EP1370659A2 - Proteines, polynucleotides codant pour celles-ci et methodes les utilisant - Google Patents

Proteines, polynucleotides codant pour celles-ci et methodes les utilisant

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Publication number
EP1370659A2
EP1370659A2 EP02761846A EP02761846A EP1370659A2 EP 1370659 A2 EP1370659 A2 EP 1370659A2 EP 02761846 A EP02761846 A EP 02761846A EP 02761846 A EP02761846 A EP 02761846A EP 1370659 A2 EP1370659 A2 EP 1370659A2
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EP
European Patent Office
Prior art keywords
amino acid
polypeptide
nucleic acid
seq
acid sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP02761846A
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German (de)
English (en)
Inventor
Muralidhara Padigaru
John P. Ii Alsobrook
Steven D. Colman
Kimberly A. Spytek
Ferenc Boldog
Corine A. M. Vernet
Li Li
Suresh Shenoy
Stacie Casman
Xiaojia Guo
Shlomit Edinger
John Macdougall
Uriel M. Malyankar
Meera Patturajan
Richard A. Shimkets
Carol Pena
Velizar Tchernev
Bryan D. Zerhusen
Isabelle Millet
Charles E. Miller
Denise M. Lepley
Glennda Smithson
Jason Baumgartner
John Herrmann
John A. Peyman
Linda Gorman
Peter Mezes
Raymond J. Taupier, Jr.
Valerie Gerlach
William M. Grosse
Xiaohong Liu
Karen Ellerman
Mark Rothenberg
David J. Stone
Catherine E. Burgess
Ramesh Kekuda
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CuraGen Corp
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CuraGen Corp
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Priority claimed from PCT/US2002/001311 external-priority patent/WO2002068647A2/fr
Publication of EP1370659A2 publication Critical patent/EP1370659A2/fr
Ceased legal-status Critical Current

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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts

Definitions

  • the invention relates to polynucleotides and the polypeptides encoded by such polynucleotides, as well as vectors, host cells, antibodies and recombinant methods for producing the polypeptides and polynucleotides, as well as methods for using the same.
  • the present invention is based in part on nucleic acids encoding proteins that are new members of the following protein families: fibromodulin, secretin receptor precursor, B7-H2, B7-H1, prostasin, lysosomal acid lipase, tryptase 4, P450, mitsugumin29, micromolar calcium-activated neutral proteasel, P2X2C, DIABLO, HRPET-1 related protein, B7-H2B, galactosyltransferase, lymphocyte antigen precursor, pepsinogen C and ALR. More particularly, the invention relates to nucleic acids encoding novel polypeptides, as well as vectors, host cells, antibodies, and recombinant methods for producing these nucleic acids and polypeptides.
  • the invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides.
  • novel nucleic acids and polypeptides are referred to herein as NONX, or ⁇ ON1, ⁇ ON2, ⁇ ON3, ⁇ ON4, ⁇ ON5, ⁇ ON6, ⁇ ON7, ⁇ ON8, ⁇ ON9, ⁇ OV10, ⁇ ON11, ⁇ ON12, ⁇ ON13, ⁇ ON14, ⁇ ON15, ⁇ ON16, ⁇ ON17 and ⁇ ON18 nucleic acids and polypeptides.
  • ⁇ ONX nucleic acid or polypeptide sequences.
  • the invention provides an isolated ⁇ ONX nucleic acid molecule encoding a ⁇ ONX polypeptide that includes a nucleic acid sequence that has identity to the nucleic acids disclosed in SEQ ID ⁇ OS:l, 3, 5, 1, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53 and 55.
  • the NONX nucleic acid molecule will hybridize under stringent conditions to a nucleic acid sequence complementary to a nucleic acid molecule that includes a protein-coding sequence of a ⁇ ONX nucleic acid sequence.
  • the invention also includes an isolated nucleic acid that encodes a NONX polypeptide, or a fragment, homo log, analog or derivative thereof.
  • the nucleic acid can encode a polypeptide at least 80% identical to a polypeptide comprising the amino acid sequences of SEQ ID ⁇ OS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54 and 56.
  • the nucleic acid can be, for example, a genomic DNA fragment or a cDNA molecule that includes the nucleic acid sequence of any of SEQ ID NOS.l, 3, 5, 1, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53 and 55.
  • an oligonucleotide e.g., an oligonucleotide which includes at least 6 contiguous nucleotides of a NONX nucleic acid (e.g., SEQ ID ⁇ OS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53 and 55) or a complement of said oligonucleotide.
  • substantially purified NONX polypeptides SEQ ID ⁇ OS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54 and 56.
  • the NONX polypeptides include an amino acid sequence that is substantially identical to the amino acid sequence of a human ⁇ ONX polypeptide.
  • the invention also features antibodies that immunoselectively bind to ⁇ ONX polypeptides, or fragments, homologs, analogs or derivatives thereof.
  • the invention includes pharmaceutical compositions that include therapeuticaUy- or prophylactically-effective amounts of a therapeutic and a pharmaceutically- acceptable carrier.
  • the therapeutic can be, e.g. , a ⁇ ONX nucleic acid, a ⁇ ONX polypeptide, or an antibody specific for a ⁇ ONX polypeptide.
  • the invention includes, in one or more containers, a therapeuticaUy- or prophylactically-effective amount of this pharmaceutical composition.
  • the invention includes a method of producing a polypeptide by culturing a cell that includes a ⁇ ONX nucleic acid, under conditions allowing for expression of the ⁇ OVX polypeptide encoded by the D ⁇ A. If desired, the ⁇ ONX polypeptide can then be recovered.
  • the invention includes a method of detecting the presence of a ⁇ ONX polypeptide in a sample. In the method, a sample is contacted with a compound that selectively binds to the polypeptide under conditions allowing for formation of a complex between the polypeptide and the compound. The complex is detected, if present, thereby identifying the ⁇ ONX polypeptide within the sample.
  • the invention also includes methods to identify specific cell or tissue types based on their expression of a NOVX.
  • Also included in the invention is a method of detecting the presence of a NONX nucleic acid molecule in a sample by contacting the sample with a ⁇ ONX nucleic acid probe or primer, and detecting whether the nucleic acid probe or primer bound to a ⁇ ONX nucleic acid molecule in the sample.
  • the invention provides a method for modulating the activity of a ⁇ ONX polypeptide by contacting a cell sample that includes the ⁇ ONX polypeptide with a compound that binds to the ⁇ ONX polypeptide in an amount sufficient to modulate the activity of said polypeptide.
  • the compound can be, e.g., a small molecule, such as a nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, lipid or other organic (carbon containing) or inorganic molecule, as further described herein.
  • a therapeutic in the manufacture of a medicament for treating or preventing disorders or syndromes including, e.g., trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections, Non Hippel-Lindau
  • NDL Alzheimer's disease
  • stroke Tuberous sclerosis
  • hypercalceimia Parkinson's disease
  • Huntington's disease Cerebral palsy
  • Epilepsy Lesch- ⁇ yhan syndrome
  • multiple sclerosis Ataxia-telangiectasia
  • leukodystrophies behavioral disorders, addiction, anxiety, pain, actinic keratosis, acne, hair growth diseases, allopecia, pigmentation disorders, endocrine disorders, connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, Shprintzen-Goldberg syndrome, genodermatoses, contractural arachnodactyly, inflammatory disorders such as osteo- and rheumatoid-arthritis, inflammatory bowel disease, Crohn's disease; immunological disorders, AIDS; cancers including but not limited to lung cancer, colon cancer, neoplasm; aden
  • compositions of the present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the polypeptides can be used as immunogens to produce antibodies specific for the invention, and as vaccines. They can also be used to screen for potential agonist and antagonist compounds.
  • a cD ⁇ A encoding ⁇ ONX may be useful in gene therapy, and ⁇ ONX may be useful when administered to a subject in need thereof.
  • the compositions of the present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the invention further includes a method for screening for a modulator of disorders or syndromes including, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the method includes contacting a test compound with a ⁇ ONX polypeptide and determining if the test compound binds to said ⁇ ONX polypeptide. Binding of the test compound to the ⁇ ONX polypeptide indicates the test compound is a modulator of activity, or of latency or predisposition to the aforementioned disorders or syndromes.
  • Also within the scope of the invention is a method for screening for a modulator of activity, or of latency or predisposition to disorders or syndromes including, e.g., the diseases and disorders disclosed above and or other pathologies and disorders of the like by administering a test compound to a test animal at increased risk for the aforementioned disorders or syndromes.
  • the test animal expresses a recombinant polypeptide encoded by a NOVX nucleic acid.
  • Expression or activity of NONX polypeptide is then measured in the test animal, as is expression or activity of the protein in a control animal which recombinantly- expresses ⁇ ONX polypeptide and is not at increased risk for the disorder or syndrome.
  • the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide, a NOVX nucleic acid, or both, in a subject (e.g., a human subject). The method includes measuring the amount of the NOVX polypeptide in a test sample from the subject and comparing the amount of the polypeptide in the test sample to the amount of the NOVX polypeptide present in a control sample.
  • an alteration in the level of the NOVX polypeptide in the test sample as compared to the control sample indicates the presence of or predisposition to a disease in the subject.
  • the predisposition includes, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the expression levels of the new polypeptides of the invention can be used in a method to screen for various cancers as well as to determine the stage of cancers.
  • the invention includes a method of treating or preventing a pathological condition associated with a disorder in a mammal by administering to the subject a NOVX polypeptide, a NOVX nucleic acid, or a NOVX-specif ⁇ c antibody to a subject (e.g., a human subject), in an amount sufficient to alleviate or prevent the pathological condition.
  • a subject e.g., a human subject
  • the disorder includes, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the invention can be used in a method to identity the cellular receptors and downstream effectors of the invention by any one of a number of techniques commonly employed in the art. These include but are not limited to the two-hybrid system, affinity purification, co-precipitation with antibodies or other specific-interacting molecules.
  • NOVX nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOVX substances for use in therapeutic or diagnostic methods.
  • These NOVX antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOVX proteins have multiple hydrophilic regions, each of which can be used as an immunogen. These NOVX proteins can be used in assay systems for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.
  • the NOVX nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below.
  • the potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.
  • the present invention provides novel nucleotides and polypeptides encoded thereby.
  • NOVX nucleic acids or “NOVX polynucleotides” and the corresponding encoded polypeptides are referred to as “NOVX polypeptides” or “NOVX proteins.” Unless indicated otherwise, “NOVX” is meant to refer to any of the novel sequences disclosed herein.
  • Table A provides a summary of the NOVX nucleic acids and their encoded polypeptides. TABLE 1. Sequences and Corresponding SEQ ID Numbers
  • NONX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts.
  • the various ⁇ ONX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, ⁇ ONX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the ⁇ ONX polypeptides belong.
  • ⁇ ON1 is homologous to the Fibromodulin family of proteins.
  • the ⁇ ON1 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: repair of damage to cartilage and ligaments; therapeutic applications to joint repair, and other diseases, disorders and conditions of the like.
  • fibromodulin participates in the assembly of the extracellular matrix by virtue of its ability to interact with type I and type II collagen fibrils and to inhibit fibrillogenesis in vitro.
  • NOV2 is homologous to the Secretin receptor precursor-like family of proteins.
  • NOV2 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, developmental diseases, MHCLI and III diseases (immune diseases), taste and scent detectabihty disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders;control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of apetite), noninsulin-dependent diabetes mellitus (NIDDMl), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure
  • NOV3 is homologous to the B7-H2 like proteins.
  • the NOV3 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from brain disorders including epilepsy, eating disorders, schizophrenia, ADD, and cancer; heart disease; inflammation and autoimmune disorders including Crohn's disease, IBD, allergies, rheumatoid and osteoarthritis, inflammatory skin disorders, allergies, blood disorders; psoriasis colon cancer, leukemia, AIDS; thalamus disorders; metabolic disorders including diabetes and obesity; lung diseases such as asthma, emphysema, cystic fibrosis, and cancer; pancreatic disorders including pancreatic insufficiency and cancer; and prostate disorders including prostate cancer, as well as other diseases, disorders and conditions.
  • NOV4 is homologous to the B7-H1 like proteins.
  • NOV4 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from brain disorders including epilepsy, eating disorders, schizophrenia, ADD, and cancer; heart disease; inflammation and autoimmune disorders including Crohn's disease, LBD, allergies, rheumatoid and osteoarthritis, inflammatory skin disorders, blood disorders; psoriasis colon cancer, leukemia, AIDS; thalamus disorders; metabolic disorders including diabetes and obesity; lung diseases such as asthma, emphysema, cystic fibrosis and cancer; pancreatic disorders including pancreatic insufficiency and cancer; and prostate disorders including prostate cancer and other diseases, disorders and conditions of the like.
  • B7 family members like B7RP-1 (B7 Related Protein-1), B7-1, and B7-2, with antigen receptors such as CD28, CTLA-4 (Cytotoxic T Lymphocyte-associated Antigen 4) and ICOS (Inducible Co-Stimulatory molecule).
  • B7RP-1 B7 Related Protein-1
  • B7-1, and B7-2 antigen receptors
  • antigen receptors such as CD28, CTLA-4 (Cytotoxic T Lymphocyte-associated Antigen 4) and ICOS (Inducible Co-Stimulatory molecule).
  • CD28 CD28
  • CTLA-4 Cytotoxic T Lymphocyte-associated Antigen 4
  • ICOS Insulible Co-Stimulatory molecule
  • NOV5 is homologous to the Prostasin protein family.
  • nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation and other diseases, disorders and conditions of the like.
  • proteolytic enzymes including prostate- specific antigen (OMIM #176820) and acrosin (OMIM #102480). These enzymes are involved in the postejaculatory hydrolysis of proteins and in semen coagulation and liquefaction (Yu et al. (1995)) obtained partial amino acid sequence of a 40-kD protein isolated from seminal fluid originally by Yu et al. (1994). The protein, designated serine prote
  • the precursor, proprostasin is cleaved between residues 12 and 13 to produce a 12-amino acid light chain and a 299-amino acid heavy chain which are associated through a disulfide bond.
  • the predicted amino acid sequence is between 34 and 42% identical to human acrosin, plasma k ' allikrein (OMIM #229000), and hepsin (OMIM #142440).
  • NOV6 is homologous to the Lysosomal acid lipase family of proteins.
  • NOV6 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, Wolman disease and cholesteryl ester storage disease.
  • Lysosomal acid lipase-A (LIP A), the enzyme deficient in the presumably allelic Wolman disease and cholesterol ester storage disease (OMIM #278000), is located on chromosome 10.
