WO2002066643A2 - Proteines, polynucleotides codant pour ces proteines et procedes d'utilisation - Google Patents

Proteines, polynucleotides codant pour ces proteines et procedes d'utilisation Download PDF

Info

Publication number
WO2002066643A2
WO2002066643A2 PCT/US2001/048732 US0148732W WO02066643A2 WO 2002066643 A2 WO2002066643 A2 WO 2002066643A2 US 0148732 W US0148732 W US 0148732W WO 02066643 A2 WO02066643 A2 WO 02066643A2
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
polypeptide
nucleic acid
seq
ofthe
Prior art date
Application number
PCT/US2001/048732
Other languages
English (en)
Other versions
WO2002066643A3 (fr
Inventor
Uriel M. Malyankar
Suresh G. Shenoy
Kimberly A. Spytek
Bryan D. Zerhusen
Meera Patturajan
Xiaojia Guo
Ramesh Kekuda
Esha A. Gangolli
Richard A. Shimkets
Raymond J. Taupier, Jr.
Li Li
Muralidhara Padigaru
Original Assignee
Curagen Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Curagen Corporation filed Critical Curagen Corporation
Publication of WO2002066643A2 publication Critical patent/WO2002066643A2/fr
Publication of WO2002066643A3 publication Critical patent/WO2002066643A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
    • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
    • C12N9/2462—Lysozyme (3.2.1.17)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants

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 ofthe following protein families: Membrane protein/neuropilin/metalloproteinase- like protein-like, Fibrillin-like, KIAAl 589-like, WD 40 motif-like, Opioid Bing Cell Adhesion Molecule-like, Triacylglycerol lipase-like, IGE Receptor Beta Subunit-like, Munc 18-like, Immunoglobulin-like and Type II Cytokeratin-like. 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.
  • Neuropilins play an active role in angiogenesis as they are receptors for VEGF and may regulate VEGF-induced angiogenesis. Neuropilins are also expressed by tumor cells and may play a role in tumor angiogenesis. Neuropilins also play a role in axon guidance as they bind to semaphorins and and in combination with plexins regulate the signal transduction events in neurons. Hence neuropilin-like molecules play an important role in embryonic development and the dedifferention events seen in cancer. These molecules probably play an important role in regulation of angiogenesis, cancer, development and neurological conditions.
  • the MAM domain is characteristic ofthe extracellular region of membrane associated proteins such as meprin (a cell surface glycoprotein); A5 antigen (a developmentally-regulated cell surface protein); and receptor-like tyrosine protein phosphatase. These proteins although functionally diverse; resemble receptors comprising a signal peptide, an N-terminal extracellular domain, a single transmembrane domain and an intracellular domain.
  • the MAM domain might play a role in cell adhesion.
  • Fibrillin is a very large molecule whose primary structure is now known from the cloning and sequencing of 10 kb of cDNA. Fibrillin is the major component of extracellular micro fibrils and is widely distributed in connective tissue throughout the body. Mutations in the fibrillin- 1 (FBN1) gene, on chromosome 15q21.1, have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities.
  • FBN1 fibrillin- 1
  • Fibrillin- 1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg syndrome (PMID: 9401003, PMLD: 8575254, PMID: 7584608).
  • Opioid binding cell adhesion molecules are members ofthe cell adhesion molecule family with homology to the immunoglobulin protein superfamily. OBCAMs are seen both in the developing nervous system as well as in the mature adult brain. They may play a role in neuronal outgrowth and development, probably by modulating cell-cell interactions. In addition, OBCAMs are known to affect the regulation and functioning of opioid receptors. Chronic morphine treatment downregulates the expression of at least one member of this family. Therefore, these proteins could mediate long-term effects on brain function by opioid usage and may be used as a therapeutic in that context.
  • pancreatic triglyceride lipase is essential for the efficient digestion of dietary fats.
  • Pancreatic triglyceride lipase is the archetype ofthe lipase gene family that includes two homologues of pancreatic triglyceride lipase, pancreatic lipase-related proteins 1 and 2.
  • the cDNA sequences encoding pancreatic triglyceride lipase and the related proteins have been described.
  • pancreatic triglyceride lipase has been determined alone and in a complex with colipase, a pancreatic protein required for lipase activity in the duodenum (Lowe, Molecular mechanisms of rat and human pancreatic triglyceride lipases. J Nutr 127(4):549-57, 1997).
  • Fc epsilon RI The high-affinity receptor for immunoglobulin E, Fc epsilon RI, is found exclusively on mast cells and basophils. When multivalent allergens bind to the receptor-bound IgE, the consequent aggregation ofthe receptors leads to the release of mediators responsible for allergic symptoms.
  • Fc epsilon RI is a tetrameric complex of non-covalently attached subunits: one IgE-binding alpha subunit, one beta subunit and a dimer of disulphide- linked gamma subunits (Blank et al., Complete structure and expression in transfected cells of high affinity IgE receptor. Nature 337(6203).T87-9, 1989).
  • IgE receptors of mast cells Fc epsilon RI
  • Fc epsilon RI localize to coated pits and internalize after cross-linking.
  • Muncl8-1 The Muncl8-2 gene comprises 19 exons whose sizes range from 50 to 158 bp, with a total gene size of approximately 11 kb. A single transcript of 2.1 kb is expressed in multiple non-neuronal murine tissues. Muncl8-2 has a striking resemblance to Muncl8-1 in structure despite only 60% sequence identity, suggesting a recent gene duplication event (Agrawal et al., Gene structure and promoter function of murine Muncl8-2, a nonneuronal exocytic Seel homo log. Biochem Biophys Res Commun 276(3):817-22, 2000).
  • 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 NOVX, or NOV1, NOV2, NOV3, NOV4, NOV5, NOV6, NOV7, NOV8, NOV9 and NOV10 nucleic acids and polypeptides.
  • NOVX nucleic acid or polypeptide sequences.
  • the invention provides an isolated NOVX nucleic acid molecule encoding a NOVX polypeptide that includes a nucleic acid sequence that has identity to the nucleic acids disclosed in SEQ ID NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45 and 47.
  • the NOVX 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 NOVX nucleic acid sequence.
