR55
    GPR56
    GPR6
    GPR61
    GPR62
    GPR63
    GPR65
    GPR66
    GPR68
    GPR7
    GPR73L1
    GPR75
    GPR77
    GPR80
    GPR81
    GPR82
    GPR83
    GPR84
    GPR85
    GPR86
    GPR88
    GPR92
    GPRC5B
    GPRC5C
    GPRC5D
    GRCA
    GRM1
    GRM2
    GRM3
    GRM4
    GRM5
    GRM6
    GRM7
    GRM8
    GRPR
    H963
    HCRTR1
    HCRTR2
    HRH1
    HRH2
    HRH3
    HTR1A
    HTR1B
    HTR1D
    HTR1F
    HTR2A
    HTR2B
    HTR2C
    HTR4
    HTR5A
    HTR6
    HTR7
    HUMNPIIY20
    KIAA0758
    KIAA1828
    LEC1
    LEC2
    LEC3
    LGR6
    LGR7
    LGR8
    LHCGR
    LTB4R
    MAS1
    MC3R
    MC4R
    MC5R
    MRG
    MRGE
    MRGF
    MTNR1A
    NMBR
    NMU2R
    NPFF1R
    NPY1R
    NPY2R
    NPY5R
    NTSR1
    NTSR2
    OA1
    OPN1MW
    OPN3
    OPRD1
    OPRK1
    OPRL1
    OPRM1
    OXTR
    P2RY1
    P2RY12
    P2RY2
    P2RY6
    P2Y5
    PGR1
    PGR10
    PGR11
    PGR13
    PGR14
    PGR15
    PGR17
    PGR18
    PGR20
    PGR21
    PGR22
    PGR25
    PGR27
    PGR28
    PGR3
    PGR7
    PGR8
    PTAFR
    PTGDR
    PTGER1
    PTGER3
    PTGER4
    PTGFR
    PTHR1
    PTHR2
    RAI3
    RDC1
    RE2
    RRH
    SMOH
    SREB3
    SSTR1
    SSTR2
    SSTR3
    SSTR4
    SSTR5
    TACR1
    TACR3
    TEM5
    TM7SF1
    TM7SF1L1
    TM7SF1L2
    TM7SF3
    TPRA40
    TRHR
    TRHR2
    TSHR
    VIPR2
    VLGR1
  • Brainstem and midbrain. GPCRs 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 polymorphs 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
    GPCRs Expressed in the Brainstem
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRA1A
    ADRA1D
    ADRA2A
    ADRA2B
    ADRB1
    ADRB2
    AGR9
    AGTR1
    AGTR2
    AGTRL1
    AVPR1A
    AVPR2
    BAI1
    BAI2
    BAI3
    BDKRB1
    BDKRB2
    BLR1
    BRS3
    C5R1
    CALCR
    CALCRL
    CASR
    CCBP2
    CCKAR
    CCKBR
    CCR1
    CCR5
    CCR6
    CCR7
    CCRL1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKBR1L2
    CMKLR1
    CNR1
    CNR2
    CRHR1
    CRHR2
    CX3CR1
    CXCR4
    CXCR6
    CYSLT1
    DJ287G14
    DRD1
    DRD2
    DRD3
    DRD5
    EBI2
    EDG1
    EDG2
    EDG3
    EDG4
    EDG5
    EDG6
    EDG7
    EDG8
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL1
    F2RL2
    FKSG79
    FPR1
    FPR-RS2
    FY
    FZD1
    FZD10
    FZD2
    FZD3
    FZD4
    FZD5
    FZD6
    FZD7
    G2A
    GABBR1
    GALR1
    GALR2
    GHSR
    GIPR
    GLP1R
    GPCR150
    GPR1
    GPR10
    GPR101
    GPR103
    GPR105
    GPR12
    GPR14
    GPR15
    GPR17
    GPR18
    GPR19
    GPR2
    GPR20
    GPR21
    GPR22
    GPR23
    GPR24
    GPR26
    GPR27
    GPR3
    GPR30
    GPR31
    GPR34
    GPR35
    GPR37