  • LIP A Lysosomal acid lipase-A
  • OMIM #278000 cholesterol ester storage disease
  • LIPA may serve an important role in cellular metabolism by releasing cholesterol. The liberated cholesterol suppresses further cholesterol synthesis and stimulates esterification of cholesterol within the cell.
  • NOV7 is homologous to Tryptase 4.
  • the NOV7 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: diabetes, Von Hippel-Lindau (VHL) syndrome, pancreatitis, obesity, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, transplantation, fertility, endometriosis, Hirschsprung's disease , Crohn's Disease, appendicitis and other diseases, disorders and conditions of the like.
  • VHL Von Hippel-Lindau
  • ASD atrioventricular canal defect
  • tryptase is a structurally unique and mast cell specific trypsin-like serine protease. Recent biological and immunological investigations have implicated tryptase as a mediator in the pathology of numerous allergic and inflammatory conditions including rhinitis, conjunctivitis, and most notably asthma. A growing body of data further implicates tryptase in certain gastrointestinal, dermatological, and cardiovascular disorders as well. The recent availability of potent, and selective tryptase inhibitors, though, has facilitated the validation of this protease as an important therapeutic target as well.
  • NOV8 is homologous to the P450 family of proteins. Since the NOV8 protein of the invention is ubiquitously expressed in many tissues, the NOV8 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in the treatment certain pathologies and disorders.
  • the P450 gene superfamily is a biologically diverse class of oxidase enzymes; members of the class are found in all organisms.
  • P450 proteins are clinically and toxicologically important in humans; they are the principal enzymes in the metabolism of drugs and xenobiotic compounds, as well as in the synthesis of cholesterol, steroids and other lipids. Induction of some P450 genes can also be a risk factor for several types of cancer. This diversity of function is mirrored in the diversity of nucleotide and protein sequences; there are currently over 100 human P450 forms described. Allelic forms of many cytochrome P450 genes have been identified as causing quantitatively different rates of drug metabolism, and hence are important to consider in the development of safe and effective human pharmaceutical therapies. See, e.g., review in E. Tanaka, J Clinical Pharmacy & Therapeutics 24:323-329, 1999.
  • NOV9 is homologous to the Mitsugumin 29 protein.
  • the NOV9 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: Wiskott-Aldrich syndrome, Aldrich syndrome, eczema-thrombocytopenia- immunodeficiency syndrome, thrombocytopenia, night blindness, amyotrophic lateral sclerosis, Batten disease, ceroid lipofuscinosis, Rett syndrome, Pick disease (lobar atrophy), cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, Non
  • Mitsugumin29 is involved in the formation of specialized endoplasmic reticulum systems in skeletal muscle and renal tubule cells.
  • the subcellular distribution and protein structure suggest that mitsugumin29 is involved in communication between the T-tubular and junctional SR membranes.
  • NON10 is homologous to members of Micromolar calcium-activated neutral protease 1 family of proteins.
  • the ⁇ ON10 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: diabetes, Non Hippel- Lindau (VHL) syndrome, pancreatitis, obesity, hypercalceimia, ulcers, endometriosis, fertility, hemophilia, hypercoagulation, idiopathic tl rombocytopenic purpura, autoimmume disease, allergies, immunodeficiencies, transplantation, graft versus host disease, psoriasis, actinic keratosis, tuberous sclerosis, acne, hair growth/loss, allopecia, pigmentation disorders, endocrine disorders, hemophilia, lymphaedema, and other diseases, disorders and conditions of the like.
  • the predicted sequence described here belongs to the calpain protease family.
  • the calpains, or calcium-activated neutral proteases, are nonlysosomal intracellular cysteine proteases (Richard, et al.). Calpain is an intracellular protease involved in many important cellular functions that are regulated by calcium.
  • NO VI 1 is homologous to the P2X2C-like proteins.
  • the NO VI 1 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from pain, since P2X receptor activation of sensory neurones has been demonstrated in in vivo pain models, including the rat hindpaw and knee-joint preparations, as well as in inflammatory models.
  • P2X4 and/or P2X6 receptors in the CNS also seem to be involved in pain pathways.
  • Non-nociceptive P2 receptors on sensory nerves are present in muscle and on sensory endings in the heart and lung that initiate reflex activity involving vagal afferent and efferent nerve fibres (Br J Anaesth 2000 Apr;84(4):476-88).
  • the compositions of the present invention may also have efficacy for treatment of patients suffering from diabetes, obesity, syndrome X, and other diseases, disorders and conditions of the like.
  • NOV12 is related to the DIABLO-like proteins.
  • the NOV12 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: cancer, trauma, bacterial and viral infections, regeneration (in vitro and in vivo), fertility, diabetes, autoimmune disease, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, hypercalceimia, Lesch-Nyhan syndrome, Von Hippel-Lindau (NHL) syndrome, tuberous sclerosis, endocrine disorders, Alzheimer's disease, stroke, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection and other diseases
  • DIABLO protein direct LAP binding protem with low pi performs a critical function in apoptosis by eliminating the inhibitory effect of IAPs (inhibitor of apoptosis proteins) on caspases (1).
  • This protein is also known as Smac for second mitochondria-derived activator of caspase.
  • DIABLO/Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis. Mitochondrial import and cleavage of its signal peptide are required for DIABLO/Smac to gain its apoptotic activity.
  • overexpression of DIABLO/Smac has been shown to increase cellular sensitivity to apoptotic stimuli (2).
  • ⁇ ON13 is homologous to the HRPET-1 related protein.
  • the ⁇ OV13 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, diabetes, Von Hippel- Lindau (NHL) syndrome, pancreatitis, fertility, endometriosis, xerostomia, cirrhosis, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, autoimmume disease, allergies, immunodeficiencies, graft
  • Huntington's disease cerebral palsy, epilepsy, Lesch- ⁇ yhan syndrome, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neuroprotection, systemic lupus erythematosus, asthma, emphysema, scleroderma, ARDS, psoriasis, actinic keratosis, acne, hair growth/loss, allopecia, pigmentation disorders, endocrine disorders, renal artery stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, Lesch-Nyhan syndrome and other diseases, disorders and conditions of the like.
  • the HRPET-1 related protein is highly conserved across species, among C. elegans,
  • HRPET-1 related protein shows homology with plant adhesion molecules, suggesting that the HRPET-1 related protein is likely a cell adhesion
  • NOV14 is homologous to B7-H2B protein.
  • the NOV14 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: brain disorders including epilepsy, eating disorders, schizophrenia, ADD, and
  • NOV15 is homologous to galactosyltransferase-like proteins. Thus, the NOV15
  • nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: proteodermatan sulfate, defective biosynthesis of PDS, defective biosynthesis of dermatan sulfate proteoglycan xylosylprotein 4-beta-galactosyltransferase deficiency xgpt deficiency galactosyltransferase I deficiency, Ehlers-Danlos syndrome, cardiomyopathy, Atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, endometriosis, fertility, Von Hip
  • the enzyme galactosyltransferase (EC 2.4.1.38) catalyzes the reaction involving UDP- galactose and ⁇ -acetylglucosamine for the production of galactose beta-l,4- ⁇ - acetylglucosamine.
  • the galactosyltransferase enzyme can also form a heterodimer with the regulatory protein alpha-lactalbumin to form lactose synthetase (EC 2.4.1.22).
  • galactosyltransferases may be components of plasma membranes where they may function in intercellular recognition and/or adhesion.
  • NON 16 is homologous to Lymphocyte antigen precursor-like proteins.
  • the ⁇ ON16 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from cancer,trauma, regeneration, viral/bacterial/parasitic infections.
  • ⁇ ON17 is homologous to Pepsinogen C-like proteins.
  • the ⁇ ON17 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: ulcer, hypertension (Scand J Clin Lab Invest Suppl 1992;210:111-9), gastric mucosal inflammation and atrophy, and other diseases, disorders and conditions of the like.
  • PGC gene polymorphism has been associated with gastric ulcer and can be a subclinical marker of the genetic predisposition to gastric ulcer (Nippon Rinsho 1996 Apr;54(4):l 149-54).
  • pepsinogen A and pepsinogen C (PGC) might indicate gastric mucosal inflammation and atrophy.
  • Body gastric mucosa produces both PGA and PGC, while antral mucosa produces only PGC. Therefore, diseases involving mainly the aiitrum, such as H. pylori infection, are mainly indicated by the variations in serum PGC than in serum PGA.
  • H. pylori infection diseases involving mainly the aiitrum, such as H. pylori infection
  • serum PGC significantly increases (Recenti Prog Med 1999 Jun;90(6):342-6).
  • the gastric aspartic proteinases (pepsin A, pepsin B, gastricsin/pepsinogen C and chymosin) are synthesized in the gastric mucosa as inactive precursors, known as zymogens. 5
  • the gastric zymogens each contain a prosegment (i.e. additional residues at the N-terminus of the active enzyme) that serves to stabilize the inactive form and prevent entry of the substrate to the active site.
  • zymogens Upon ingestion of food, each of the zymogens is released into the gastric lumen and undergoes conversion into active enzyme in the acidic gastric juice.
  • NON 18 is homologous to ALR-like proteins.
  • the ⁇ ON18 nucleic acids, LO polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example, the treatment of patients suffering from: cancers such as acute lymphoid leukemia, acute myeloid leukemia, translocation-associated leukemias, and other diseases, disorders and conditions of the like.
  • ALL-1 is involved in human acute leukemia through chromosome L5 translocations or internal rearrangements.
  • ALL-1 is the human homologue of Drosophila trithorax.
  • the latter is a member of the trithorax group (trx-G) genes which together with the Polycomb group (Pc-G) genes act as positive and negative regulators, respectively, to determine the body structure of Drosophila.
  • trx-G trithorax group
  • Pc-G Polycomb group
  • the ⁇ ONX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance ⁇ ONX activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small 25 molecules that modulate or inhibit, e.g., neurogenesis, cell differentiation, cell proliferation, hematopoiesis, wound healing and angiogenesis.
  • One ⁇ OVX protein of the invention includes four fibromodulin-like proteins.
  • the disclosed proteins have been named ⁇ OVla, ⁇ OVlb, ⁇ OVlc and ⁇ OVld. NO VI a
  • NOVla designated CuraGen Acc. No. CG-56201-01
  • CuraGen Acc. No. CG-56201-01 which encodes a novel fibromodulin-like protein and includes the 1455 nucleotide sequence (SEQ ID NO:l) is shown in Table 1 A.
  • An open reading frame for the mature protein was identified beginning with an ATG initiation codon at nucleotides 197-199 and ending with a TGA stop codon at nucleotides 1445-1447. Putative untranslated regions are underlined in Table 1A, and the start and stop codons are in bold letters.
  • the disclosed NOVla nucleic acid sequence maps to chromosome 1 and has 1050 of
  • the NOVla polypeptide (SEQ ID NO:2) is 416 amino acid residues in length and is presented using the one-letter amino acid code in Table IB.
  • the SignalP, Psort and/or Hydropathy results predict that NOVla has a signal peptide and is likely to be localized to the lysosome (lumen) with a certainty of 0.5500.
  • a NOVla polypeptide is located outside the cell with a certainty of 0.3700, the endoplasmic reticulum (membrane) with a certainty of 0.1000, or in the endoplasmic reticulum (lumen) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV1 a peptide between amino acid positions 18 and 19, i.e. at the dash in the sequence SQA-QY.
  • the NOVla amino acid sequence have 336 of 353 amino acid residues (95%) identical to, and 338 of 353 amino acid residues (95%) similar to, the 376 amino acid residue ptnr:SWISSNEW-ACC:Q06828 protein from Homo sapiens (Human) (FIBROMODULIN PRECURSOR (FM) (COLLAGEN-BINDING 59 KDA PROTEIN)) (E - 3.9e- 184 ).
  • SNPs small nucleotide polymorphisms
  • a disclosed NOVlb (designated CuraGen Acc. No. CG56201-02), which includes the 965 nucleotide sequence (SEQ ID NO:3) shown in Table ID.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 57-59 and ending with a TGA codon at nucleotides 963-965. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions are underlined.
  • NOVlb polypeptide (SEQ ID NO:4) is 302 amino acid residues in length and is presented using the one-letter amino acid code in Table IE.
  • the SignalP, Psort and/or Hydropathy results predict that NOVlb has a signal peptide and is likely to be localized to the lysosome (lumen) with a certainty of 0.4595.
  • a NOVlb polypeptide is located to the outside of the cell with a certainty of 0.3700, the endoplasmic reticulum (membrane) with a certainty of 0.1000, or the endoplasmic reticulum (lumen) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOVla peptide between amino acid positions 18 and 19, i.e. at the dash in the sequence SQA-QY.
  • NO Vic A disclosed NOVlc (designated CuraGen Acc. No. CG56201-04), which includes the
  • the nucleic acid sequence of NOVlc maps to chromosome 1 and has 1036 of 1065 bases (97%) identical to a gb:GENBANK-ID:HSFiBR
  • acc:X72913.1 mRNA from Homo sapiens (H.sapiens gene for fibromodulin) (E 9.4e " ).
  • the NOVlc polypeptide (SEQ ID NO:6) is 360 amino acid residues in length and is presented using the one-letter amino acid code in Table IG.
  • the SignalP, Psort and/or Hydropathy results predict that NOVlc has a signal peptide and is likely to be localized to the lysosome (lumen) with a certainty of 0.5305.
  • a NOVlc polypeptide is located to the outside of the cell with a certainty of 0.3700, the endoplasmic reticulum (membrane) with a certainty of 0.1000, or the endoplasmic reticulum (lumen) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV1 c peptide between amino acid positions 18 and 19, i.e. at the dash in the sequence SQA-QY.
  • NOVlc is expressed in at least the following tissues: aorta, bone marrow, brain, cartilage, cochlea, colon, heart, kidney, liver, lung, lymph node, lymphoid tissue, mammary glandbreast, muscle, ovary, pancreas, parathyroid gland, parotid salivary glands, placenta, prostate, retina, salivary glands, skin, spinal chord, stomach, testis, thyroid, uterus, whole organism.
  • a disclosed NOVld (designated CuraGen Acc. No. CG56201-01; Assembly 224700033), which includes the 1053 nucleotide sequence (SEQ ID NOJ) shown in Table IH.
  • SEQ ID NOJ 1053 nucleotide sequence shown in Table IH.
  • An open reading frame for the mature protein was identified beginning with an GGA codon at nucleotides 1-3 and ending with a GAG codon at nucleotides 1051-1053. The start and stop codons of the open reading frame are highlighted in bold type.
  • the NOVld polypeptide (SEQ ID NO: 8) is 360 amino acid residues in length and is presented using the one-letter amino acid code in Table II.
  • the SignalP, Psort and/or Hydropathy results predict that NOVlc has a signal peptide and is likely to be localized to the lysosome (lumen) with a certainty of 0.5305.