  • the invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, 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 NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46 and 48.
  • 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 LO NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45 and 47.
  • an oligonucleotide e.g., an oligonucleotide which includes at least 6 contiguous nucleotides of a NOVX nucleic acid (e.g., SEQ LD NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45 and 47) or a complement of said oligonucleotide.
  • a NOVX nucleic acid e.g., SEQ LD NOS:l, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45 and 47
  • substantially purified NOVX polypeptides SEQ LD NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46 and 48).
  • the NOVX polypeptides include an amino acid sequence that is substantially identical to the amino acid sequence of a human NOVX polypeptide.
  • the invention also features antibodies that immunoselectively bind to NOVX polypeptides, or fragments, homologs, analogs or derivatives thereof.
  • the invention includes pharmaceutical compositions that include therapeutically- or prophylactically-effective amounts of a therapeutic and a pharmaceutically- acceptable carrier.
  • the therapeutic can be, e.g., a NOVX nucleic acid, a NOVX polypeptide, or an antibody specific for a NOVX polypeptide.
  • the invention includes, in one or more containers, a therapeutically- or prophylactically-effective amount of this pharmaceutical composition.
  • the invention includes a method of producing a polypeptide by culturing a cell that includes a NOVX nucleic acid, under conditions allowing for expression of the NOVX polypeptide encoded by the DNA. If desired, the NOVX polypeptide can then be recovered.
  • the invention includes a method of detecting the presence of a NOVX polypeptide in a sample.
  • 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 NOVX 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 NOVX nucleic acid molecule in a sample by contacting the sample with a NOVX nucleic acid probe or primer, and detecting whether the nucleic acid probe or primer bound to a NOVX nucleic acid molecule in the sample.
  • the invention provides a method for modulating the activity of a NOVX polypeptide by contacting a cell sample that includes the NOVX polypeptide with a compound that binds to the NOVX 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, Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch-Nyhan 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 arach
  • the therapeutic can be, e.g., a NOVX nucleic acid, a NOVX polypeptide, or a NOVX- specific antibody, or biologically-active derivatives or fragments thereof.
  • the compositions ofthe present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders ofthe 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 cDNA encoding NOVX may be useful in gene therapy, and NOVX may be useful when administered to a subject in need thereof.
  • the compositions ofthe present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders ofthe 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 ofthe like.
  • the method includes contacting a test compound with a NOVX polypeptide and determining if the test compound binds to said NOVX polypeptide. Binding ofthe test compound to the NOVX 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 ofthe 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 ofthe 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 NOVX polypeptide is then measured in the test animal, as is expression or activity ofthe protein in a control animal which recombinantly- expresses NOVX polypeptide and is not at increased risk for the disorder or syndrome.
  • the expression of NOVX polypeptide in both the test animal and the control animal is compared. A change in the activity of NOVX polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency ofthe 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 ofthe NOVX polypeptide in a test sample from the subject and comparing the amount ofthe polypeptide in the test sample to the amount ofthe NOVX polypeptide present in a control sample.
  • An alteration in the level ofthe 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 ofthe like.
  • the expression levels ofthe new polypeptides ofthe 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-specific antibody to a subject (e.g., a human subject), in an amount sufficient to alleviate or prevent the pathological condition.
  • the disorder includes, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders ofthe like.
  • the invention can be used in a method to identity the cellular receptors and downstream effectors ofthe 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 ofthe 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.
  • 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. Included in the invention are the novel nucleic acid sequences and their encoded polypeptides. The sequences are collectively referred to herein as “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 ofthe novel sequences disclosed herein. Table A provides a summary ofthe NOVX nucleic acids and their encoded polypeptides.
  • NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts.
  • the various NOVX nucleic acids and polypeptides according to the invention are useful as novel members ofthe protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members ofthe family to which the NOVX polypeptides belong.
  • NOV1 is homologous to a Membrane Protein/ Neuropilin/Metalloproteinase-like family of proteins.
  • the NOV1 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; cancer, trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections, Von Hippel-Lindau (VHL) syndrome , Alzheimer's disease, stroke, Parkinson's disease, Huntington's disease, Cerebral palsy, Multiple sclerosis, hair growth diseases, endocrine disorders and/or other pathologies/disorders.
  • NOV2 is homologous to a Fibrillin-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; connective tissue disorders, such as severe neonatal Marfan syndrome, Marfan syndrome, 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; adenocarcinoma; lymphoma; prostate cancer; uterus cancer, leukemia or pancreatic cancer; Neurologic diseases, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, inflammation, Parkinson's disease, osteoporosis, multiple sclerosis; angina pectoris, myocardial infarction, benign prostatic and/or other pathologies/disorders.
  • connective tissue disorders such as severe neonatal Marfan syndrome, Marfan syndrome, inflammatory disorders such as osteo- and rheumatoid-arthritis,
  • NOV3 is homologous to a family of KIAAl 589-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: inflammatory disorders such as osteo- and rheumatoid-arthritis, inflammatory bowel disease; immunological disorders, AIDS; cancers including but not limited to lung cancer, colon cancer, leukemia or pancreatic cancer.; skin disorders, Neurologic diseases, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, endocrine diseases, muscle disorders, inflammation and wound repair; multiple sclerosis; angina pectoris, myocardial infarction, ulcers, benign prostatic hypertrophy and/or other pathologies/disorders.
  • NOV4 is homologous to the WD 40 motif-like family of proteins.
  • NOV4 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated, for example; cancer, Diabetes, Von Hippel-Lindau (VHL) syndrome, Obesity Systemic lupus erythematosus , Autoimmune disease, Asthma, Von Hippel-Lindau (VHL) syndrome , Alzheimer's disease, Stroke,
  • NOV5 is homologous to the Opioid Bing Cell Adhesion Molecule-like protein family.
  • NOV5 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example: Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, Lesch- Nyhan syndrome, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neurodegeneration and/or other pathologies/disorders.
  • VHL Von Hippel-Lindau
  • NOV6 is homologous to the Triacylglycerol lipase-like 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: Diabetes, Von Hippel-Lindau (VHL) syndrome, Obesity, Von Hippel-Lindau (VHL) syndrome,
  • NOV7 is homologous to members ofthe IGE Receptor Beta Subunit-like family of proteins.