    GPR37L1
    GPR4
    GPR41
    GPR43
    GPR45
    GPR48
    GPR49
    GPR50
    GPR51
    GPR54
    GPR56
    GPR6
    GPR61
    GPR62
    GPR63
    GPR65
    GPR66
    GPR68
    GPR7
    GPR73
    GPR73L1
    GPR74
    GPR75
    GPR77
    GPR80
    GPR81
    GPR82
    GPR83
    GPR84
    GPR85
    GPR86
    GPR87
    GPR88
    GPR90
    GPR92
    GPRC5B
    GPRC5C
    GPRC5D
    GRCA
    GRM1
    GRM2
    GRM3
    GRM4
    GRM5
    GRM7
    GRM8
    GRPR
    H963
    HCRTR1
    HCRTR2
    HGPCR11
    HGPCR2
    HRH1
    HRH2
    HRH3
    HTR1A
    HTR1B
    HTR1D
    HTR1F
    HTR2A
    HTR2B
    HTR2C
    HTR4
    HTR5A
    HTR6
    HTR7
    HUMNPIIY20
    KIAA0758
    KIAA1828
    LEC1
    LEC2
    LEC3
    LGR6
    LGR8
    LHCGR
    MAS1
    MC2R
    MC3R
    MC4R
    MC5R
    MRG
    MRGE
    MRGF
    MTNR1A
    NMBR
    NMU2R
    NPFF1R
    NPY2R
    NPY5R
    NTSR1
    NTSR2
    OA1
    OPN1MW
    OPN3
    OPRD1
    OPRK1
    OPRL1
    OPRM1
    OXTR
    P2RY1
    P2RY12
    P2RY2
    P2RY6
    P2Y5
    PGR10
    PGR11
    PGR13
    PGR14
    PGR15
    PGR16
    PGR18
    PGR20
    PGR21
    PGR22
    PGR23
    PGR27
    PGR28
    PGR3
    PGR7
    PPYR1
    PTAFR
    PTGDR
    PTGER1
    PTGER2
    PTGER3
    PTGER4
    PTGFR
    PTGIR
    RAI3
    RDC1
    RE2
    RRH
    SALPR
    SCTR
    SMOH
    SREB3
    SSTR1
    SSTR2
    SSTR3
    SSTR4
    TACR2
    TACR3
    TEM5
    TM7SF1
    TM7SF1L1
    TM7SF1L2
    TM7SF3
    TPRA40
    TRHR
    TRHR2
    TSHR
    VIPR2
    VLGR1
  • Cerebellum. GPCRs 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 GPCR in the cerebellum. These polypeptides, or polymorphs 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 9
    GPCRs Expressed in the Cerebellum
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRA1A
    ADRA1D
    ADRA2A
    ADRA2B
    ADRB1
    ADRB2
    AGR9
    AGTR1
    AGTR2
    AGTRL1
    AVPR2
    BAI1
    BAI2
    BAI3
    BDKRB1
    BLR1
    C3AR1
    C5R1
    CALCR
    CALCRL
    CCKBR
    CCR1
    CCR5
    CCR6
    CCR7
    CCR8
    CCR9
    CCRL1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKLR1
    CNR1
    CNR2
    CRHR1
    CRHR2
    CX3CR1
    CXCR4
    CXCR6
    CYSLT1
    CYSLT2
    DJ287G14
    DRD2
    DRD3
    DRD4
    DRD5
    EBI2
    EDG1
    EDG2
    EDG3
    EDG4
    EDG5
    EDG7
    EDG8
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL1
    F2RL2
    F2RL3
    FPR1
    FPR-RS2
    FY
    FZD1
    FZD10
    FZD2
    FZD3
    FZD4
    FZD5
    FZD6
    FZD7
    FZD8
    G2A
    GABBR1
    GALR1
    GALR2
    GALR3
    GCGR
    GIPR
    GLP1R
    GLP2R
    GPCR150
    GPR1
    GPR10
    GPR105
    GPR12
    GPR14
    GPR15
    GPR17
    GPR18
    GPR19
    GPR2