  • a NOVlc polypeptide is located to the outside of the cell with a certainty of 0.3700, the endoplasmic reticulum (membrane) with a certainty of 0.1000, or the endoplasmic reticulum (lumen) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOVlc peptide between amino acid positions 18 and 19, i.e. at the dash in the sequence SQA-QY.
  • NOVlc is expressed in at least the following tissues: aorta, bone marrow, brain, cartilage, cochlea, colon, heart, kidney, liver, lung, lymph node, lymphoid tissue, mammary gland/breast, muscle, ovary, pancreas, parathyroid gland, parotid salivary glands, placenta, prostate, retina, salivary glands, skin, spinal cord, stomach, testis, thyroid, uterus, whole organism. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence of NO V 1 d.
  • NOVla, NOVlb, NOVlc and NOVld are very closely homologous as is shown in the amino acid alignment in Table 1 J.
  • NOVl Homologies to any of the above NOVl proteins will be shared by the other NOVl proteins insofar as they are homologous to each other as shown above. Any reference to NOVl is assumed to refer to both of the NOVl proteins in general, unless otherwise noted.
  • NOVla also has homology to the amino acid sequences shown in the BLASTP data listed in Table IK.
  • Tables IM and IN list the domain description from DOMAIN analysis results against NOVl . This indicates that the NOVl sequence has properties similar to those of other proteins known to contain these domains.
  • Leucine rich repeat N-terminal domain (Accno. gnl
  • Leucine Rich Repeats pfam00560 are short sequence motifs present in a number of proteins with diverse functions and cellular locations. Leucine Rich Repeats are often flanked by cysteine rich domains. This domain is often found at the N- terminus of tandem leucine rich repeats.
  • the fibromodulin precursor precursor (collagen-binding 59 kd protein) binds to type I and type II collagen and affects the rate of fibrils formation. It also binds keratan sulfate chains and belongs to the small interstitial proteoglycans family. This protein also contains 10 repeated leucine-rich (lrr) segments.
  • Fibromodulin is a member of a family of small interstitial proteoglycans that also includes decorin (DCN; OMIM 125255), biglycan (BGN; OMIM 301870), and lumican (LDC; OMIM 600616).
  • the core proteins of these proteoglycans are structurally related, consisting of a central region composed of leucine-rich repeats flanked by disulfide-bonded terminal domains, with that for fibromodulin possessing up to 4 keratan sulfate chains within its leucine-rich domain. Fibromodulin exhibits a wide tissue distribution, with the highest abundance observed in articular cartilage, tendon, and ligament.
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • a protein therapeutic such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), (v) an agent promoting tissue regeneration in vitro and in vivo, and (vi) a biological defense weapon.
  • the nucleic acids and proteins of the invention have applications in the diagnosis and/or treatment of various diseases and disorders.
  • the compositions of the present invention will have efficacy for the treatment of patients suffering from: repair of damage to cartilage and ligaments; therapeutic applications to joint repair, as well as other diseases, disorders and conditions.
  • novel nucleic acid encoding the fibromodulin-like protein of the invention, or fragments thereof, are useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOVl protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOVl epitope is from about amino acids 30 to 32.
  • a contemplated NOVl epitope is from about amino acids 45 to 49. In other specific embodiments, contemplated NOVl epitopes are from about amino acids 65 to 80, 105 to 120, 140 to 150, 155 to 180, 190 to 192, 198 to 200, 210 to 215, 220 to 225, 230 to 250 and 280 to 300. NOV2
  • NOV2 includes three novel secretin receptor precursor-like proteins. The disclosed proteins have been named NOV2a, NOV2b, and NOV2c.
  • NOV2a A disclosed NOV2a nucleic acid (designated as CuraGen Acc. No. CG56213-01), which encodes a novel secretin receptor precursor-like protein includes the 1280 nucleotide sequence (SEQ ID NO:9) shown in Table 2A. An open reading frame for the mature protein was identified beginning with and ACT codon at nucleotides 1-3 and ending with a TGA codon at nucleotides 1264-1266. Putative untranslated regions are underlined in Table 2A, and the start and stop codons are in bold letters.
  • the nucleic acid sequence of NOV2amaps to chromosome 2ql4.1 has 868 of 932 bases (93%) identical to a gb:GENBANK-ID:HSU13989
  • acc:U13989.1 mRNA from Homo sapiens (Human secretin receptor mRNA, complete eds) (E 2.5e ⁇ ).
  • the NOV2a polypeptide (SEQ ID NO: 10) is 421 amino acid residues in length and is presented using the one-letter amino acid code in Table .
  • the SignalP, Psort and/or Hydropathy results predict that NOV2a is likely to be localized at the plasma membrane with a certainty of 0.6000.
  • a NON2a polypeptide is located to the Golgi body with a certainty of 0.4000, the endoplasmic reticulum (membrane) with a certainty of 0.3000, or the microbody (peroxisome) with a certainty of 0.3000.
  • Table IB Encoded NON2a Protein Sequence (SEQ ID ⁇ O:10)
  • NON2a is expressed in at least the following tissues: pancreas, lung. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources.
  • S ⁇ Ps small nucleotide polymorphisms
  • a disclosed NOV2b nucleic acid (designated as CuraGen Acc. No. CG56213-02), which includes the 789 nucleotide sequence (SEQ ID NO: 11) shown in Table 2D.
  • An open reading frame for the mature protein was identified with an ATG codon beginning at nucleotides 76-78 and ending with a TGA codon at nucleotides 559-561. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions are underlined and found upstream from the initiation codon and downstream from the termination codon.
  • the nucleic acid sequence of NOV2b maps to chromosome 2ql4.1 has 472 of 526 bases (89%) identical to a gb:GENBANK-ID:HSU28281
  • acc:U28281.1 mRNA from Homo sapiens (Human secretin receptor mRNA, complete eds) (E 4. Ie " ).
  • the NOV2b polypeptide (SEQ ID NO: 12) is 161 amino acid residues in length and is presented using the one-letter amino acid code in Table 2E.
  • the SignalP, Psort and/or Hydropathy results predict that NOV2b has a signal peptide and is likely to be localized at the plasma membrane with a certainty of 0.4600.
  • a NOV2b polypeptide is located to the microbody (peroxisome) with a certainty of 0.2543, the endoplasmic reticulum (membrane) with a certainty of 0.1000, or the endoplasmic reticulum (lumen) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV2b peptide between amino acid positions 61 and 62, i.e. at the dash in the sequence LHC-TR.
  • NOV2b is expressed in at least the following tissues: pancreas, lung. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence of NOV2b.
  • NOV2c nucleic acid designated as CuraGen Acc. No. CG56213-03
  • CuraGen Acc. No. CG56213-03 which includes the 1633 nucleotide sequence (SEQ ID NO: 13) shown in Table 2F.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 109-111 and ending with a TAA codon at nucleotides 979-981. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions are underlined and found upstream from the initiation codon and downstream from the termination codon.
  • Table 2F NOV2c Nucleotide Sequence (SEQ ID NO:13)
  • the nucleic acid sequence of NOV2c maps to chromosome 2ql4.1 invention has 960 of 961 bases (99%) identical to a gb:GENBANK-TD:HSU28281
  • acc:U28281.1 mRNA from Homo sapiens (Human secretin receptor mRNA, complete eds) (E 0.0).
  • the NOV2c polypeptide (SEQ ID NO: 14) is 290 amino acid residues in length and is presented using the one-letter amino acid code in Table 2G.
  • the SignalP, Psort and/or Hydropathy results predict that NOV2c has a signal peptide and is likely to be localized extracellularly at the plasma membrane with a certainty of 0.4600.
  • a NOV2c polypeptide is located to the microbody (peroxisome) with a certainty of 0.1589, the endoplasmic reticulum (membrane) with a certainty of 0.1000, or the endoplasmic reticulum (lumen) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV7c peptide between amino acid positions 27 and 28 at the dash in the sequence TGA-LP.
  • NOV2c is expressed in at least the following tissues: : pancreas, lung. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence of NOV2c.
  • NOV2a, NOV2b and NOV2c are very closely homologous as is shown in the amino acid alignment in Table 2H.
  • NOV2a SSSLVMLLVALGILCAFRRLHCTR YIHMHLFVSFILRALSGFIKDAVL] 176 NOV2b SSSLVMLLVALGILCAFRRLHCTR
  • NOV2a QLEVQKK QQ HLREFPLHPVASFSNSTKASHLEQSQGTCRTSII 421 NOV2b 1 61 NOV2c 290 Homologies to any of the above NOV2 proteins will be shared by the other NOV2 proteins insofar as they are homologous to each other as shown above. Any reference to NOV2 is assumed to refer to both of the NOV2 proteins in general, unless otherwise noted.
  • NOV2a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 21.
  • N0V2a 325 gi
  • Tables 2K, 2L and 2M list the domain description from DOMAIN analysis results against NOV2. This indicates that the NOV2 sequence has properties similar to those of other proteins known to contain these domains.
  • This extracellular domain contains four conserved cysteines that probably for disulphide bridges.
  • the domain is found in a variety of hormone receptors. It may be a ligand binding domain.
  • Secretin (SCT; OMHVI #182099) occupies a unique position in the history of gastrointestinal hormones because it was the first to be discovered, in duodenal mucosa by Bayliss and Starling (1902). This 27-amino acid peptide stimulates the secretion of bicarbonate, enzymes, and potassium ion by the pancreas. Ishihara et al. (1991) isolated a cDNA encoding the rat secretin receptor. The nucleotide sequence showed that the secretin receptor has a calculated molecular weight of 48,696.
  • OMIM #168468 parathyroid hormone receptor
  • OMIM #138032 glucagon-like receptor
  • OMBVI #114131 calcitonin receptor
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.
  • compositions of the present invention will have efficacy for treatment of patients suffering from: developmental diseases, MHCII and III diseases (immune diseases), taste and scent detectabihty disorders, Burkitt's lymphoma, corticoneurogenic disease, signal transduction pathway disorders, retinal diseases including those involving photoreception, cell growth rate disorders; cell shape disorders, feeding disorders; control of feeding; potential obesity due to over-eating; potential disorders due to starvation (lack of apetite), noninsulin-dependent diabetes mellitus (NIDDM1), bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), pain, cancer (including but not limited to Neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension
  • polypeptides can be used as immunogens to produce antibodies specific for the invention, and as vaccines. They can also be used to screen for potential agonist and antagonist compounds. or example, a cDNA encoding the NOV2 protein may be useful in gene therapy, and the NOV2 protein may be useful when administered to a subject in need thereof.
  • compositions of the present invention will have efficacy for treatment of patients suffering from bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-l or HIV-2), pain, cancer (including but not limited to Neoplasm; adenocarcinoma; lymphoma; prostate cancer; uterus cancer), anorexia, bulimia, asthma, Parkinson's disease, acute heart failure, hypotension, hypertension, urinary retention, osteoporosis, Crohn's disease; multiple sclerosis; and treatment of Albright hereditary ostoeodystrophy, angina pectoris, myocardial infarction, ulcers, asthma, allergies, benign prostatic hypertrophy, and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retardation and dyskinesias, such as Huntington's disease or Gilles de la Tourette syndrome and/or other pathologies and disorders.
  • cancer including but not limited to Neoplasm; adenocarcinoma; lymphoma; prostate
  • novel nucleic acid encoding the NOV2 protein, and the NOV2 protein of the invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation; colon cancer, colorectal cancer; colorectal cancer; familial nonpolyposis, type 6; esophageal cancer; hepatoblastoma; hypobetalipoproteinemia, familial, 2; lung
  • novel nucleic acid encoding the secretin receptor precursor-like protein of the invention, or fragments thereof, are useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV2 protein has multiple hydrophilic regions, each of which can be used as an immunogen. i one embodiment, a contemplated NOV2 epitope is from about amino acids 10 to 25.
  • a contemplated NOV2 epitope is from about amino acids 70 to 80.
  • contemplated NO V2 epitopes include from about amino acids 100 to 120, 160 to 170, 230 to 235, 255 to 260, 310 to 320, 370 to 380 and 400 to 405.
  • NOV3 NOV3 includes two novel B7-H2 like proteins.
  • the disclosed proteins have been named NOV3a and NOV3b.
  • a disclosed NOV3 a nucleic acid (designated as CuraGen Acc. No. CG55790-03), which encodes a novel B7-H2-like protein and includes the 1449 nucleotide sequence (SEQ ID NO: 15) shown in Table 3 A.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 2-4 and ending with a TGA codon at nucleotides 908-910. Putative untranslated regions downstream from the termination codon and upstream from the initiation codon are underlined in Table 3 A, and the start and stop codons are in bold letters.
  • the NOV3a polypeptide (SEQ ID NO: 16) is 302 amino acid residues in length and is presented using the one-letter amino acid code in Table 3B.
  • NOV3a has a signal peptide and is likely to be localized to the plasma membrane with a certainty of 0.4600.
  • a NOV3a polypeptide is located to the lysosome (lumen) with a certainty of 0.2000, the endoplasmic reticulum (membrane) with a certainty of 0.1000, or the endoplasmic reticulum (lumen) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for aNOV3a peptide between amino acid positions 18 and 19, i.e. at the dash in the sequence LRA-DT.
  • NOV3a amino acid sequence has 302 of 302 amino acid residues (100%) identical to, and 302 of 302 amino acid residues (100%) similar to, the 302 amino acid residue ptnr:TREMBLNEW-ACC:AAG01176 protein from Homo sapiens (Human) (TRANSMEMBRANE PROTE
  • NOV3a is expressed in at least the following tissues: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea and uterus. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence of NOV3a.
  • SNPs small nucleotide polymorphisms
  • a disclosed NOV3b nucleic acid (designated as CuraGen Acc. No. CG55790-04), encoding a novel B7-H2-like protein, which includes the 8250 nucleotide sequence (SEQ ID NO: 17) shown in Table 3E.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 4-6 and ending with a termination codon at nucleotides 1420-1422.
  • the start and stop codons of the open reading frame are highliglited in bold type. Putative untranslated regions are underlined and found upstream from the initiation codon and downstream from the termination codon.