  • NOV7 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; inflammatory disorders such as osteo- and rheumatoid-arthritis, inflammatory bowel disease, AIDS; cancers including but not limited to lung cancer, colon cancer, leukemia or pancreatic cancer.; asthma; psoriasis; skin disorders, renal disorders immunological disorders, bone diseases, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, endocrine diseases, muscle disorders, wound repair, bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), anorexia, bulimia, asthma, osteoporosis, multiple sclerosis; benign prostatic hypertrophy, schizophrenia, manic depression, delirium, dementia, severe mental retardation and dyskinesias, such as Huntington's disease, Gilles de la Tourette syndrome and/or other pathologies/disorders.
  • inflammatory disorders such as osteo- and
  • NOV8 is homologous to the Munc 18-like family of proteins.
  • NOV8 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; 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, leukemia or pancreatic cancer.; psoriasis; neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, endocrine diseases, muscle disorders, wound repair, bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), Parkinson's disease, acute heart failure, hypotension, hypertension, osteoporosis, multiple sclerosis; angina pectoris, myocardial infarction, psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia, severe mental retard
  • NOV9 is homologous to members ofthe Immunoglobulin-like family of proteins.
  • 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; 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, leukemia or pancreatic cancer.; psoriasis; neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, endocrine diseases, muscle disorders, wound repair, bacterial, fungal, protozoal and viral infections (particularly infections caused by HIV-1 or HIV-2), Parkinson's disease, acute heart failure, hypotension, hypertension, osteoporosis, multiple sclerosis; angina pectoris, myocardial infarction, psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium,
  • NOV 10 is homologous to members ofthe Type II Cytokeratin-like family of proteins.
  • the NOV 10 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; inflammatory and infectious diseases such as AIDS; Neurologic diseases, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, endocrine diseases, muscle disorders, wound repair, 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, 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
  • the NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function.
  • the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit, e.g., neurogenesis, cell differentiation, cell proliferation, hematopoiesis, wound healing and angiogenesis. Additional utilities for the NOVX nucleic acids and polypeptides according to the invention are disclosed herein.
  • NOV1 includes two novel Membrane protein neuropilin/metalloproteinase-like proteins disclosed below. The disclosed proteins have been named NOV1 a and NOVlb. NOVla
  • NOVla nucleic acid of 1668 nucleotides also referred to as SC40376139
  • Table 1 A An open reading frame was identified beginning with an ATG initiation codon at nucleotides 7-9 and ending with a TGA codon at nucleotides 1453-1455. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 1 A, and the start and stop codons are in bold letters.
  • Table 1A NOVla Nucleotide Sequence (SEQ ID NO:l).
  • the NOVla nucleic acid sequence maps to chromosome 14 and has 1030 of 1128 bases (91%) identical to a Macacafascicularis brain mRNA (gb:GENBANK- ID:AB047834
  • acc:AB047834.1) (E 3.2e "201 ).
  • Similiarity information was assessed using public nucleotide databases including all GenBank databases and the GeneSeq patent database. Chromosome information was assigned using OMIM and the electronic northern tool from Curatools to derive the the chromosomal mapping ofthe SeqCalling assemblies, Genomic clones, and/or EST sequences that were included in the invention.
  • the "E-value” or “Expect” value is a numeric indication ofthe probability that the aligned sequences could have achieved their similarity to the BLAST query sequence by chance alone, within the database that was searched.
  • the probability that the subject (“Sbjct”) retrieved from the NOVla BLAST analysis, e.g., Macacafascicularis brain mRNA, matched the Query NOVla sequence purely by chance is 3.2e " .
  • the Expect value (E) is a parameter that describes the number of hits one can "expect" to see just by chance when searching a database of a particular size. It decreases exponentially with the Score (S) that is assigned to a match between two sequences. Essentially, the E value describes the random background noise that exists for matches between sequences.
  • the Expect value is used as a convenient way to create a significance threshold for reporting results.
  • the default value used for blasting is typically set to 0.0001.
  • the Expect value is also used instead ofthe P value (probability) to report the significance of matches.
  • an E value of one assigned to a hit can be interpreted as meaning that in a database ofthe current size one might expect to see one match with a similar score simply by chance.
  • An E value of zero means that one would not expect to see any matches with a similar score simply by chance. See, e.g., http://www.ncbi.nlm.nih.gov/Education/BLASTinfo/. Occasionally, a string of X's or N's will result from a BLAST search.
  • the disclosed NOVla polypeptide (SEQ ID NO:2) encoded by SEQ ID NO:l has 482 amino acid residues and is presented in Table IB using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOVla does not contain a signal peptide and is likely to be localized to the plasma membrane with a certainty of 0.7000.
  • Table IB Encoded NOVla protein sequence (SEQ ID NO:2).
  • QMESYDGTLRIVNVSRE SGMYRCQTSQYNGFNVKPREALVQLIVQYPPAVEPAFLEIRQGQDRSVTMSCRVLRAYPIRV LTYE RLGNKLLRTGQFDSQEYTEYAVKSLSNENYGVYNCSIINEAGAGRCSFLVTGGKAYAPEFYYDTYNPVWQNRHRVY SYSLQWTQMNPDAVDRIVAYR GIRQAGQQRWWEQEIKINGNIQKGE ITYNLTE IKPEAYEVRLTPLTKFGEGDSTIRV IKYSPVNPHL ⁇ EFHCGFEDGNICLFTQDDTDNFDWTKQSTATRNTKYTPNTGPNADRSGSKEGFYMYIETSRPRLEGEKAR SPVFSIAPALFSARLLSPVFSIAPKNPYGPTNTAYCFSFFYHMYGQHIGVLNVY RLKGQTTI
  • NOVla is predicted to be expressed in brain tissues because ofthe expression pattern of a closely related Macaca fascicularis brain cDNA, clone:QccE-16296 homolog (GENBANK-ID: gb:GENBANK-ID: AB047834
  • NOVlb nucleic acid of 1608 nucleotides also referred to as CG55014-02
  • Table lC An open reading frame was identified beginning with an ATG initiation codon at nucleotides 6-8 and ending with a TGA codon at nucleotides 1404-1406. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 1C, and the start and stop codons are in bold letters.