    GPR21
    GPR22
    GPR23
    GPR24
    GPR26
    GPR27
    GPR30
    GPR34
    GPR35
    GPR37
    GPR37L1
    GPR4
    GPR43
    GPR44
    GPR45
    GPR48
    GPR49
    GPR50
    GPR51
    GPR54
    GPR55
    GPR62
    GPR63
    GPR66
    GPR68
    GPR73L1
    GPR75
    GPR77
    GPR80
    GPR81
    GPR82
    GPR83
    GPR84
    GPR85
    GPR86
    GPR87
    GPR90
    GPR92
    GPRC5B
    GPRC5C
    GRCA
    GRM1
    GRM2
    GRM3
    GRM4
    GRM5
    GRM7
    GRM8
    H963
    HCRTR1
    HCRTR2
    HGPCR11
    HGPCR19
    HM74
    HRH1
    HRH2
    HRH3
    HTR1A
    HTR1B
    HTR1F
    HTR2A
    HTR2B
    HTR2C
    HTR4
    HTR5A
    HTR7
    HUMNPIIY20
    IL8RA
    KIAA0758
    KIAA1828
    LEC1
    LEC2
    LEC3
    LGR6
    LGR7
    LHCGR
    LTB4R
    LTB4R2
    MAS1
    MC3R
    MC4R
    MC5R
    MRG
    MRGE
    MRGF
    MrgG
    NMBR
    NPY5R
    NPY6R
    NTSR1
    NTSR2
    OA1
    OPN3
    OPRD1
    OPRL1
    OPRM1
    OXTR
    P2RY1
    P2RY12
    P2RY2
    P2RY4
    P2RY6
    P2Y10
    P2Y5
    PGR1
    PGR11
    PGR12
    PGR13
    PGR14
    PGR15
    PGR16
    PGR18
    PGR20
    PGR21
    PGR22
    PGR23
    PGR26
    PGR27
    PGR28
    PGR3
    PGR4
    PGR7
    PGR8
    PTAFR
    PTGDR
    PTGER1
    PTGER2
    PTGER3
    PTGER4
    PTGFR
    PTGIR
    PTHR1
    PTHR2
    RAI3
    RDC1
    RE2
    RHO
    RRH
    SCTR
    SMOH
    SREB3
    SSTR1
    SSTR2
    SSTR3
    SSTR4
    SSTR5
    TAR1
    TBXA2R
    TEM5
    TM7SF1
    TM7SF1L1
    TM7SF1L2
    TM7SF3
    TPRA40
    TRHR2
    TSHR
    VIPR2
  • Cerebral cortex. GPCRs 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 GPCR activity, expression, or stability in the cerebral cortex. These polypeptides, or polymorphs 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
    GPCRs Expressed in the Cortex
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRA1A
    ADRA1D
    ADRA2A
    ADRA2B
    ADRA2C
    ADRB1
    ADRB2
    AGR9
    AGTR1
    AGTRL1
    AVPR2
    BAI1
    BAI2
    BAI3
    BDKRB2
    C3AR1
    C5R1
    CALCR
    CALCRL
    CASR
    CCBP2
    CCKBR
    CCR1
    CCR2
    CCR5
    CCR6
    CCR7
    CCR9
    CCRL1
    CCXCR1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKBR1L2
    CMKLR1
    CNR1
    CNR2
    CRHR1
    CRHR2
    CX3CR1
    CXCR4
    CXCR6
    CYSLT1
    CYSLT2
    DJ287G14
    DRD1
    DRD2
    DRD3
    DRD5
    EBI2
    EDG1
    EDG2
    EDG3
    EDG4
    EDG5
    EDG7
    EDG8
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL1
    F2RL2
    F2RL3
    FPR1
    FPR-RS2
    FY
    FZD1
    FZD10
    FZD2
    FZD3
    FZD4
    FZD5
    FZD6
    FZD7
    FZD8
    G2A
    GABBR1
    GALR1
    GALR2
    GCGR
    GHSR
    GLP1R
    GLP2R