  • Table 3E. NOV3b Nucleotide Sequence (SEQ ID NO:17)
  • MRLGSPGL F FSSLRADTQEKEVRAMVGSDVE SCACPEGSRFDLNDVYVY QTSESKTWTYHIPQNSSLENV DSRYRNRA MSPAGMLRGDFSLRLFNVTPQDEQKFHC VLSQS GFQEVLSVEVTLHVAANFSVPWSAPHSPSQD ELTFTCTSINGYPRP VYWINKTDNS LDQALQNDTVFLNMRGLYDVVSVLRIARTPSVNIGCCIE VLLQQMLTV GSQTGNDIGERDKITENPVSTGEKNAATWSILAVLCLL WAVAIGWVCRDRCLQHSYAGAWAVSPETE TGEFAV GSSRFWGAQGRLGCQ SFRVSK FQKAKVPC EQ LFLETQRSPRWCAWHF QPPLGMGWHPGVHFVT RWDFPNM HRSRETSARPPRSPVPSPDQGVQGGSRHRRPAPMGCPEWVQAPAPSPRGVSRAGPGTGAQPLWG SGSG
  • NOV3a and NOV3b are very closely homologous as is shown in the amino acid alignment in Table 3G.
  • NOV3a ⁇ RLGSPGLLF LFSSLRADTQEKEVRAMVGSDVELSCACPEGSRFDLRAID 1 NOV3b 4RLGSPGLLFLLFSSLRADTQEKEVRAMVGSDVELSCACPEGSRFDLSD
  • NOV3a iWVAVAIG VCRDRCLQHSYAGA AV 300
  • NOV3b AATWSILAVLCLLWVAVAIGWVCRDRCLQHSYAGAWAVSPETE TC 300
  • NOV3 Homologies to any of the above NOV3 proteins will be shared by the other NOV3 proteins insofar as they are homologous to each other as shown above. Any reference to NOV3 is assumed to refer to both of the NOV3 proteins in general, unless otherwise noted.
  • NOV3a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 3H.
  • N0V3a 58 sp I 075144 JFLLFSSLRADTQEKEVRAMVGSDVELSCACPEGSRFDL DVYVYWQTSI 100 ref
  • N0V3a 302 sp I 075144 SRFWGAQGRLGCQLSFRVSKNFQKAKVPCLEQLLFLETQRSPRWCARHFL 398 ref
  • N0V3a 302 sp I 075144 QPPLGMGWHPGVHFVTLRWDFPNMHRSRETSARPPRSPVPSPDQGVQGGS 448 ref
  • N0V3a 302 sp I 075144 MGCPEWVQAPAPSPRGVSRAGPGTGAQPLWGVWSGSGHRQLLSVAATPAA 548 ref
  • N0V3a 302 s I 075144 LVCPSVPGAT 558 ref
  • Table 3J lists the domain description from DOMAIN analysis results against NOV3. This indicates that the NOV3 sequence has properties similar to those of other proteins known to contain these domains.
  • IL interleukin
  • B7-1 and B7-2 share only -20% homology in their amino acids, they have similar tertiary structures and costimulatory functions.
  • B7-CD28 family may also participate in the regulation of cellular and humoral immune responses.
  • One of the new members is an inducible costimulator (ICOS), a CD28-like receptor.
  • An F44 monoclonal antibody (mAb) against human ICOS costimulates T-cell growth and increases secretion of several cytokines including IL-10, interferon-, and IL- 4, but not IL-2 in the presence of optimal doses of anti-CD3 antibody.
  • B7h /B7RP-1 Another new B7 family member is mouse B7h /B7RP-1.
  • B7h/B7RP-1 does not bind to CD28 and CTLA-4 and can costimulate T-cell growth in the presence of antigenic signals. It has been shown that surface expression of B7h/B7RP- 1 is up-regulated by tumor necrosis factor- in the 3T3 fibroblast line and the increase of B7h/B7RP-1 messenger RNA (mRNA) is also observed in nonlymphoid tissues exposed to lipopolysaccharide (LPS). It has been demonstrated that B7h/B7RP-1 is a ligand for mouse CRP-1, a mouse homologue ofhuman ICOS.
  • mRNA messenger RNA
  • B7RP-1 fusion protein in transgenic mice leads to hyperplasia in several lymphoid organs and treatment of mice with B7h/B7RP-1 fusion protein enhanced oxazolone-induced contact hypersensitivity.
  • a new member of the human B7 family, B7-H1 has recently been reported.
  • B7-H1 shares ⁇ 20% identical amino acid sequence with B7-1 and B7-2 in the Ig V- and Ig C-like extracellular domains but differs more profoundly from B7-1 andB7-2 in the cytoplasmic domain. It is unlikely that B7-H1 is a human homologue of mouse B7h/B7RP-1 because identity of amino acids between them is less than 30%.
  • B7- Hl does not bind to CD28, CTLA-4, and ICOS. Surface expression of B7-H1 canbe detected in the majority of activated CD14 + macrophages and a fraction of activated T cells.
  • B7-H1 costimulates T-cell responses in the presence of suboptimal doses of anti-CD3 mAb, enhances aUogeneic mixed lymphocyte response, and preferentially induces IL-10 secretion from T cells.
  • BJ homologue 2 B7-H2
  • B7-H2 protein is detected in monocyte-derived immature dendritic cells.
  • Soluble B7-H2 and immunoglobulin (Ig) fusion protein, B7-H2Ig binds activated but not resting T cells and the binding is abrogated by inducible costimulator Ig (ICOSIg), but not CTLA4Ig.
  • ICOSIg inducible costimulator Ig
  • CTLA4Ig CTLA4Ig
  • ICOSIg inducible costimulator Ig
  • ICOSIg stains Chinese hamster ovary cells transfected with B7-H2 gene.
  • costimulation of T-cell proliferation by B7-H2Ig is dose- dependent and correlates with secretion of interleukin (IL)-2, whereas optimal CD3 ligation preferentially stimulates IL-10 production.
  • IL interleukin
  • B7-H2 is a putative ligand for the ICOS T-cell molecule.
  • PMID 11023515
  • UI 20477846
  • the T cell-specific cell surface receptors CD28 and CTLA4 are important regulators of the immune system.
  • CD28 potently enhances those T-cell functions essential for an effective antigen-specific immune response
  • CTLA4 counterbalances the CD28-mediated signals and thus prevents an otherwise fatal overstimulation of the lymphoid system.
  • monoclonal antibodies against activated human T cells another member of this family of molecules, 'inducible costimulator,' symbolized ICOS has been identified.
  • the ICOS-specific monoclonal antibody did not react with resting human peripheral blood T cells, but stained CD4+ and CD 8+ T lymphocytes that had been activated by stimulation of the T-cell antigen receptor complex.
  • Immunoprecipitations defined the ICOS antigen as a disulfide-linked dimer with an apparent relative molecular mass of 55 to 60 kD.
  • Protein purification by SDS-PAGE indicated that ICOS is expressed on the cell surface as a homodimeric protein, with the 2 chains differing only in their posttranslational modification.
  • the full-length ICOS cDNA of 2,641 basepairs was cloned from a MOLT-4V T lymphoblast cDNA library.
  • the predicted mature ICOS is a type I transmembrane molecule that consists of a single immunoglobulin V-like domain, stabilized by conserved cysteine residues at positions 42 and 109; a transmembrane region of approximately 23 amino acids; and a cytoplasmic tail of 35 amino acids. It shows close structural resemblance to CD28 and CTLA4.
  • the cysteine residue located at position 141 of CD28, also found in CTLA4 is apparently involved in forming the disulfide bridge between the homodimeric chains of these proteins, and is also found in ICOS at position 136.
  • ICOS matches CD28 in potency and enhances all basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, upregulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B cells.
  • ICOS has to be de novo induced on the T-cell surface and does not upregulate the production of interleukin-2 (IL2), but superinduces the synthesis of interleukin- 10 (IL10), a B-cell differentiation factor.
  • IL2 interleukin-2
  • IL10 interleukin- 10
  • ICOS is highly expressed on tonsillar T cells, which are closely associated with B cells in the apical light zone of germinal centers, the site of tenninal B-cell maturation
  • Icos-deficient mice have been generated and it has been determined that the absence of Icos did not impair T-cell development. However, T-cell activation in terms of proliferation and IL2 production was impaired. Differentiated Icos -/- cells were able to produce IFNG but not IL4 or IL2. In vivo immunization also revealed a defect in IL2 and IL4 production and a reduction in serum IgGl and IgE. Using allergy models, _ it has been found that Icos was not required for Th2 cell differentiation, but rather it regulated IL4 and IL13 production.
  • EAE experimental autoimmune encephalitis
  • Icos -/- mice developed greatly enhanced disease compared with wildtype mice, even with a genetic background otherwise associated with resistance to EAE.
  • Splenocytes from the knockout and wildtype mice produced undetectable levels of IL4 and similar levels of IL10 and IFNG; however, cells from the Icos -/- mice produced no IL13, whereas wildtype mice made abundant amounts.
  • ICOS may have an important negative regulatory role, through the induction of IL13, in protection against inflammatory diseases.
  • Icos-deficient mice had similar basal levels of IgM, slightly elevated IgG3, and reduced IgGl, IgG2a, and IgE compared to wildtype mice.
  • Immunized knockout and wildtype mice except in the presence of the highly inflammatory complete Freund's adjuvant, also had similar levels of IgM- specific antibody but reduced IgGl- and IgG2a-specific antibody and reduced germinal center formation. Class switching from IgM to IgG was restored in Icos -/- mice by stimulation of CD40.
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • nucleic acids and proteins of the invention have applications in the diagnosis and/or treatment of various diseases and disorders.
  • compositions of the present invention may have efficacy for the treatment of patients suffering from brain disorders including epilepsy, eating disorders, schizophrenia, ADD, and cancer; heart disease; inflammation and autoimmune disorders including Crohn's disease, IBD, allergies, rheumatoid and osteoarthritis, inflammatory skin disorders, allergies, blood disorders; psoriasis colon cancer, leukemia AIDS; thalamus disorders; metabolic disorders including diabetes and obesity; lung diseases such as asthma, emphysema, cystic fibrosis, and cancer; pancreatic disorders including pancreatic insufficiency and cancer; and prostate disorders including prostate cancer, as well as other diseases, disorders and conditions.
  • brain disorders including epilepsy, eating disorders, schizophrenia, ADD, and cancer
  • heart disease inflammation and autoimmune disorders including Crohn's disease, IBD, allergies, rheumatoid and osteoarthritis, inflammatory skin disorders, allergies, blood disorders; psoriasis colon cancer, leukemia AIDS; thalamus disorders; metabolic
  • novel nucleic acid encoding the B7-H2-like protein of the invention, or fragments thereof, are useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti- NOVX Antibodies" section below.
  • the disclosed NOV3 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV3 epitope is from about amino acids 20 to 25.
  • a contemplated NOV3 epitope is from about amino acids 40 to 42. In other specific embodiments, contemplated NO V3 epitopes are from about amino acids 48 to 55, 60 to 75, 90 to 120, 145 to 180, 230 to 250 and 270 to 290.
  • NOV4 NOV4 includes two novel B7-Hl-like proteins. The disclosed proteins have been named NOV4a and NOV4b.
  • a disclosed NOV4a nucleic acid (designated as CG56110_01), encodes a novel B7- Hl-like protein and includes the 4582 nucleotide sequence (SEQ ID NO:19) shown in Table 4A.
  • An openreading frame for the mature protein was identified beginning with an ATG codon at nucleotides 10-12 and ending with a TAA codon at nucleotides 887-889. Putative untranslated regions downstream from the termination codon and upstream from the initiation codon are underlined in Table 4A, and the start and stop codons are in bold letters.
  • the nucleic acid sequence of NOV4a maps to chromosome 9 has 672 of 873 bases (76%) identical to a gb:GENBANK-ID:AF317088
  • acc:AF317088.1 mRNA from Mus musculus (Mus musculus B7-H1 protein mRNA, complete eds) (E 8.5e "106 ).
  • the NOV4a polypeptide (SEQ ID NO:20) is 290 amino acid residues in length and is presented using the one-letter amino acid code in Table 4B.
  • the SignalP, Psort and/or Hydropathy results predict that NOV4a has a signal peptide and is likely to be localized to the plasma membrane with a certainty of 0.4600.
  • a NOV4a polypeptide is located to the endoplasmic reticulum (membrane) with a certainty of 0.1000, the endoplasmic reticulum (lumen) with a certainty of 0.1000, or outside of the cell with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV4a peptide between amino acid positions 18 and 19, i.e. at the dash in the sequence LNA-FT.
  • NOV4a amino acid sequence has 202 of 290 amino acid residues (69%) identical to, and 236 of 290 amino acid residues (81%) similar to, the 290 amino acid residue ptnr:TREMBLNEW-ACC:AAG18509 protein from Mus musculus (Mouse) (PD-1-LIGAND PRECURS
  • NOV4a is expressed in at least the following tissues LPS treated dendritic cells, LPS treated monocytes and macrophages, brain, cervix, ovary, pituitary gland, placenta, uterus, whole organism. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and/or RACE sources.
  • SNPs small nucleotide polymorphisms
  • a disclosed NO V4b nucleic acid(designated as CG56110-04), which is a splice variant of NOV4a, includes the 745 nucleotide sequence (SEQ ID NO:21) shown in Table 4D.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 1-3 and ending with a TAG codon at nucleotides 535-537. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions are underlined and found upstream from the initiation codon and downstream from the termination codon.
  • the nucleic acid sequence of NOV4b maps to chromosome 9 and has 530 of 530 bases (100%) identical to a gb:GENBANK-ID:AF233516
  • acc:AF233516.1 mRNA from Homo sapiens (Homo sapiens PD-1-ligand precursor, mRNA, complete eds) (E 2.8e " ).
  • a NOV4b polypeptide (SEQ ID NO:22) is 178 amino acid residues and is presented using the one letter code in Table 4E. Signal P, Psort and/or Hydropathy results predict that NOV4b contains a signal peptide and is likely to be localized outside of the cell with a certainty of 0.4180. In other embodiments, NOV4b is localized to the endoplasmic reticulum (membrane) with a certainty of 0.1000, the endoplasmic reticulum (lumen) with a certainty of 0.1000 or the microbody (peroxisome) with a certainty of 0.1000. The most likely cleavage site for a NOV4b peptide is between amino acids 18 and 19, at: LNA-FT.
  • NOV4b is expressed in at least the following tissues: mammalian tissue, uterus. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence of NOV4b.
  • NOV4a and NON4b are very closely homologous as is shown in the amino acid alignment in Table 4F.
  • NOV4a 100 N0V4b l&Mwi «ft.al ⁇ ..a ⁇ »lN. ⁇ 100
  • N0V4a TTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLC 250 N0V4b 178
  • NOV4 Homologies to any of the above NOV4 proteins will be shared by the other NO V4 proteins insofar as they are homologous to each other as shown above. Any reference to NOV4 is assumed to refer to both of the NOV4 proteins in general, unless otherwise noted.
  • NOV4a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 4G.
  • Tables 41 and 4J list the domain description from DOMAIN analysis results against NOV4. This indicates that the NOV4 sequence has properties similar to those of other proteins known to contain these domains.