  • Table lC NOVlb Nucleotide Sequence (SEQ ID NO:3).
  • the NOVlb nucleic acid sequence has 1538 of 1557 bases (98%) identical to a Macacafascicularis brain mRNA (gb:GENBANK-ID:AB047834
  • acc:AB047834.1) (E 0.0).
  • the disclosed NOVlb polypeptide (SEQ ID NO:4) encoded by SEQ ID NO:3 has 466 amino acid residues and is presented in Table ID using the one-letter amino acid code.
  • Signal P, Psort and/or Hydropathy results predict that NOVlb does not contain a signal peptide and is likely to be localized to the plasma membrane with a certainty of 0.7000.
  • NOVlb is expressed in at least the following tissues: brain. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Literature sources, and/or RACE sources. In addition, NOVlb is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Macaca fascicularis brain cDNA, clone:QccE- 16296 homolog (GENBANK-ID: gb:GENBANK- ⁇ D:AB047834
  • SNPs small nucleotide polymorphisms
  • Depth represents the number of clones covering the region ofthe SNP.
  • the putative allele frequence (PAF) is the fraction of these clones containing the SNP.
  • NOVla and NOVlb are very closely homologous as is shown in the amino acid alignment in Table 1 G.
  • NOV1 Homologies to any ofthe above NOV1 proteins will be shared by the other NOV1 proteins insofar as they are homologous to each other as shown above. Any reference to NOV1 is assumed to refer to both ofthe NOV1 proteins in general, unless otherwise noted.
  • NOVla also has homology to the amino acid sequences shown in the BLASTP data listed in Table IH.
  • NOVla The presence of identifiable domains in NOVla, as well as all other NOVX proteins, was determined by searches using software algorithms such as PROSITE, DOMAIN, Blocks, Pfam, ProDomain, and Prints, and then determining the Interpro number by crossing the domain match (or numbers) using the Interpro website (http:www.ebi.ac.uk/ interpro).
  • DOMAIN results for NOVla as disclosed in Tables 1 J and IK, were collected from the conserveed Domain Database (CDD) with Reverse Position Specific BLAST analyses. This BLAST analysis software samples domains found in the Smart and Pfam collections.
  • NOVla This indicates that the NOVla sequence has properties similar to those of other proteins known to contain these domains.
  • Table 1J Domain Analysis of NOVla gnl I Smart I smart00137, MAM, Domain in meprin, A5, receptor protein tyrosine phosphatase u (and others); Likely to have an adhesive function. Mutations in the meprin MAM domain affect noncovalent associations within meprin oligomers. In receptor tyrosine phosphatase mu-like molecules the MAM domain is important for homophilic cell-cell interactions. (SEQ ID NO: 54)
  • NOVla 378 NVYLRLKGQTTIENPLWSSSGNKGQRWNEAHVNIYPITS-FQLIFEGIRGPGIEGDIAID 436
  • VEGF- Rl vascular endothelial growth factor receptors
  • VEGF-R2 neuropilin-1
  • neuropilin-1 were simultaneously expressed in the identical 14 tissues.
  • the isoform VEGF121 was constitutively expressed in all the tissues examined, whereas the expression of VEGF165 was confined to the 7 tissues that also expressed VEGF-R2 and neuropilin-1.
  • vascular density of fibrovascular tissues evaluated by immunohistochemistry for CD34 was significantly higher in the cases with the expression of VEGF-R2 and neuropilin-1 than in those without their expression (P ⁇ 0.01), whereas VEGF-R1 expression had no such relationship with the vascular density.
  • the fibrovascular tissues that expressed VEGF 165 together with VEGF-R2 and neuropilin-1 were found in significantly younger patients (P ⁇ 0.01).
  • In situ hybridization and immunohistochemical studies demonstrated that glial cells in the fibrovascular tissues express and produce VEGF.
  • VEGF-R2 and neuropilin-1 Coexpression of VEGF-R2 and neuropilin-1 is suggested to facilitate fibrovascular proliferation in diabetic retinopathy (Ishida et al., Coexpression of VEGF receptors VEGF-R2 and neuropilin-1 in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 41(7): 1649- 56, 2000.)
  • semaphorins In the developing nervous system axons navigate with great precision over large distances to reach their target areas. Chemorepulsive signals such as the semaphorins play an essential role in this process. The effects of one of these repulsive cues, semaphorin 3 A (Sema3A), are mediated by the membrane protein neuropilin-1 (Npn-1). Recent work has shown that neuropilin-1 is essential but not sufficient to form functional Sema3A receptors and indicates that additional components are required to transduce signals from the cell surface to the cytoskeleton. It was shown that members of the plexin family interact with the neuropilins and act as co-receptors for Sema3 A.
  • Neuropilin/plexin interaction restricts the binding specificity of neuropilin-1 and allows the receptor complex to discriminate between two different semaphorins. Deletion ofthe highly conserved cytoplasmic domain of Plexin-Al or -A2 creates a dominant negative Sema3A receptor that renders sensory axons resistant to the repulsive effects of Sema3A when expressed in sensory ganglia. These data suggest that functional semaphorin receptors contain plexins as signal-transducing and neuropilins as ligand-binding subunits (Rohm et al., Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A. Mech Dev 93(l-2):95-104, 2000).
  • VEGF Vascular endothelial growth factor
  • flt-1, KDR, and neuropilin-1 are present on endothelial cells and other cell types.
  • flt-1, KDR, and neuropilin-1 are present on cultured HMC, and VEGF(165) induces HMC proliferation.
  • flt-1 and KDR receptors are expressed in the mesangium in mesangioproliferative disease (Thomas et al., Vascular endothelial growth factor receptors in human mesangium in vitro and in glomerular disease. J Am Soc Nephrol 2000 l l(7):1236-43, 2000).
  • VEGF Vascular endothelial growth factor
  • VEGF 165 but not VEGF121, was cloned and purified from tumor cells.
  • This isoform-specific VEGF receptor (VEGF165R) is identical to human neuropilin-1, a receptor for the collapsin/semaphorin family that mediates neuronal cell guidance.