    GPCR150
    GPR1
    GPR10
    GPR101
    GPR103
    GPR105
    GPR12
    GPR14
    GPR17
    GPR18
    GPR19
    GPR20
    GPR21
    GPR22
    GPR23
    GPR24
    GPR26
    GPR27
    GPR3
    GPR30
    GPR31
    GPR34
    GPR35
    GPR37
    GPR37L1
    GPR4
    GPR41
    GPR43
    GPR44
    GPR45
    GPR48
    GPR50
    GPR51
    GPR54
    GPR55
    GPR56
    GPR6
    GPR61
    GPR62
    GPR63
    GPR66
    GPR68
    GPR7
    GPR73
    GPR73L1
    GPR74
    GPR75
    GPR77
    GPR80
    GPR81
    GPR82
    GPR83
    GPR84
    GPR85
    GPR86
    GPR87
    GPR88
    GPR92
    GPRC5B
    GPRC5C
    GPRC5D
    GRCA
    GRM1
    GRM2
    GRM3
    GRM4
    GRM5
    GRM7
    GRM8
    GRPR
    H963
    HCRTR1
    HCRTR2
    HM74
    HRH1
    HRH2
    HRH3
    HTR1A
    HTR1B
    HTR1D
    HTR1F
    HTR2A
    HTR2B
    HTR2C
    HTR4
    HTR5A
    HTR6
    HTR7
    HUMNPIIY20
    IL8RA
    KIAA0758
    KIAA1828
    LEC1
    LEC2
    LEC3
    LGR6
    LGR7
    LGR8
    LHCGR
    LTB4R
    MAS1
    MC1R
    MC3R
    MC4R
    MC5R
    MRG
    MRGE
    MRGF
    NMBR
    NPY1R
    NPY5R
    NTSR1
    NTSR2
    OPN1MW
    OPN3
    OPRD1
    OPRK1
    OPRL1
    OPRM1
    OXTR
    P2RY1
    P2RY12
    P2RY6
    P2Y10
    P2Y5
    PGR1
    PGR10
    PGR11
    PGR13
    PGR14
    PGR15
    PGR16
    PGR18
    PGR20
    PGR21
    PGR22
    PGR25
    PGR26
    PGR28
    PGR3
    PGR7
    PGR8
    PTAFR
    PTGDR
    PTGER1
    PTGER3
    PTGER4
    PTGFR
    PTHR1
    PTHR2
    RAI3
    RDC1
    RE2
    SALPR
    SCTR
    SMOH
    SREB3
    SSTR1
    SSTR2
    SSTR3
    SSTR4
    SSTR5
    TACR3
    TBXA2R
    TEM5
    TM7SF1
    TM7SF1L1
    TM7SF1L2
    TM7SF3
    TPRA40
    TRHR
    TRHR2
    TSHR
    VIPR1
    VIPR2
    VLGR1
  • Frontal cortex. GPCRs 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 polymorphs 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
    GPCRs Expressed in the Frontal Cortex
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRA1A
    ADRA1D
    ADRA2A
    ADRA2B
    ADRA2C
    ADRB1
    ADRB2
    AGR9
    AGTR1
    AGTR2
    AGTRL1
    AVPR1A
    BAI1
    BAI2
    BAI3
    BDKRB1
    BDKRB2
    C3AR1
    C5R1
    CALCRL
    CASR
    CCBP2
    CCKAR
    CCKBR
    CCR1
    CCR2
    CCR5
    CCR6
    CCR7
    CCRL1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKLR1
    CNR1
    CNR2
    CRHR1
    CRHR2
    CX3CR1
    CXCR4
    CXCR6
    CYSLT1
    DJ287G14
    DRD1
    DRD2
    DRD3
    DRD4
    DRD5
    EBI2
    EDG1
    EDG2
    EDG3
    EDG5
    EDG7
    EDG8
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL1
    F2RL2
    F2RL3
    FPR1
    FPR-RS2
    FSHR
    FY
    FZD1
    FZD10
    FZD2
    FZD3
    FZD4
    FZD5
    FZD6
    FZD9