  • Length 86 residues , 98 . 8% aligned
  • Engagement of CTLA4 by B7-1 or B7-2 may inhibit proliferation and interleukin-2 (IL2) production.
  • IL2 interleukin-2
  • Antibody against the CD28-related molecule ICOS can stimulate T-cell growth and induce IL10 and IL4 production.
  • Binding analysis demonstrated no interaction between B7H1 and ICOS, CTLA4, or CD28. Stimulation of T cells in the presence of B7H1 enhanced proliferation and the preferential production of IL10 and gamma- interferon (IFNG), but not IL4, in an IL2-dependent manner.
  • IFNG gamma- interferon
  • RNA blot hybridization indicated that PDLl was upregulated in monocytes by treatment with IFNG and in dendritic cells and keratinocytes by treatment with IFNG together with other activators.
  • B7-1 and B7-2 were upregulated in parallel with PDLl. Expression of PDLl was also upregulated in B cells activated by surface Ig cross-linking.
  • iTIM cytoplasmic immunoreceptor tyrosine-based inhibitory motif
  • B7-1 (CD80) and B7-2 (CD86) are genetically and structurally related molecules expressed on antigen-presenting cells. Both bind CD28 to co-stimulate T lymphocytes, resulting in proliferation and cytokine production.
  • the extracellular portions of B7-1 and B7-2 which bind to CD28 and CTLA-4 are related to Ig variable (V) and Ig constant (C) domain sequences.
  • V Ig variable
  • C Ig constant
  • B7-1 and B7-2 soluble recombinant forms of B7-1 and B7-2 containing either both of the Ig-like extracellular domains or the individual IgV or IgC domains coupled to an Ig Fc tail.
  • Soluble B7-1 and B7-2 bind to CD28 and CTLA-4, and effectively co-stimulate T lymphocytes resulting in their proliferation and the secretion of cytokines.
  • the IgV domain of B7-2 binds CD28 and CTLA-4, competes with B7-1 and B7-2 for binding to these receptors, and co-stimulates T lymphocytes.
  • Cross-linked soluble B7-2v was the most potent co- stimulatory molecule tested and was active at a concentration approximately 100-fold lower than cross-linked soluble B7-1 or B7-2 proteins. When bound to tosyl-activated beads, B7-2v was capable of sustaining multiple rounds of T cell expansion. These data complement the description of naturally occurring variants to suggest that T cell co-stimulation in vivo may be regulated by soluble or truncated forms of B7 proteins.
  • B7 family members like B7RP-1 (B7 Related Protein-1), B7-1, and B7-2, with antigen receptors such as CD28, CTLA-4 (Cytotoxic T Lymphocyte-associated Antigen 4) and ICOS (Inducible Co-Stimulatory molecule).
  • B7RP-1 B7 Related Protein-1
  • B7-1, and B7-2 antigen receptors
  • antigen receptors such as CD28, CTLA-4 (Cytotoxic T Lymphocyte-associated Antigen 4) and ICOS (Inducible Co-Stimulatory molecule).
  • CD28 CD28
  • CTLA-4 Cytotoxic T Lymphocyte-associated Antigen 4
  • ICOS Insulible Co-Stimulatory molecule
  • ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature. 409, 97-101 (2001).; McAdam, A.J., et al. ICOS is critical for CD40- mediated antibody class switching. Nature. 409, 102-105 (2001).; Tafuri, A., et al. ICOS is essential for effective T-helper-cell responses. Nature. 409, 105-109 (2001).; Yoshinaga, S.K., et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature.
  • the B7 family members B7-1 and B7-2 interact with CD28 and constitute an essential T-cell co-stimulatory pathway in the initiation of antigen-specific humoral and cell-mediated immune response.
  • B7-H1 a third member of the B7 family, called B7-H1 that does not bind CD28, cytotoxic T-lymphocyte A4 or ICOS (inducible co-stimulator).
  • B7-H1 a third member of the B7 family
  • ICOS inducible co-stimulator
  • CD28 OMFM #186760
  • B7-1 CD80; OMLM #112203
  • B7-2 CD86; OMIM #601020
  • Engagement of CTLA4 OMIM #123890
  • B7-1 or B7-2 may inhibit proliferation and interleukin-2 (IL2; OMIM #147680) production.
  • IL2 interleukin-2
  • Antibody against the CD28-related molecule ICOS can stimulate T-cell growth and induce IL10 (OMTM #124092) and IL4 (OMTM #147780) production.
  • IL10 OMTM #124092
  • IL4 OMTM #147780
  • B7-1 and B7-2 homologs By searching an EST database for B7-1 and B7-2 homologs, followed by RT-PCR of a placenta cDNA library, Dong et al. (1999) obtained a cDNA encoding B7-H1 (B7 homolog-1). Sequence analysis predicted that the 290-amino acid type I transmembrane protein, which is 20% and 15% identical to B7-1 and B7-2, respectively, has immunoglobulin V-like and C-like domains and a 30-amino acid cytoplasmic tail.
  • Northern blot analysis detected 4.1- and 7.2-kb B7-H1 transcripts most abundantly in heart, skeletal muscle, placenta, and lung, with weak expression in thymus, spleen, kidney, and liver, and no expression in brain, colon, and small intestine.
  • Fluorescence-activated cell sorting (FACS) analysis demonstrated B7-H1 expression on a fraction of monocytes and, weakly, on T and B cells. Activation significantly increased expression on both T cells and monocytes, and, to a lesser extent, on B cells.
  • Binding analysis demonstrated no interaction between B7-H1 and ICOS, CTLA4, or CD28. Stimulation of T cells in the presence of B7-H1 enhanced proliferation and the preferential production of IL10 and gamma-interferon (IFNG; OMIM #147570), but not IL4, in an IL2-dependent manner.
  • IFNG gamma-interferon
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool.
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • compositions of the present invention will have efficacy for treatment of patients suffering from: brain disorders including epilepsy, eating disorders, schizophrenia, ADD, and cancer; heart disease; inflammation and autoimmune disorders including Crohn's disease, IBD, allergies, rheumatoid and osteoarthritis, inflammatory skin disorders, blood disorders; psoriasis colon cancer, leukemia AIDS; thalamus disorders; metabolic disorders including diabetes and obesity; lung diseases such as asthma, emphysema, cystic fibrosis, and cancer; pancreatic disorders including pancreatic insufficiency and cancer; and prostate disorders including prostate cancer, immune-mediated pathogenesis, T-cell- mediated diseases, multiple sclerosis, colitis, cancer, trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections and other diseases, disorders and conditions of the like.
  • brain disorders including epilepsy, eating disorders, schizophrenia, ADD, and cancer
  • heart disease inflammation and autoimmune disorders including Crohn's disease, IBD, allergies,
  • a contemplated NOV4 epitope is from about amino acids 40 to 45. In another embodiment, a contemplated NOV4 epitope is from about amino acids 52 to 55.
  • contemplated NOV4 epitopes are from about amino acids 60 to 68, 70 to 90, 110 to 112, 130 to 140, 142 to 145, 150 to 155, 157 to 160, 175 to 190, 220 to 240 and 260 to 280.
  • NOV5 includes two novel prostasin-like proteins. The disclosed proteins have been named NOV5a and NOV5b.
  • a disclosed NOV5a nucleic acid (designated as CuraGen Acc. No. CG56142-01), encodes a novel prostasin-like protein and includes the 866 nucleotide sequence (SEQ ID NO:23) shown in Table 5A.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 19-21 and ending with a TGA codon at nucleotides 820-822. Putative untranslated regions downstream from the termination codon and upstream from the initiation codon are underlined in Table 2A, and the start and stop codons are in bold letters.
  • Table 5A NOV5a Nucleotide Sequence (SEQ ID NO:23)
  • the nucleic acid sequence of NOV5a maps to chromosome 16 has 421 of 639 bases (65%) identical to a gb:GENBANK-ID:AF175522
  • acc:AF175522.1 mRNA from Homo sapiens (Homo sapiens transmembrane tryptase mRNA, complete eds) (E 1.2e "30 ).
  • the NOV5a polypeptide (SEQ ID NO:25) is 267 amino acid residues in length and is presented using the one-letter amino acid code in Table 5B.
  • the SignalP, Psort and/or Hydropathy results predict that NOV5a has a signal peptide and is likely to be localized outside of the cell with a certainty of 0.6902.
  • a NOV5a polypeptide is located to the endoplasmic reticulum (membrane) with a certainty of 0.1000, the endoplasmic reticulum (lumen) with a certainty of 0.1000, or the lysosome (lumen) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV5a peptide between amino acid positions 18 and 19, i.e. at the dash in the sequence ACG-QP.
  • NOV5a is expressed in at least the following tissues: endometrium cancer tissue. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and/or RACE sources. Possible small nucleotide polymorphisms (SNPs) found for NOV5a are listed in Tables
  • a disclose NOV5b nucleic acid (designated as CuraGen Acc. No. CG56142-02), encodes a novel prostasin-like protein and includes the 1020 nucleotide sequence (SEQ ID NO:25) shown in Table 5D.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 91-93 and ending with a TAA codon at nucleotides 931-933. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions are underlined and found upstream from the initiation codon and downstream from the termination codon.
  • the nucleic acid sequence of NOV5bmaps to chromosome 16 has 561 of 863 bases (65%) identical to a gb:GENBANK-ID:HSA306593
  • acc:AJ306593.1 mRNA from Homo sapiens (Homo sapiens mRNA for marapsin (MPN gene)) (E 4.8e "47 ).
  • NOV5b polypeptide (SEQ ID NO:26) is 280 amino acid residues in length and is presented using the one-letter amino acid code in Table 5E.
  • NOV5b polypeptide is located to the plasma membrane with a certainty of 0.1900, the endoplasmic reticulum (lumen) with a certainty of 0.1000, or the outside of the cell with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV5b peptide between amino acid positions 22 and 23, i.e. at the dash in the sequence TQG-RK.
  • NOV5a and NOV5b are very closely homologous as is shown in the amino acid alignment in Table 5F.
  • NOV5a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 5G.
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool.
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.
  • compositions of the present invention will have efficacy for treatment of patients suffering from: cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, cancer, trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis , atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, s
  • novel nucleic acid encoding the prostasin-like protein of the invention, or fragments thereof, are useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods.
  • These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV5 protein has multiple
  • a contemplated NOV5 epitope is from about amino acids 30 to 35. In another embodiment, a contemplated NOV5 epitope is from about amino acids 40 to 45. In other specific embodiments, contemplated NO V5 epitopes are from about amino acids 70 to 80, 95 to 105, 110 to 115, 140 to 150, 160 to 170, 175 to 180, 190 to 195, 220 to 225, 230 to 240, 245 to 248, 249 to 252 and 260 to 262.
  • NOV6 includes three novel lysosomal acid lipase-like proteins.
  • the disclosed proteins have been named NOV6a and NOV6b.
  • a disclosed NOV6a nucleic acid (designated as CuraGen Acc. No. CG50159-01), encodes a novel lysosomal acid lipase-like protem and includes the 1267 nucleotide sequence (SEQ ID NO:27) shown in Table 6A.
  • SEQ ID NO:27 1267 nucleotide sequence shown in Table 6A.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 9-10 and ending with a TAA codon at nucleotides 1127-1129.
  • Putative untranslated regions downstream from the termination codon and upstream from the initiation codon are underlined in Table 6A, and the start and stop codons are in bold letters.
  • the nucleic acid sequence of NOV6a maps to chromosome 10 and has 545 of 820 bases (66%) identical to a gb:GENBANK- ⁇ D:RNLIP
  • acc:X02309.1 mRNA from Rattus norvegicus (Rat mRNA for lingual lipase) (E 2.5e "71 ).
  • the NOV6a polypeptide (SEQ ID NO:28) is 373 amino acid residues in length and is presented using the one-letter amino acid code in Table 6B.
  • the SignalP, Psort and/or Hydropathy results predict that NOV6a has a signal peptide and is likely to be localized to the lysosome (lumen) with a certainty of 0.5500.
  • aNOV6a polypeptide is located to the outside of the cell with a certainty of 0.3700, the microbody (peroxisome) with a certainty of 0.2967, or the endoplasmic reticulum (membrane) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV6a peptide between amino acid positions 17 and 18, i.e. at the dash in the sequence LNA-GG.
  • SNPs small nucleotide polymorphisms
  • NOV6b A disclosed NOV6b nucleic acid (designated as CuraGen Acc. No. CG50159-02), encodes a novel lysosomal acid lipase-like protein and includes the 1267 nucleotide sequence (SEQ ID NO:29) shown in Table 6D.
  • SEQ ID NO:29 An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 8-10 and ending with a TAA codon at nucleotides 1126-1128. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions are underlined and found upstream from the initiation codon and downstream from the termination codon.
  • the nucleic acid sequence of NOV6b maps to chromosome 17 and has 545 of 820 bases (66%) identical to a gb:GENBANK-ID:RNL ⁇ P
  • acc :X02309.1 mRNA from Rattus norvegicus (Rat mRNA for lingual lipase) (E 2.5e "71 ).
  • the NOV6b polypeptide (SEQ ID NO:30) is 373 amino acid residues in length and is presented using the one-letter amino acid code in Table 6E.
  • the SignalP, Psort and/or Hydropathy results predict that NOV6b has a signal peptide and is likely to be localized to the lysosome (lumen) with a certainty of 0.5500.
  • a NOV6b polypeptide is located to the outside of the cell with a certainty of 0.3700, the microbody (peroxisome) with a certainty of 0.2967, or the endoplasmic reticulum (membrane) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for aNOV6b peptide between amino acid positions 17 and 18, i.e. at the dash in the sequence LNA-GG.
  • a disclosed NOV6c nucleic acid (designated as CuraGen Acc. No. CG50159-04), encodes a novel lysosomal acid lipase-like protein and includes the 1195 nucleotide sequence (SEQ ID NO:30) shown in Table 6F.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 8-10 and ending with a TAA codon at nucleotides 1126-1128. The start and stop codons of the open reading frame are highlighted in bold type. Putative untranslated regions are underlined and found upstream from the initiation codon and downstream from the termination codon.
  • the nucleic acid sequence of NOV6c maps to chromosome 10 and has 557 of 827 bases (67%) identical to a gb:GENBANK-ID:A01046
  • acc:A01046.1 mRNA from Homo sapiens (H.sapiens mRNA for human gastric lipase) (E 2.5e "71 ).
  • the NOV6c polypeptide (SEQ ID NO:30) is 349 amino acid residues in length and is presented using the one-letter amino acid code in Table 6G.
  • the SignalP, Psort and/or Hydropathy results predict that NOV6c has a signal peptide and is likely to be localized to the lysosome (lumen) with a certainty of 0.8306.