  • VEGF165R isoform-specific VEGF receptor
  • inhibition of VEGF165 binding to neuropilin-1 inhibits its binding to KDR and its mitogenic activity for endothelial cells.
  • neuropilin-1 is a novel VEGF receptor that modulates VEGF binding to KDR and subsequent bioactivity and therefore may regulate VEGF-induced angiogenesis (Soker et al., Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92(6):735-45, 1998).
  • NOV1 The above defined information for NOV1 suggests that this Membrane protein/neuropilin/metalloproteinase-like protein may function as a member ofthe Membrane protein/neuropilin/metalloproteinase family. Therefore, the NOV1 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the NOV1 compositions ofthe present invention will have efficacy for treatment of patients suffering from cancer, trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections, Von Hippel-Lindau (VHL) syndrome , Alzheimer's disease, stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch- Nyhan syndrome, Multiple sclerosis, Ataxia-telangiectasia, Leukodystrophies, behavioral disorders, addiction, anxiety, pain, psoriasis, actinic keratosis , acne, hair growth diseases, allopecia, pigmentation disorders and endocrine disorders.
  • VHL Von Hippel-Lindau
  • the NOV1 nucleic acid encoding Membrane protein/neuropilin/metalloproteinase-like protein, and the Membrane protein/neuropilin/metalloproteinase-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV2 includes six novel Fibrillin-like proteins disclosed below. The disclosed proteins have been named NOV2a, NOV2b, NOV2c, NOV2d, NOV2e and NOV2f.
  • NOV2a nucleic acid of 9993 nucleotides also referred to as GMAC022146_A
  • Table 2 A An open reading frame was identified beginning with an ATG initiation codon at nucleotides 166-168 and ending with a TGA codon at nucleotides 9151-9153. Putative untranslated regions upstream from the intiation codon and downstream from the termination codon are underlined in Table 2A. The start and stop codons are in bold letters.
  • Table 2A NOV2a nucleotide sequence (SEQ ID NO:5).
  • NOV2a nucleic acid sequence localized to chromsome 19, has 3196 of 4382 bases (72%) identical to a Mus musculus fibrillin 2 (fbn2) mRNA (gb:GENBANK- ID:MUSFBN2
  • acc:L39790) (E 0.0).
  • a NOV2a polypeptide (SEQ ID NO:6) encoded by SEQ ID NO:5 has 2995 amino acid residues and is presented using the one-letter code in Table 2B.
  • Signal P, Psort and/or Hydropathy results predict that NOV2a contains a signal peptide and is likely to be localized to the endoplasmic reticulum membrane with a certainty of 0.5500.
  • the most likely cleavage site for a NOV2a peptide is between amino acids 54 and 55, at: TSS-RK.
  • Table 2B Encoded NOV2a protein sequence (SEQ ID NO:6).
  • the disclosed NOV2a is expressed in at least the following tissues: testes, ovary, lung, liver, B-cells, total-fetus, spleen, Nervous System, Brain, Prosencephalon/Forebrain, Diencephalon, Pituitary Gland, Hematopoietic Tissues, Lymphoid tissue, Lymph node and Whole Organism. This information was derived by determining the tissue sources ofthe sequences that were included in the invention.
  • NOV2a sequence is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Mus musculus fibrillin 2 (fbn2) gene (GENBANK-ID: gb:GENBANK- ID:MUSFBN2
  • fbn2 Mus musculus fibrillin 2
  • NOV2b A disclosed NOV2b nucleic acid of 9894 nucleotides (also referred to as 153568997) encoding a novel Fibrillin-like protein is shown in Table 2C.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 520-522 and ending with a TGA codon at nucleotides 9052-9054. Putative untranslated regions upstream from the intiation codon and downstream from the termination codon are underlined in Table 2C, and the start and stop codons are in bold letters.
  • Table 2C NOV2b nucleotide sequence (SEQ ID NO:7).
  • CCTCCC A TTCCTCTCCTCTCTC T CCCATCTGGAC A GCCCCCAGCCTTCTGACACCCTGTTTCCCCCCCGGGACCCTGCTGC CCTTCCCC A CACC A CCT AA C A TGC A TTTCTGACCTTGCTCCTCCCACTCAAAGCTTTTCAAGGGCTCTTCATTGTCCTTG ⁇ CG AA TG A GC AAA AGCTGCATG A C A CTGCTATGCCC ⁇ CTCCTGCAACGCCTGGCCCCACCTGGCCCCACCTGGCCCTCTCTC CCCTCCCTTCC A CTTCCC A CTCCCGTCTTGCCTTGGCTGTGCACCCTCAGCCCCAAGACCCTTCTCTAACATCACACCTCC TCCAGGAAGCCTCCTCTG A CTGTTCACCGCTTCCCGGTTGGGGCTGGATGCCTCCTTGGGCTCCCAGAGGCCCCGGGGCTG CCCC A TTTGGCA A CC A CCCTGCCCTCCTCGTTGTGTTGGGTCCCATGGCTAGGGTGG
  • the disclosed NOV2b nucleic acid sequence, localized to chromsome 19, has 3617 of 5008 bases (72%) identical to a Rattus norvegicus fibrillin 2 (fbn2) mRNA (gb:GENBANK- ID:AF135060
  • acc:AF135060.1) (E 0.0).
  • a NOV2b polypeptide (SEQ ID NO:8) encoded by SEQ ID NO:7 has 2844 amino acid residues and is presented using the one-letter code in Table 2D.
  • Signal P, Psort and/or Hydropathy results predict that NOV2b contains a signal peptide and is likely to be localized to the nucleus with a certainty of 0.6000.
  • PSORT suggests that the Fibrillin-like protein may be localized in the nucleus, the NOV2b protein is similar to the Fibrillin family, some members of which are released extracellularly. Therefore it is likely that NOV2b protein shows a similar localization.
  • the most likely cleavage site for a NOV2b peptide is between amino acids 29 and 30, at: AGG-QG.
  • Table 2D Encoded NOV2b protein sequence (SEQ ID NO:8).