    G2A
    GABBR1
    GALR1
    GALR2
    GALR3
    GHRHR
    GIPR
    GLP1R
    GLP2R
    GPCR150
    GPR1
    GPR10
    GPR101
    GPR103
    GPR105
    GPR12
    GPR14
    GPR15
    GPR17
    GPR18
    GPR19
    GPR2
    GPR21
    GPR22
    GPR23
    GPR24
    GPR26
    GPR27
    GPR3
    GPR30
    GPR34
    GPR35
    GPR37
    GPR37L1
    GPR4
    GPR43
    GPR45
    GPR48
    GPR49
    GPR50
    GPR54
    GPR55
    GPR56
    GPR6
    GPR62
    GPR63
    GPR65
    GPR66
    GPR68
    GPR7
    GPR73L1
    GPR74
    GPR75
    GPR77
    GPR80
    GPR81
    GPR82
    GPR83
    GPR84
    GPR85
    GPR86
    GPR87
    GPR88
    GPR92
    GPRC5B
    GPRC5D
    GRCA
    GRM1
    GRM2
    GRM3
    GRM4
    GRM5
    GRM7
    GRM8
    GRPR
    H963
    HCRTR1
    HCRTR2
    HM74
    HRH1
    HRH2
    HRH3
    HTR1A
    HTR1B
    HTR1D
    HTR1F
    HTR2A
    HTR2B
    HTR2C
    HTR4
    HTR5A
    HTR6
    HTR7
    HUMNPIIY20
    KIAA0758
    KIAA1828
    LEC1
    LEC2
    LEC3
    LGR6
    LGR7
    LGR8
    LHCGR
    LTB4R
    MAS1
    MC2R
    MC3R
    MC4R
    MC5R
    MRG
    MRGE
    MRGF
    NMBR
    NMU2R
    NPY1R
    NPY2R
    NPY5R
    NTSR1
    NTSR2
    OA1
    OPN1MW
    OPN3
    OPRD1
    OPRK1
    OPRL1
    OPRM1
    OXTR
    P2RY1
    P2RY12
    P2RY2
    P2RY6
    P2Y10
    P2Y5
    PGR10
    PGR11
    PGR12
    PGR13
    PGR14
    PGR15
    PGR16
    PGR18
    PGR20
    PGR21
    PGR22
    PGR25
    PGR26
    PGR28
    PGR3
    PGR4
    PGR7
    PPYR1
    PTAFR
    PTGDR
    PTGER1
    PTGER3
    PTGER4
    PTGFR
    PTHR1
    RAI3
    RDC1
    RE2
    RHO
    RRH
    SCTR
    SMOH
    SREB3
    SSTR1
    SSTR2
    SSTR3
    SSTR4
    SSTR5
    TACR1
    TACR3
    TAR2
    TAR3
    TEM5
    TM7SF1
    TM7SF1L1
    TM7SF1L2
    TM7SF3
    TPRA40
    TRHR
    TRHR2
    TSHR
    VIPR1
    VIPR2
    VLGR1
  • Hippocampus. GPCRs 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 polymorphs 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
    GPCRs Expressed in the Hippocampus
    ADCYAP1R1
    ADMR
    ADORA1
    ADORA2A
    ADORA2B
    ADORA3
    ADRA1A
    ADRA1D
    ADRA2A
    ADRA2B
    ADRB1
    ADRB2
    AGR9
    AGTR1
    AGTR2
    AVPR2
    BAI1
    BAI2
    BAI3
    BDKRB1
    C3AR1
    CALCRL
    CASR
    CCKAR
    CCKBR
    CCR2
    CCR5
    CCR6
    CCRL1
    CCXCR1
    CD97
    CELSR1
    CELSR2
    CELSR3
    CHRM1
    CHRM2
    CHRM3
    CHRM4
    CHRM5
    CMKLR1
    CNR1
    CRHR1
    CRHR2
    CX3CR1
    CXCR4
    CXCR6
    CYSLT1
    DJ287G14
    DRD1
    DRD2
    DRD5
    EBI2
    EDG1
    EDG2
    EDG3
    EDG4
    EDG5
    EDG6
    EDG7
    EDG8
    EDNRA
    EDNRB
    EMR1
    ETL
    F2R
    F2RL1
    F2RL2
    F2RL3
    FY
    FZD1