  • a NOV6c polypeptide is located to the outside of the cell with a certainty of 0.3700, the microbody (peroxisome) with a certainty of 0.2944, or the endoplasmic reticulum (membrane) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV6b peptide. between amino acid positions 17 and 18, i.e. at the dash in the sequence LNA-GG. Table 6G. Encoded NOV6c Protein Sequence (SEQ ID NO:32)
  • NOV6c is expressed in at least the following tissues: pooled mammalian tissues. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the NOV6c sequence.
  • NOV6a, NOV6b and NOV6c are very closely homologous as is shown in the amino acid alignment in Table 6H.
  • NOV6 Homologies to any of the above NOV6 proteins will be shared by the other NOV6 proteins insofar as they are homologous to each other as shown above. Any reference to NOV6 is assumed to refer to both of the NOV6 proteins in general, unless otherwise noted.
  • NOV6a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 61.
  • lipase A 351 307/373 307/373 e-174 l
  • lipase A precursor 399 192/370 251/370 e-107 l
  • Table 6K list the domain description from DOMAIN analysis results against NOV6. This indicates that the NOV6 sequence has properties similar to those of other proteins known to contain these domains.
  • Length 226 residues, 96.0% aligned
  • LIPB Lysosomal acid lipase-A
  • LIP A Lysosomal acid lipase-A
  • LIPA may serve an important role in cellular metabolism by releasing cholesterol. The liberated cholesterol suppresses further cholesterol synthesis and stimulates esterification of cholesterol within the cell.
  • Lysosomal acid lipase (LIPA, or LAL), otherwise known as acid cholesteryl ester hydrolase, is coded for by a gene (LIPA) on chromosome 10.
  • LIPA Lysosomal acid lipase
  • CHD milder late- onset cholesteryl ester storage disease
  • Xanthomatous changes were observed in the liver, adrenal, spleen, lymph nodes, bone marrow, small intestine, lungs and thymus, and slight changes were found in the skin, retina, and central nervous system.
  • the adrenals were calcified. Death was thought to be due to intestinal malabsorption resulting from involvement of the gut.
  • the parents, Persian Jews, were cousins. Lipids in the plasma were normal or moderately elevated.
  • Several features suggested that the entity is distinct from hypercholesterolemia and the hyperlipidemias (q.v.). Three cases, the first from the U.S.A., were reported by Crocker et al. (Pediatrics 35: 627-640, 1965), who gave no information on ethnicity.
  • the relatively nonspecific clinical picture includes poor weight gain, vomiting, diarrhea, increasing hepatosplenomegaly with abdominal protuberance, and death by nutritional failure by 2 to 4 months of age.
  • Foam cells are found in bone marrow and vacuolated lymphocytes in peripheral blood, as in Niemann-Pick disease (257200). Diffuse punctate calcification of the adrenals is typical. Disseminated foam cell infiltration is found in many organs. Great increases in cholesterol are found in the organs.
  • Konno et al. Tohoku J. Exp. Med. 90: 375-389, 1966
  • Konno et al. Tohoku J. Exp. Med. 90: 375-389, 1966
  • Konno et al. Tohoku J. Exp. Med. 90: 375-389, 1966
  • Konno et al. Tohoku J. Exp. Med. 90: 375-389, 1966
  • Spiegel- Adolf et al. Confin. Neurol
  • cholesterol ester storage disease is a disorder allelic to Wolman disease (Assmann and Fredrickson: Acid lipase deficiency (Wolman's disease and cholesteryl ester storage disease).In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S. : Metabolic Basis of Inherited Disease. New York: McGraw- Hill (pub.) (5th ed.) 1983. Pp.
  • the chemical and enzymatic abnormalities are similar.
  • the marked difference in phenotypic expression is unexplained but is comparable to the difference between Hurler and Scheie syndromes, the late infantile and adult forms of metachromatic leukodystrophy, and the classic and visceral forms (A and B) of Niemann-Pick disease. Each of these is presumably a pair of allelic disorders.
  • Soluble glutamate oxaloacetate transaminase (138180) is also on chromosome lOq in man and 19 in mouse.
  • Anderson et al. Genomics 15: 245-247, 1993
  • Anderson and Sando J. Biol. Chem.
  • Pagani et al. (Hum. Molec. Genet. 5: 1611-1617,1996) described the molecular basis of CESD in 3 patients. They identified mutations by sequence analysis of LAL cDNA and genomic DNA. The role of the mutations as the direct cause of the disease was confirmed by measuring the LAL enzymatic activity of extracts from cells transfected with LAL mutants. The 3 CESD patients were found to be compound heterozygotes. Pagani et al. (1996) identified 3 different missense mutations, 2 splicing defects, and a null allele. Du et al. (Hum. Molec. Genet.
  • Homozygous knockout mice produced no Lipl mRNA, protein, or enzyme activity.
  • the homozygous deficient mice were born in mendelian ratios, were normal appearing at birth, and followed normal development into adulthood.
  • massive accumulation of triglycerides and cholesteryl esters occurred in several organs.
  • the liver developed a yellow- orange color and was up to 2 times larger than normal.
  • the accumulated cholesteryl esters and triglycerides were approximately 30-fold greater than normal.
  • the heterozygous mice had approximately 50% of normal enzyme activity and did not show lipid accumulation.
  • mice Male and female homozygous deficient mice were fertile and could be bred to produce progeny.
  • This mouse model is the phenotypic model ofhuman CESD and a biochemical and histopathologic mimic ofhuman Wolman disease.
  • ALLELIC VARIANTS selected examples
  • .0001 CHOLESTERYL ESTER STORAGE DISEASE [LIPA, LEU179PRO]
  • the female patient had an umbilical cord herniation at birth. At about 30 days after birth, she showed abdominal distention with hepatosplenomegaly and frequent episodes of diarrhea and vomiting. Abdominal computed tomography revealed massive hepatosplenomegaly and enlargement of the adrenal glands with calcification. Anemia and hepatic failure progressed rapidly and she died at age 114 days. The parents were first cousins. An older sister had died with similar symptoms 80 days after birth.
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • a protein therapeutic such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), (v) an agent promoting tissue regeneration in vitro and in vivo, and (vi) a biological defense weapon.
  • the nucleic acids and proteins of the invention have applications in the diagnosis and/or treatment of various diseases and disorders.
  • the compositions of the present invention will have efficacy for the treatment of patients suffering from: severe infantile-onset Wolman disease and the milder late-onset cholesteryl ester storage disease (CESD), obesity, diabetes, Von Hippel-Lindau (VHL) syndrome, and pancreatitis as well as other diseases, disorders and conditions.
  • CECD severe infantile-onset Wolman disease and the milder late-onset cholesteryl ester storage disease
  • VHL Von Hippel-Lindau
  • pancreatitis as well as other diseases, disorders and conditions.
  • the novel nucleic acid encoding the polydom-like protein of the invention, or fragments thereof, are useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • a contemplated NOV6 epitope is from about amino acids 40 to 60.
  • a contemplated NOV6 epitope is from about amino acids 70 to 80.
  • contemplated NOV6 epitopes are from about amino acids 90 to 95, 110 to 140, 150 to 152, 155 to 157, 240 to 250, 270 to 280, 310 to 315 and 320 to 325.
  • a disclosed NOV7 nucleic acid (alternatively referred to herein as CG56140-01) encodes a novel tryptase 4-like protein and includes the 1608 nucleotide sequence (SEQ ID NO:33) shown in Table 7A.
  • SEQ ID NO:33 1608 nucleotide sequence shown in Table 7A.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 1-3 and ending with a TGA codon at nucleotides 1279-1281. Putative untranslated regions are underlined in Table 7 A, and the start and stop codons are in bold letters.
  • the nucleic acid sequence of NOV7 maps to chromosome 16 and invention has 587 of 853 bases (68%) identical to a gb:GENBANK-ID:AB031329
  • acc:AB031329.1 mRNA from Homo sapiens (Homo sapiens esp-1 mRNA for eosinophil serine protease, complete eds) (E 5Je "58 ).
  • the NOV7 polypeptide (SEQ ID NO:34) is 426 amino acid residues in length and is presented using the one-letter amino acid code in Table 7B.
  • the SignalP, Psort and/or Hydropathy results predict that NOV7 has a signal peptide and is likely to be localized lysosome (lumen) with a certainty of 0.5500.
  • a NOV7 polypeptide is located to the outside of the cell with a certainty of 0.3700, the plasma membrane with a certainty of 0.1900, or the endoplasmic reticulum (membrane) with a certainty of 0.1000.
  • the SignalP predicts a likely cleavage site for a NOV7 peptide between amino acid positions 19 and 20, i.e. at the dash in the sequence GLG-KP
  • NOV7 is expressed in at least the following tissues: pancreas. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and/or RACE sources.
  • NOV7 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 7C.
  • Tables 7E and 7F list the domain description from DOMAIN analysis results against NOV7. This indicates that the NOV7 sequence has properties similar to those of other proteins known to contain these domains.
  • tryptase is a structurally unique and mast cell specific trypsin-like serine protease. Recent biological and immunological investigations have implicated tryptase as a mediator in the pathology of numerous allergic and inflammatory conditions including rhinitis, conjunctivitis, and most notably asthma. A growing body of data further implicates tryptase in certain gastrointestinal, dermatological, and cardiovascular disorders as well. The recent availability of potent, and selective tryptase inhibitors, though, has facilitated the validation of this protease as an important therapeutic target as well.
  • peptidic inhibitors e.g., APC-366
  • dibasic inhibitors i.e., pentamidine-like
  • Zn(2+)-mediated inhibitors i.e., BABIM-like
  • heparin antagonists e.g., lactoferrin
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.
  • compositions of the present invention will have efficacy for treatment of patients suffering from: diabetes, Von Hippel-Lindau (NHL) syndrome , pancreatitis, obesity, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, transplantation, fertility, endometriosis,
  • VSD ventricular septal defect
  • novel nucleic acid encoding the novel tryptase-4 protein of the invention, or fragments thereof, are useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods.
  • These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti- ⁇ OVX Antibodies" section below.
  • the disclosed ⁇ ON7 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated ⁇ ON7 epitope is from about amino acids 10 to 15.
  • a contemplated ⁇ ON7 epitope is from about amino acids 20 to 25.
  • contemplated ⁇ ON7 epitopes are from about amino acids 40 to 60, 70 to 80, 80 to 85, 120 to 160, 180 to 200, 220 to 260, 280 to 300, 340 to 360 and 420 to 430.
  • a disclosed NOV8 nucleic acid (designated as CuraGen Acc. No. CG56134-01), encodes a novel P450-like protein and includes the 1539 nucleotide sequence (SEQ ID NO:35) shown in Table 8A.
  • SEQ ID NO:35 1539 nucleotide sequence shown in Table 8A.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 1-3 and ending with a TAA codon at nucleotides 1537- 1539.
  • the start and stop codons are in bold letters in Table 8 A.
  • the nucleic acid sequence of NOV8 maps to chromosome 4 and has 158 of 252 bases (62%) identical to a gb:GENBANK-ID:AF251548
  • acc:AF251548.1 mRNA from Tribolium castaneum (Tribolium castaneum cytochrome P450 monooxigenase CYP4Q4 (CYP4Q4) mRNA, complete eds) (E 1.5e " ° 6 ).
  • the NOV8 polypeptide (SEQ ID NO:36) is 512 amino acid residues in length and is presented using the one-letter amino acid code in Table 8B.
  • the SignalP, Psort and/or Hydropathy results predict that NOV8 has a signal peptide and is likely to be localized to the plasma membrane with a certainty of 0.6000.
  • a NOV8 polypeptide is located to the Golgi body with a certainty of 0.4000, the mitochondrial intermembrane space with a certainty of 0.3131, or the endoplasmic reticulum (membrane) with a certainty of 0.3000.
  • the SignalP predicts a likely cleavage site for a NOV8 peptide between amino acid positions 39 and 40, i.e. at the dash in the sequence VAS-YA
  • ⁇ OV8 is expressed in at least the following tissues: liver, lung. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and/or
  • NOV8 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 8C.
  • N0V8 (SEQ ID NO : 36 )
  • the P450 gene superfamily is a biologically diverse class of oxidase enzymes; members of the class are found in all organisms.
  • P450 proteins are clinically and toxicologically important in humans; they are the principal enzymes in the metabolism of drugs and xenobiotic compounds, as well as in the synthesis of cholesterol, steroids and other lipids. Induction of some P450 genes can also be a risk factor for several types of cancer. This diversity of function is mirrored in the diversity of nucleotide and protein sequences; there are currently over 100 human P450 forms described. Allelic forms of many cytochrome P450 genes have been identified as causing quantitatively different rates of drug metabolism, and hence are important to consider in the development of safe and effective human pharmaceutical therapies, [reviewed in E. Tanaka, J Clinical Pharmacy & Therapeutics 24:323-329, 1999].
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool.
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.
  • novel nucleic acid encoding the P450-like protein of the invention, or fragments thereof, are useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies maybe generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti- NOVX Antibodies" section below.
  • the disclosed NOV8 protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV8 epitope is from about amino acids 20 to 25.
  • a contemplated NOV8 epitope is from about amino acids 80 to 85.
  • contemplated NOV8 epitopes are from about amino acids 110 to 115, 140 to 145, 202 to 205, 220 to 320, 330 to 335, 380 to 405, 420 to 425 and 490 to 500.
  • a disclosed NO V9 is nucleic acid (designated as CuraGen Acc. No. CG56207-01, encodes a novel mitsugumin29-like protein and includes the 813 nucleotide sequence (SEQ ID NO: 37) shown in Table 9 A.
  • An open reading frame for the mature protein was identified beginning at nucleotide 1 and ending with a TAA codon at nucleotides 805-807. Putative untranslated regions downstream from the termination codon are underlined in Table 9A, and the stop codon is in bold letters.
  • the NOV9 polypeptide (SEQ ID NO: 37) is 268 amino acid residues in length and is presented using the one-letter amino acid code in Table 9B.
  • the SignalP, Psort and/or Hydropathy results predict that NOV9 has a signal peptide and is likely to be localized to the plasma membrane with a certainty of 0.6000.
  • a NOV9 polypeptide is located to the Golgi body with a certainty of 0.4000, the endoplasmic reticulum (membrane) with a certainty of 0.3000, or the microbody (peroxisome) with a certainty of 0.3000.
  • the SignalP predicts a likely cleavage site for a NOV9 peptide between amino acid positions 50 and 51, i.e. at the dash in the sequence SCG-SY.
  • NOV9 is expressed in at least the following tissues: brain, skeletal muscle, heart. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and/or RACE sources.
  • SNPs small nucleotide polymorphisms
  • NOV9 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 9D.