  • TLEGLY ARGPLAR LLAWSA LCMAGGQGRWDGALEAAGPGRVRRRGSPGILQGPNVCGSRFHAYCCPGWRTFPGRSQC VVPICRRACGEGFCSQPNLCTCADGTLAPSCGVSRGSGCSVSCMNGGTCRGASCLCQKGYTGTVCGQPICDRGCHNGGRCI GPNRCACVYGFMGPQCERDYRTGSCFGQVGPEGCQHQLTGLVCTKALCCATVGRAWGLPCELCPAQPHPCRRGFIPNIHTG ACQDVDECQAVPGLCQGGSCVNMVGSFHCRCPVGHRLSDSSAACEDYRAGACFSV FGGRCAGDLAGHYTRRQCCCDRGRC WAAGPVPELCPPRGSNEFQQ CAQR PL PGHPG FPGLLGFGSNGMGPPLGPARLNPHGSDARGIPSLGPGNSNIGTAT NQTIDICRHFTNLCLNGRCLPTPSSY
  • NOV2b 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 ofthe sequences that were included in the derivation ofthe NOV2b sequence.
  • a disclosed NOV2c nucleic acid of 9993 nucleotides (also referred to as CG88987-01) encoding a novel Fibrillin-like protein is shown in Table 2E.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 520-522 and ending with a TGA codon at nucleotides 9151-9153.
  • Putative untranslated regions upstream from the intiation codon and downstream from the termination codon are underlined in Table 2E, and the start and stop codons are in bold letters.
  • Table 2E NOV2c nucleotide sequence (SEQ ID NO:9).
  • NOV2c nucleic acid sequence localized to chromsome 19, has 3194 of 4382 bases (72%) identical to a Mus musculus fibrillin 2 (fbn2) mRNA (gb:GENBANK- ID:MUSFBN2
  • acc:L39790.1) (E 0.0).
  • a NOV2c polypeptide (SEQ ID NO: 10) encoded by SEQ ID NO:9 has 2877 amino acid residues and is presented using the one-letter code in Table 2F.
  • Signal P, Psort and/or Hydropathy results predict that NOV2c contains a signal peptide and is likely to be localized to the nucleus with a certainty of 0.6000.
  • PSORT suggests that the Fibrillin-like protein may be localized in the nucleus, the NOV2c protein is similar to the Fibrillin family, some members of which are released extracellularly. Therefore it is likely that NOV2c protein shows a similar localization.
  • the most likely cleavage site for a NOV2c peptide is between amino acids 29 and 30, at: AGG-QG.
  • Table 2F Encoded NOV2c protein sequence (SEQ ID NO:10).
  • NOV2c 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 ofthe sequences that were included in the derivation ofthe NOV2c sequence. NOV2d
  • a disclosed NOV2d nucleic acid of 9418 nucleotides (also referred to as CG88987-02) encoding a novel Fibrillin-like protein is shown in Table 2G.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 41-43 and ending with a TGA codon at nucleotides 8576-8578.
  • Putative untranslated regions upstream from the intiation codon and downstream from the termination codon are underlined in Table 2G, and the start and stop codons are in bold letters.
  • the disclosed NOV2d nucleic acid sequence, localized to chromsome 19, has 3194 of 4382 bases (72%) identical to a Mus musculus fibrillin 2 (fbn2) mRNA (gb:GENBANK- ID:MUSFBN2
  • acc:L39790.1) (E 0.0).
  • a NOV2d polypeptide (SEQ ID NO: 12) encoded by SEQ ID NO:l 1 has 2845 amino acid residues and is presented using the one-letter code in Table 2H.
  • NOV2d contains a signal peptide and is likely to be localized to the nucleus with a certainty of 0.6000.
  • PSORT suggests that the Fibrillin-like protein may be localized in the nucleus, the NOV2d protein is similar to the Fibrillin family, some members of which are released extracellularly. Therefore it is likely that NOV2d protein shows a similar localization.
  • the most likely cleavage site for a NOV2d peptide is between amino acids 29 and 30, at: AGG-QG. Table 2H. Encoded NOV2d protein sequence (SEQ ID NO:12).
  • NOV2d 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 ofthe sequences that were included in the derivation ofthe NOV2d sequence.
  • a disclosed NOV2e nucleic acid of 8219 nucleotides (also referred to as CG88987-03) encoding a novel Fibrillin-like protein is shown in Table 21.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 49-51 and ending with a TGA codon at nucleotides 8134-8136.
  • Putative untranslated regions upstream from the intiation codon and downstream from the termination codon are underlined in Table 21, and the start and stop codons are in bold letters.
  • Table 21 NOV2e nucleotide sequence (SEQ ID NO:13).
  • NOV2e nucleic acid sequence localized to chromsome 19, has 2166 of 2977 bases (72%) identical to a Mus musculus fibrillin 2 (fbn2) mRNA (gb:GENBANK- ID:MUSFBN2
  • acc:L39790.1) (E 0.0).
  • a NOV2e polypeptide (SEQ ID NO: 14) encoded by SEQ ID NO: 13 has 2695 amino acid residues and is presented using the one-letter code in Table 2J.
  • Signal P, Psort and/or Hydropathy results predict that NOV2e contains a signal peptide and is likely to be localized to the nucleus with a certainty of 0.6000.
  • PSORT suggests that the Fibrillin-like protein may be localized in the nucleus, the NOV2e protein is similar to the Fibrillin family, some members of which are released extracellularly. Therefore it is likely that NOV2e protein shows a similar localization.
  • the most likely cleavage site for a NOV2e peptide is between amino acids 29 and 30, at: AGG-QG.
  • NOV2e is expressed in at least the following tissues: lung, colon, bone, trabecular bone cells, placenta, germ cell, melanocyte, heart, uterus, thyroid and brain. Expression information was derived from the tissue sources ofthe sequences that were included in the derivation of the NOV2e sequence.
  • NOV2f A disclosed NOV2f nucleic acid of 9154 nucleotides (also referred to as CG88987-05) encoding a novel Fibrillin-like protein is shown in Table 2K.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 41-43 and ending with a TGA codon at nucleotides 8312-8314.
  • Putative untranslated regions upstream from the intiation codon and downstream from the termination codon are underlined in Table 2K, and the start and stop codons are in bold letters.