  • Synaptophysin and synaptoporin are related glycoproteins: they are the major integral membrane proteins of a certain class of small neurosecretory vesicles, although they may also be found in vesicles of various non-endocrine cells [1, 2].
  • the polypeptide chain spans the membrane four times and possibly acts as an ion or solute channel.
  • mitsugumin29 unique to the triad junction in skeletal muscle was identified as a novel member of the synaptophysin family; the members of this family have four transmembrane segments and are distributed on intracellular vesicles.
  • Mouse mitsugumin29 cDNA and genomic DNA containing the gene has been isolated and analyzed.
  • the mitsugumin29 gene mapped to the mouse chromosome 3 F3-H2 is closely related to the synaptophysin gene in exon-intron organization, which indicates their intimate relationship in molecular evolution.
  • RNA blot hybridization and immunoblot analysis revealed that mitsugumin29 is expressed abundantly in skeletal muscle and at lower levels in the kidney, hnmunofluorescence microscopy demonstrated that mitsugumin29 exists specifically in cytoplasmic regions of the proximal and distal tubule cells in the kidney. The results obtained may suggest that mitsugumin29 is involved in the formation of specialized endoplasmic reticulum systems in skeletal muscle and renal tubule cells.
  • excitation-contraction (E-C) coupling requires the conversion of the depolarization signal of the invaginated surface membrane, namely the transverse (T-) tubule, to Ca2+ release from the sarcoplasmic reticulum (SR).
  • Signal transduction occurs at the junctional complex between the T-tubule and SR, designated as the triad junction, which contains two components essential for E-C coupling, namely the dihydropyridine receptor as the T-tubular voltage sensor and the ryanodine receptor as the SR Ca2+-release channel.
  • MG29 mitsugumin29
  • T cell surface transverse
  • SR sarcoplasmic reticulum
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool.
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.
  • compositions of the present invention will have efficacy for treatment of patients suffering from: Wiskott-Aldrich syndrome, Aldrich syndrome, eczema-thrombocytopenia-iirrmunodeficiency syndrome, thrombocytopenia, night blindness, amyotrophic lateral sclerosis, Batten disease, ceroid lipofuscinosis, Rett syndrome, Pick disease (lobar atrophy), cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, Von Hip
  • compositions of the present invention will have efficacy for treatment of patients suffering from: diabetes,Von Hippel-Lindau (VHL) syndrome , pancreatitis, obesity, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, transplantation, fertility, endometriosis, Hirschsprung's disease , Crohn's disease, appendicitis and other diseases, disorders and conditions of the like.
  • VHL diabetes,Von Hippel-Lindau
  • pancreatitis obesity
  • cardiomyopathy atherosclerosis
  • hypertension congenital heart defects
  • aortic stenosis atrial septal defect
  • A-V atrioventricular canal
  • novel nucleic acid encoding the mitsugumin 29 protein of the invention, or fragments thereof, are useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV9 protein has multiple hydrophilic regions, each of which can be used as an immunogen. In one embodiment, a contemplated NOV9 epitope is from about amino acids 20 to 25.
  • a contemplated NOV9 epitope is from about amino acids 30 to 35. In other specific embodiments, contemplated NOV9 epitopes are from about amino acids 60 to 65, 75 to 105, 145 to 155, 170 to 175, 180 to 185 and 240 to 260.
  • the disclosed NOV10 nucleic acid (designated as CuraGen Acc. No. CG56127-01), encodes a novel micromolar calcium-activated neutral protease 1 -like protem and includes the 2542 nucleotide sequence (SEQ ID NO: 39) shown in Table 10A.
  • SEQ ID NO: 39 The 2542 nucleotide sequence shown in Table 10A.
  • An open reading frame for the mature protein was identified beginning with an ATG codon at nucleotides 260-262 and ending with a TAA codon at nucleotides 2318-2320. Putative untranslated regions downstream from the termination codon and upstream from the initiation codon are underlined in Table 10A, and the start and stop codons are in bold letters.
  • the nucleic acid sequence of NOVIO maps to chromosome 2 and has 574 of 909 bases (63%) identical to a gb:GENBANK-ID:AF221129
  • acc:AF221129.1 mRNA from Bos taurus (Bos taurus micromolar calcium-dependent neutral protease large subunit (CAPN1) mRNA, complete eds) (E 1.4e "31 ).
  • the NOVIO polypeptide (SEQ ID NO:39) is 686 amino acid residues in length and is presented using the one-letter amino acid code in Table 10B.
  • the SignalP, Psort and/or Hydropathy results predict that NOVIO is likely to be localized microbody (peroxisome) with a certainty of 0.7480.
  • a NOV10 polypeptide is located to the plasma membrane with a certainty of 0.7000, the endoplasmic reticulum (membrane) with a certainty of 0.2000, or the mitochondrial inner membrane with a certainty of 0.1000.
  • NOVIO is expressed in at least the following tissues: pancreas, colon, skin, lung, breast, uterus, placenta, lymph, leukopheresis, eye, and marrow. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and or RACE sources.
  • NOVIO also has homology to the amino acid sequences shown in the BLASTP data listed in Table IOC.
  • Tables 10E and 10F list the domain description from DOMAIN analysis results against NOVIO. This indicates that the NOVIO sequence has properties similar to those of other proteins known to contain these domains.
  • the predicted sequence described here belongs to the calpain protease family.
  • the calpains, or calcium-activated neutral proteases, are nonlysosomal intracellular cysteine proteases (Richard, et al.). Calpain is an intracellular protease involved in many important cellular functions that are regulated by calcium.
  • the mammalian calpains include 2 ubiquitous proteins, CAPNl and CAPN2, as well as 2 stomach-specific proteins, and CAPN3, which is muscle-specific.
  • the ubiquitous enzymes consist of heterodimers with distinct large subunits associated with a common small subunit, all of which are encoded by different genes. The association of tissue-specific large subunits with a small subunit has not yet been demonstrated.
  • the large subunits of calpains can be subdivided into 4 domains; domains I and III, whose functions remain unknown, show no homology with known proteins. The former, however, may be important for the regulation of the proteolytic activity. Domain II shows similarity with other cysteine proteases, which share histidine, cysteine, and asparagine residues at their active sites. Domain TV comprises 4 EF-hand structures that are potential calcium-binding sites. In addition, 3 unique regions with no known homology are present in the muscle-specific CAPN protein, namely NS, IS1, and IS2, the latter containing a nuclear translocation signal. These regions may be important for the muscle-specific function of CAPN3 (Richard, et al.).
  • LGMD2A limb girdle muscular dystrophy type 2A
  • capn3-deficient mice are fully fertile and viable. Allele transmission in intercross progeny demonstrated a statistically significant departure from Mendel's law. capn3 -deficient mice show a mild progressive muscular dystrophy that affects a specific group of muscles. The age of appearance of myopathic features varies with the genetic background, suggesting the involvement of modifier genes.
  • Affected muscles manifest a similar apoptosis-associated perturbation of the IkappaBalpha/nuclear factor kappaB pathway as seen in LGMD2A patients, hi addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations (Richard, et al).
  • SS Sjogren syndrome
  • Anti-Fas antibody-induced apoptotic salivary gland cells result in specific alpha-fodrin cleavage to the 120 kDa fragment in vitro.
  • Preincubation with a combination of calpain and caspase inhibitor peptides could be responsible for inhibition of the 120 kDa alpha-fodrin cleavage.
  • an increase in apoptotic protease activities including calpain and caspases may be involved in the progression of alpha-fodrin proteolysis and tissue destruction in the development of SS (Hayashi et al).
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool.
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.
  • compositions of the present invention will have efficacy for treatment of patients suffering from: diabetes, Von Hippel-Lindau (VHL) syndrome, pancreatitis, obesity, hypercalceimia, ulcers, endometriosis, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, autoimmume disease, allergies, immunodeficiencies, transplantation, graft versus host disease, psoriasis, actinic keratosis, tuberous sclerosis, acne, hair growth/loss, allopecia, pigmentation disorders, endocrine disorders, hemophilia, lymphaedema, and other diseases, disorders and conditions of the like.
  • VHL Von Hippel-Lindau
  • novel nucleic acid encoding micromolar calcium-activated neutral protease-1 protein of the invention, or fragments thereof, are useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. These materials are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOVIO protein has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOVIO epitope is from about amino acids 5 to 90.
  • a contemplated NOVIO epitope is from about amino acids 105 to 110.
  • contemplated NOV10 epitopes are from about amino acids 170 to 180, 230 to 310, 370 to 400, 420 to 430, 450 to 455, 460 to 465, 480 to 485, 510 to 515, 570 to 580 and 680 to 690.
  • a disclosed NOV11 nucleic acid (designated CuraGen Acc. No. CG56179-01) encodes a novel P2X2C-like protein and includes the 1422 nucleotide sequence (SEQ ID NO: 41) which is shown in Table 11 A.
  • SEQ ID NO: 41 1422 nucleotide sequence which is shown in Table 11 A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TGA codon at nucleotides 1420-1422.
  • the start and stop codons are in bold letters in Table 11 A.
  • the nucleic acid sequence of NON11 maps to chromosome 1 and has 990 of 991 bases (99%) identical to a gb:GE ⁇ BA ⁇ K-ID:AF190824
  • acc:AF190824.1 mRNA from Homo sapiens (Homo sapiens P2X2C receptor (P2X2) mRNA, complete eds) (E 3.6e "295 ).
  • a NOVl 1 polypeptide (SEQ ID NO:42) is 473 amino acid residues and is presented using the one letter code in Table 1 IB. The SignalP, Psort and/or Hydropathy results predict that NOVl 1 has a signal peptide and is likely to be localized to the mitochondrial inner membrane with a certainty of 0.6577.
  • a NOVl 1 polypeptide is located to the plasma membrane with a certainty of 0.6500, the microbody (peroxisome) with a certainty of 0.3556, or the Golgi body with a certainty of 0.3000.
  • the SignalP predicts a likely cleavage site for a NOVl 1 peptide between amino acid positions 68 and 69, i.e. at the dash in the sequence SYQ-ES.
  • NOVl 1 is expressed in at least the following tissues: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum; brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus.
  • tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and/or RACE sources.
  • SNPs small nucleotide polymorphisms found for NOVl 1 are listed in Tables l lC and l lD.
  • NOVl 1 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 1 IE.
  • Table 1 IG lists the domain description from DOMAIN analysis results aga NOVl 1. This indicates that the NOVl 1 sequence has properties similar to those o proteins known to contain these domains.
  • P2X receptors are membrane ion channels gated by extracellular adenosine triphosphate (ATP); nucleotides also activate a family of seven transmembrane G p coupled receptors (P2Y).
  • P2X recept'ors are widely expressed on mammalian cells, can be broadly differentiated into three groups. The first group is almost equally w ⁇ by ATP and its analog alpha beta methyleneATP (alpha beta meATP), whereas a s ⁇ is not activated by alpha beta meATP.
  • a third-group type of receptor distinguished by the fact that the channel opening is followed by cell permeabilizat lysis if the agonist application is continued for more than a few seconds. Seven cD] been cloned that encode P2X receptor subunits. When expressed individually in he systems, P2X1 and P2X3 subunits form channels activated by ATP or alpha beta rr whereas P2X2, P2X4, and P2X5 form channels activated by ATP but not alpha bet P2X6 receptors do not express readily, and P2X7 receptors correspond closely in tl properties to P2Z. Further phenotypes can be produced when two subunits are coex indicating hetero-multimerization.
  • Electrophysiological experiments on dissociated muscle and neurons have revealed three distinct phenotypes of P2X receptor: (1) a desensitizing, beta-methylene ATP-sensitive response typical of most smooth muse non-desensitizing, alpha,beta-methylene ATP-insensitive response characteristic oi phaeochromocytoma cells and rat superior cervical ganglion neurons; and (3) a nor desensitizing, alpha, beta-methylene ATP-sensitive response observed in sensory n
  • the third phenotype observed in native cell- result from co-assembly of subunits of the cloned receptors.
  • co-expressic show that these two forms of the P2X receptor do not heteropolymerize. Therefore. desensitizing, alpha, beta-methylene ATP-sensitive response observed in sensory n result from a distinct P2X receptor or from heteropolymerization of more than one P2X purinoceptor.
  • P2X receptor cDNAs There are seven P2X receptor cDNAs currently known. Six homomeric (P2 P2X3, P2X4, P2X5, P2X7) and three heteromeric (P2X2/P2X3, P2X4/P2X6, P2X1 P2X receptor channels have been characterized in heterologous expression systems Homomeric P2X1 and P2X3 receptors are readily distinguishable by their rapid desensitization, the agonist action of alpha beta methyleneATP, and the block by 2' (2,4,6-trinitrophenyl)-ATP. P2X2 receptors are unique among homomeric forms in potentiation by low pH.
  • Homomeric P2X4 receptors are much less sensitive to anta suramin and pyridoxal 5-phosphate-6-azo-2',4'-disulfonic acid.
  • Homomeric P2X7 r are the only form in which 2',3'-O-(4-benzoylbenzoyl)-ATP is more potent than Al heteromeric P2X2 P2X3 receptor resembles P2X2 in slow desensitization kinetics ; potentiation by low pH and is similar to P2X3 with respect to agonism by alpha bet methyleneATP and block by 2',3'-O-(2,4,6-trinitrophenyl)-ATP.
  • P2X3 receptors are selectively ⁇ predominantly on small-diameter nociceptive sensory neurones in the dorsal root, ti and nodose ganglia, particularly the non-peptidergic subpopulations labelled with ti IB4.
  • P2X2/3 labelling is also present in inner lamina II of the spinal cord and in ser projections to skin and viscera, but few receptors are present in skeletal muscle.
  • P2. receptors are down-regulated after peripheral nerve injury and their expression can regulated by glial cell-derived neurotrophic factor.
  • P2X receptor activation of sense neurones has been demonstrated in in vivo pain models, including the rat hindpaw i joint preparations, as well as in inflammatory models.
  • P2X4 and/or P2X6 receptors also seem to be involved in pain pathways.
  • Non-nociceptive P2 receptors on sensoi are present in muscle and on sensory endings in the heart and lung that initiate refle involving vagal afferent and efferent nerve fibres.
  • the protein similarity information, expression pattern, and map location for NOVl 1 protein and nucleic acid disclosed herein suggest that it may have importai and/or physiological functions characteristic of the ATP P2X receptor family.
  • Ther nucleic acids and proteins of the invention are useful in potential diagnostic and the applications and as a research tool.
  • a protein therapeutic serving as a specific or selective or protein diagnostic and/or prognostic marker, wherein the presence or amount of acid or the protein are to be assessed, as well as potential therapeutic applications s following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antiboi (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid usef therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regei vitro and in vivo (vi) biological defense weapon.
  • compositions of the present invention are useful in potential diagn therapeutic applications implicated in various diseases and disorders described belc other pathologies.
  • the compositions of the present invention may hav ⁇ for treatment of patients suffering from pain, since P2X receptor activation of sense neurones has been demonstrated in in vivo pain models, including the rat hindpaw ; joint preparations, as well as in inflammatory models.
  • P2X4 and/or P2X6 receptors also seem to be involved in pain pathways.
  • Non-nociceptive P2 receptors on sensoi are present in muscle and on sensory endings in the heart and lung that initiate reflc- involving vagal afferent and efferent nerve fibres (Br J Anaesth 2000 Apr;84(4):47 compositions of the present invention may also have efficacy for treatment of patie suffering from diabetes, obesity, syndrome X, and other diseases, disorders and cor the like.
  • the novel nucleic acid encoding the P2X2C-like protein of the invention, o: thereof, are useful in diagnostic applications, wherein the presence or amount of th ⁇ acid or the protein are to be assessed. These materials are further useful in the gene antibodies that bind immunospecifically to the novel substances of the invention fo therapeutic or diagnostic methods.
  • NOVl 1 protein has multiple hyc regions, each of which can be used as an immunogen.
  • a contei NOVl 1 epitope is from about amino acids 5 to 10.
  • a conte NOVl 1 epitope is from about amino acids 20 to 25.
  • - contemplated NOVl 1 epitopes are from about amino acids 40 to 50, 70 to 80, 95 tc to 148, 195 to 215, 250 to 300, 340 to 360, 370 to 380, 410 to 430 and 455 to 465.
  • NOV12 nucleic acid designated CuraGen Acc. No. CG56132- a novel DIABLO-like protein and includes 1823 nucleotides (SEQ ID NO: 43) whi in Table 12 A.
  • An open reading frame was identified beginning with an ATG initiat at nucleotides 31-33 and ending with a TGA codon at nucleotides 1606-1608. Puta untranslated regions upstream from the initiation codon and downstream from the t codon are underlined in Table 12 A, and the start and stop codons are in bold letters Table 12A.
  • NOV12 Nucleotide Sequence SEQ ID NO:43
  • the nucleic acid sequence of NOVl 2 invention has 909 of 918 bases (99% ⁇ to a gb:GENBANK-ID:AK000088
  • a NOV12 polypeptide (SEQ ID NO:43) is 525 amino acid residues and is r using the one letter code in Table 12B.
  • the SignalP, Psort and/or Hydropathy resu that NOVl 2 is likely to be localized to the endoplasmic reticulum (membrane) wit! of 0.8500.
  • a NOV12 polypeptide is located to the plas membrane with a certainty of 0.4400, the microbody (peroxisome) with a certainty or the mitochondrial inner membrane with a certainty of 0.1000.
  • the NOVl 2 in this invention is expressed in at least the following tissues: I hypothalamus, kidney, prostate, retina, tonsils, breast, whole organism. This inforn derived by determining the tissue sources of the sequences that were included in th including but not limited to SeqCalling sources, Public EST sources, Literature sou RACE sources.
  • NOVl 2 also has homology to the amino acid sequences shown in the BLAJ listed in Table 12C.
  • Tables 12E, 12F and 12G list the domain description from DOMAIN analy; against NOVl 2. This indicates that the NOVl 2 sequence has properties similar to other proteins known to contain these domains.
  • Apoptosis or programmed cell death is an essential process in metazoan de ⁇ and homeostasis that is carried out by caspases.
  • the DIABLO protein direct LAP t protein with low pi
  • IAPs inhibitor of apoptosis proteins
  • This protein is also Smac for second mitochondria-derived activator of caspase.
  • DIABLO/Smac is non mitochondrial protein but is released into the cytosol when cells undergo apoptosis Mitochondrial import and cleavage of its signal peptide are required for DIABLO/5 gain its apoptotic activity.
  • DIABLO/Smac has been increase cellular sensitivity to apoptotic stimuli (2).
  • the protein described in this invention is homologous to the DIABLO/Sma and is therefore predicted to play a role in apoptosis. It contains a BTB/POZ domai five copies of the kelch motif. The BTB/POZ domain has been shown to mediate h dimerisation and in some instances heteromeric dimerization (3).
  • Kelch is a 50-resi named after the Drosophila mutant in which it was first identified (4). The known f kelch-containing proteins are diverse.
  • the gene described in this invention maps to chromosome 14 and based on its expression pattern may contribute to a number of diseases such as cancer, inflammation/autoimmune diseases, metabolic diseases an disorders, among others.
  • diseases such as cancer, inflammation/autoimmune diseases, metabolic diseases an disorders, among others.
  • this gene may be useful as a diagnostic or prognostic gene therapy.
  • NOVl 2 protein and nucleic acid disclosed herein suggest that NOVl 2 may have in structural and/or physiological functions characteristic of the DIABLO family.
  • the nucleic acids and proteins of the invention are useful in potential diagnostic and the applications and as a research tool.
  • a protein therapeutic serving as a specific or selective or protein diagnostic and/or prognostic marker, wherein the presence or amount of acid or the protein are to be assessed, as well as potential therapeutic applications s following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antiboi (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid usef therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regei vitro and in vivo (vi) biological defense weapon.
  • compositions of the present invention will have for treatment of patients suffering from: cancer, trauma, bacterial and viral infectio; regeneration (in vitro and in vivo), fertility, diabetes, autoimmune disease, renal art stenosis, interstitial nephritis, glomerulonephritis, polycystic kidney disease, syste ⁇ erythematosus, renal tubular acidosis, IgA nephropathy, hypercalceimia, Lesch-Ny syndrome, Von Hippel-Lindau (VHL) syndrome, tuberous sclerosis, endocrine disc Alzheimer's disease, stroke, hypercalceimia, Parkinson's disease, Huntington's dise cerebral palsy, epilepsy, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, disorders, addiction, anxiety, pain, neurode
  • the novel nucleic acid encoding the DIABLO-like protein of the i fragments thereof are useful in diagnostic applications, wherein the presence or an nucleic acid or the protein are to be assessed. These materials are further useful in generation of antibodies that bind immunospecifically to the novel substances of th for use in therapeutic or diagnostic methods. These antibodies may be generated ac methods known in the art, using prediction from hydrophobicity charts, as describe "Anti-NOVX Antibodies" section below.
  • the disclosed NOVl 2 protein has multij hydrophilic regions, each of which can be used as an immunogen. In one embodin contemplated NOVl 2 epitope is from about amino acids 5 to 7. In another embodi contemplated NOVl 2 epitope is from about amino acids 10 to 15.
  • contemplated NOV12 epitopes are from about amino acids 80 to 90, 140 to 145, 170 to 180, 190 to 192, 198 to 205, 220 to 270, 295, 320, 340 to 370, 4 420 to 470, 490 to 500.
  • a disclosed NOV13 nucleic acid designated CuraGen Acc. No. CG56195- a novel HRPET-1 related protein- like protein and includes 1970 nucleotides (SEQ is shown in Table 13 A.
  • the nucleic acid sequence of NOVl 3 maps to chromosome 22 and has 891 bases (72%) identical to a gb:GENBANK-ID:AK023192
  • acc:AK023192.1 mRNA sapiens (Homo sapiens cDNA FLJ13130 fis, clone NT2RP3002972, weakly simila Halocynthia roretzi mRNA for HrPET-1) (E 0.0).
  • a NOV13 polypeptide (SEQ LD NO:46) is 508 amino acid residues and is r using the one letter code in Table 13B.
  • Signal P, Psort and/or Hydropathy results p NOVl 3 is likely to be localized at the plasma membrane with a certainty of 0.7000 embodiement, NOVl 3 is likely to be localized to the nucleus with a certainty of 0.- endoplasmic reticulum (membrane) with a certainty of 0.2000 or the mitochondrial membrane with a certainty of 0.1000.
  • the NOVl 3 amino acid sequence have 438 of 438 amino acid residues (10 ⁇ identical to, and 438 of 438 amino acid residues (100%) similar to, the 438 amino .
  • NOVl 3 is expressed in at least the following tissues: bone marrow, brain, b dermis, epidermis, heart, kidney, liver, lung, lymph node, lymphoid tissue, mamma information was derived by determining the tissue sources of the sequences that wc in the invention including but not limited to SeqCalling sources, Public EST source Literature sources, and/or RACE sources.
  • sequence is predicted to expressed in the following tissues because of the expression pattern of (GENBANI gb:GENBANK-LD:AK023192
  • Tables 13E and 13F list the domain description from DOMAIN analysis re NOVl 3. This indicates that the NOVl 3 sequence has properties similar to those o proteins known to contain these domains.
  • NOVl 3 is highly conserved across species, among C. elegans, Drosophila, human. It's predicted to be membrane associated. The high conservation in primary indicates that it has important biological functions, although currently unknown. TI 1 related protein also shows homology with plant adhesion molecules, suggesting t HRPET-1 related protein is likely a cell adhesion molecule involved in cell interacl migration.
  • NOVl 3 protein and nucleic acid disclosed herein suggest that it may have importai and or physiological functions characteristic of the cell adhesion molecule family.
  • the nucleic acids and proteins of the invention are useful in potential diagnostic anc therapeutic applications and as a research tool. These include serving as a specific ⁇ nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence c of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule ⁇
  • an antibody target therapeutic, diagnostic, drug targeting/cytotoxic antibody
  • nucleic acid useful in gene therapy gene delivery/gene ablation
  • a compos promoting tissue regeneration in vitro and in vivo biological defense weapon.
  • compositions of the present invention will hav ⁇ for treatment of patients suffering from: cardiomyopathy, atherosclerosis, hyperten congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular s (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, di; Hippel-Lindau (VHL) syndrome, pancreatitis, fertility, endometriosis, xerostomia, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, autoimmume allergies, immunodeficiencies, graft versus host disease, lymphedema , hemophilia hypercoagulation, Alzheimer's disease, stroke
  • the novel nucleic acid encoding the HRPET-1 related protein of the invent fragments thereof are useful in diagnostic applications, wherein the presence or an nucleic acid or the protein are to be assessed. These materials are further useful in generation of antibodies that bind immunospecifically to the novel substances of tb for use in therapeutic or diagnostic methods. These antibodies may be generated a ⁇ methods known in the art, using prediction from hydrophobicity charts, as describe "Anti-NOVX Antibodies" section below.
  • the disclosed NOVl 3 protein has multi] hydrophilic regions, each of which can be used as an immunogen. In one embodin contemplated NOVl 3 epitope is from about amino acids 2 to 70. In another embo ⁇ contemplated NOVl 3 epitope is from about amino acids 90 to 120.
  • contemplated NOVl 3 epitopes are from about amino acids 125 to 21 215, 220 to 230, 310 to 320, 380 to 390, 390 to 398, 410 to 425 and 480 to 500.
  • a disclosed NOV14 nucleic acid (designated CuraGen Acc. No. CG55790- encoding a B7-H2-like protein includes 8270 nucleotides (SEQ ID NO: 47) and is Table 14A.
  • An open reading frame was identified beginning with an ATG initiatio nucleotides 24-26 and ending with a TAG codon at nucleotides 1443-1445.
  • a put. untranslated region downstream from the termination codon is underlined in Table the start and stop codons are in bold letters.
  • Table 14A. NOV14 Nucleotide Sequence (SEQ ID NO:47)
  • the nucleic acid sequence of NOVl 4 maps to chromosome 21 and has 480 bases (79%) identical to a gb:GENBANK-ID:AP001753
  • acc:AP001753.1 mRNA sapiens (Homo sapiens genomic DNA, chromosome 21q, section 97/105) (E 1.5 ⁇
  • a NOVl 4 polypeptide (SEQ ID NO:48) is 473 amino acid residues and is ] using the one letter code in Table 14B. Signal P, Psort and/or Hydropathy results ] NOVl 4 contains a signal peptide and is likely to be localized at the plasma membi certainty of 0.4600. In other embodiments, NOVl 4 is localized to the endoplasmic (membrane) with a certainty of 0.1000, endoplasmic reticulum (lumen) with a certa 0.1000 or the outside of the cell with a certainty of 0.1000. The most likely cleavaj NOV14 peptide is between amino acids 18 and 19, at: LRA-DT.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

Cette invention se rapporte à des séquences d'acides nucléiques qui codent de nouveaux polypeptides. Cette invention concerne également des polypeptides codés par ces séquences d'acides nucléiques et des anticorps, qui se fixent de façon immunospécifique à ces polypeptides, ainsi que des dérivés, des variants, des mutants ou des fragments d'un tel polypeptide, polynucléotide ou anticorps. Cette invention concerne en outre des procédés thérapeutiques, diagnostiques et de recherche pour le diagnostic, le traitement et la prévention d'affections impliquant l'un de ces nouveaux acides nucléiques et protéines humains.
EP02761846A 2001-01-16 2002-01-16 Proteines, polynucleotides codant pour celles-ci et methodes les utilisant Ceased EP1370659A2 (fr)

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US26245401P 2001-01-18 2001-01-18
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US265530 2001-01-31
US26859501P 2001-02-14 2001-02-14
US27240901P 2001-02-28 2001-02-28
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US27677701P 2001-03-16 2001-03-16
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US29167201P 2001-05-17 2001-05-17
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US34520201P 2001-11-09 2001-11-09
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CN114891069A (zh) * 2022-05-13 2022-08-12 厦门大学 特异性靶向mCNα的二元环肽配体及其获得方法
CN117417432A (zh) * 2023-12-18 2024-01-19 海南热带海洋学院崖州湾创新研究院 红鳍东方鲀生长激素及其应用

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Publication number Priority date Publication date Assignee Title
CN114470154A (zh) * 2022-01-27 2022-05-13 华南理工大学 一种甜杏仁油糖蛋白酚酸纳米肠道益生菌促进剂及其制备和应用
CN114470154B (zh) * 2022-01-27 2023-11-07 华南理工大学 一种甜杏仁油糖蛋白酚酸纳米肠道益生菌促进剂及其制备和应用
CN114891069A (zh) * 2022-05-13 2022-08-12 厦门大学 特异性靶向mCNα的二元环肽配体及其获得方法
CN114891069B (zh) * 2022-05-13 2024-01-30 厦门大学 特异性靶向mCNα的二元环肽配体及其获得方法
CN117417432A (zh) * 2023-12-18 2024-01-19 海南热带海洋学院崖州湾创新研究院 红鳍东方鲀生长激素及其应用
CN117417432B (zh) * 2023-12-18 2024-03-01 海南热带海洋学院崖州湾创新研究院 红鳍东方鲀生长激素及其应用

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