  • the disclosed NO V2f nucleic acid sequence, localized to chromsome 19, has 3401 of 3689 bases (92%) identical to a Homo sapiens KIAAl 776 protein (fibrillin3) mRNA (gb:GENBANK-ID:AB053450
  • acc:AB053450.2) (E 0.0).
  • a NO V2f polypeptide (SEQ ID NO:16) encoded by SEQ ID NO:15 has 2757 amino acid residues and is presented using the one-letter code in Table 2L.
  • Signal P, Psort and/or Hydropathy results predict that NO V2f contains a signal peptide and is likely to be localized to the nucleus with a certainty of 0.6000.
  • PSORT suggests that the Fibrillin-like protein may be localized in the nucleus, the NO V2f protein is similar to the Fibrillin family, some members of which are released extracellularly. Therefore it is likely that NO V2f protein shows a similar localization.
  • the most likely cleavage site for a NOV2f peptide is between amino acids 29 and 30, at: AGG-QG.
  • NOV2f is expressed in at least the following tissues: Mammalian Tissue, Brain and Lung. Expression information was derived from the tissue sources ofthe sequences that were included in the derivation ofthe NO V2f sequence.
  • NOV2f is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Homo sapiens mRNA homolog for KIAAl 776 protein (fibrillin3) (gb:GENBANK-ID:AB053450
  • a closely related Homo sapiens mRNA homolog for KIAAl 776 protein gb:GENBAN
  • SNPs small nucleotide polymorphisms
  • NOV2a - NOV2f are very closely homologous as is shown in the amino acid alignment in Table 2N.
  • NOV2a fa ⁇ ma tt »t ⁇ a» aiM ⁇ 'MM«Maattx ⁇ a «t»miimw NOV2b NOV2c SSAACEDYDECSTIPGICEGGECTNTVSSYFCKCPPGFYTSPDGTLHGQS NOV2d SSAACEDYDECSTIPGICEGGECTNTVSSYFCKCPPGFYTSPDGTLHGOS NOV2e SSAACEDY " NOV2f ⁇ 3 ⁇ H8E3B ⁇ S3iE ⁇ SSS3BMtB3 ⁇ 8iiBS
  • NOV2 Homologies to any ofthe 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 ofthe NOV2 proteins in general, unless otherwise noted.
  • NOV2a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 2O.
  • Tables 2Q - 2X list the domain description from DOMAIN analysis results against NOV2a. This indicates that the NOV2a sequence has properties similar to those of other proteins known to contain these domains.
  • NOV2a 1816 GTCQNELAFNVTRKMCCCSYNIGQA NRPCEACPTPISPDYQIL 1859 l l l l 11+ llll l + l I II I I I + +1+ I 00683 1 GRCSNPLPGRVTKSECCCSL--GRAWGTPCEPCPVPGTAEYKTL 42
  • NOV2a 979 SRCEVNLQGASLRSECCATLGAA GSPCERCEIDPACARG 1018
  • NOV2a 462 GRCAGDLAGHYTRRQCCCDRGRCWAAGPVPELCPPRGSNEFQQL 505
  • Length 42 residues, 97.6% aligned
  • Fibrillins 1 and 2 are the main constituents ofthe extracellular micro fibrils responsible for the biomechanical properties of most tissues and organs. They are cysteine-rich glycoproteins predominantly made of multiple repeats homologous to the calcium-binding epidermal growth factor module, and are translated as precursor proteins cleaved by furine/PACE-like activities. Fibrillins polymerize extracellularly as parallel bundles of head- to-tail monomers. Binding to calcium rigidifies the structure ofthe monomers and the supramolecular organization ofthe macroaggregates. Elastic fibers form a network that contributes to the elasticity and resilience of tissues such as the skin. Histopatho logic and ultrastructural abnormalities in the elastic fibers have been observed in several diseases ofthe skin and other tissues.
  • NOV2 protein may function as a member of a family of novel Fibrillin-like proteins. Therefore, the NOV2 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the NOV2 compositions ofthe present invention will have efficacy for treatment of patients suffering from connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and 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, leukemia or pancreatic cancer.; blood disorders; asthma; psoriasis; vascular disorders, hypertension, skin disorders, renal disorders including Alport syndrome, immunological disorders, tissue injury, fibrosis disorders, bone diseases, Ehlers- Danlos syndrome type NI, VII, type IV, S-linked cutis laxa and Ehlers-Danlos syndrome type V, osteogenesis imperfecta, Neurologic diseases
  • the NOV2 nucleic acid encoding Fibrillin-like proteins, and the Fibrillin-like proteins ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV3 nucleic acid of 2713 nucleotides also referred to as GSAL442663.1 A
  • Table 3A An open reading frame was identified beginning with a ATG initiation codon at nucleotides 1-3 and ending with a TAG codon at nucleotides 2711-2713. The start and stop codons are in bold letters in Table 3A.
  • Table 3 A NOV3 Nucleotide Sequence (SEQ ID NO: 17)
  • the disclosed NOV3 nucleic acid sequence maps to chromosome 14 and has 2502 of 2518 bases (99%) identical to a Homo sapiens KIAAl 589 protein mRNA (gb:GENBANK- ID:AB046809
  • acc:AB046809.1) (E 0.0).
  • a disclosed NOV3 protein (SEQ ID NO: 18) encoded by SEQ ID NO: 17 has 891 amino acid residues, and is presented using the one-letter code in Table 3B.
  • Signal P, Psort and/or Hydropathy results predict that NOV3 contains a signal peptide, and is likely to be localized to the nucleus with a certainty of 0.6000 and to the mitochondrial matrix space with a certainty of 0.4811.
  • the most likely cleavage site for a NOV3 peptide is between amino acids 19and 20, at: AKC-GP.
  • Table 3B Encoded NOV3 protein sequence (SEQ ID NO:18).
  • NOV3 is expressed in at least the following tissues: Adrenal Gland/Suprarenal gland, Ascending Colon, Bone, Bone Marrow, Brain, Colon, Heart, Kidney, Liver, Lung, Lymphoid tissue, Mammary gland/Breast, Oesophagus, Ovary, Pituitary Gland, Prostate, Retina, Skeletal Muscle, Small Intestine, Testis, Thyroid, Tongue, Umbilical Vein, Uterus and Whole Organism.
  • tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Genomic Clone sources, Literature sources, and/or RACE sources.
  • NOV3 is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Homo sapiens KIAAl 589 protein mRNA homolog, (GENBANK-ID: gb:GENBANK-ID:AB046809
  • a closely related Homo sapiens KIAAl 589 protein mRNA homolog GenBANK-ID: gb:GENBANK-ID:AB046809
  • Ascending Colon Bone, Bone M
  • NOV3 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 3C.
  • Tables 3E - 3H list 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.
  • Length 69 residues, 92.8% aligned
  • NOV3 708 Y RPNSQILSCNKCATSFKDNDTKHHCRACGEGFCDSCSSKTRPVPERG GPAPVRVCDN 767
  • the FYVE zinc finger is named after four proteins that it has been found in: Fabl, YOTB/ZK632.12, Vacl, and EEA1.
  • the FYVE finger has been shown to bind two Zn++ ions.
  • NOV3 may function as a member of a KIAAl 589 protein family. Therefore, the NOV3 nucleic acids and proteins ofthe invention are useful in potential therapeutic and diagnostic applications. For example, a cDNA encoding the NOV3 protein may be useful in gene therapy, and the NOV3 protein may be useful when administered to a subject in need thereof.
  • compositions ofthe present invention will have efficacy for treatment of patients suffering from 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, leukemia or pancreatic cancer.; blood disorders; asthma; psoriasis; vascular disorders, hypertension, skin disorders, renal disorders including Alport syndrome, immunological disorders, tissue injury, fibrosis disorders, bone diseases, Ehlers- Danlos syndrome type VI, VII, type IV, S-linked cutis laxa and Ehlers-Danlos syndrome type V, osteogenesis imperfecta, Neurologic diseases, Brain and/or autoimmune disorders like encephalomyelitis, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, endocrine diseases, muscle disorders, inflammation and wound repair, bacterial, fungal, protozoal and viral infections (particularly infections caused
  • NOV3 nucleic acid encoding KIAA1589-like protein, and the KIAAl 589-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • a disclosed NOV4 nucleic acid of 1761 nucleotides (designated CuraGen Ace. No. GSAL442663.1_B) encoding a novel WD40-motifprotein-like protein is shown in Table 4A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 48-50and ending with a TAA codon at nucleotides 1536-1538.
  • Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 4A, and the start and stop codons are in bold letters.
  • the nucleic acid sequence ofNOV4 maps to chromosome 14 and has 1282 of 1287 bases (99%) identical to a Homo sapiens DKFZp434Kl 14 mRNA (gb.GENBANK- ID:HSM800674
  • acc:AL080157.1) (E 2.6e- 282 ).
  • a NOV4 polypeptide (SEQ ID NO:20) encoded by SEQ ID NO: 19 is 496 amino acid residues and is presented using the one letter code in Table 4B. Signal P, Psort and/or Hydropathy results predict that NOV4 does not contain a signal peptide and is likely to be localized to the nucleus with a certainty of 0.9600.
  • NOV4 is expressed in at least the following tissues: cancer tissue, pancreas, fetal lung NbHL19W, testis NHT, B-cell and brain. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Genomic Clone sources, Literature sources, and/or RACE sources. In addition, NOV4 is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Homo sapiens DKFZp434Kl 14 mRNA homolog (GENBANK-ID: gb:GENBANK-ID: HSM800674
  • Rhabdomyosarcoma neuroepithelium, pancreas, fetal lung, NbHL19W, testis NHT, B-cell and brain.
  • NOV4 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 4C.
  • Dactylin encoding a novel member ofthe F-box/WD40 protein family was recently cloned and characterized.
  • the Dactylin gene comprises nine exons distributed in more than 85 kb of genomic DNA and encoding a protein with four WD40 repeats and an F-box motif.
  • WD40 repeat domains include the COP1 (constitutively photomorphogenic 1) protein in Arabidopsis which is a repressor of light-regulated development and it mammalian homologue which acts within the nucleus to repress photomorphogenic development (Wang et al., Evidence for functional conservation of a mammalian homologue ofthe light-responsive plant protein COP1. Curr Biol 9(13):711-4, 1999).
  • Another protein which contains the WD40 repeat domain is the Schizosaccharomyces pombe 72 kDa TFIID subunit.
  • This protein contains several significant highly conserved regions including the WD40 repeats, that are indispensable for the viability (Yamamoto et al., Molecular genetic elucidation ofthe tripartite structure ofthe Schizosaccharomyces pombe 72 kDa TFIID subunit which contains a WD40 structural motif. Genes Cells 2(4):245-54, 1997).
  • NON4 suggests that this ⁇ OV4 protein may function as a member of a WD40-motif protein-like protein family. Therefore, the NOV4 nucleic acids and proteins ofthe invention are useful in potential therapeutic and diagnostic applications. For example, a cDNA encoding the NOV4 protein may be useful in gene therapy, and the NOV4 protein may be useful when administered to a subject in need thereof.
  • compositions ofthe present invention will have efficacy for treatment of patients suffering from cancer, trauma, regeneration (in vitro and in vivo), viral/bacterial/parasitic infections DiabetesNon Hippel-Lindau (NHL) syndrome , Pancreatitis, Obesity Systemic lupus erythematosus , Autoimmune disease, Asthma, Emphysema, Scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome , 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, Neuroprotection Fertility Myasthenia gravis, Leukodystrophies, Pain, Neuroprotection
  • NOV4 nucleic acid encoding WD40-motif protein-like protein, and the WD40-motif protein-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV5 includes four novel Opioid Binding Cell Adhesion Molecule-like proteins disclosed below. The disclosed proteins have been named NOV5a, NOV5b, NOV5c and NOV5d.
  • a disclosed NOV5a nucleic acid of 1018 nucleotides (also referred to as 139785504) encoding a novel Opioid Binding Cell Adhesion Molecule-like protein is shown in Table 5 A.
  • An open reading frame lacking a signal peptide was identified beginning with an CTG at nucleotides 1-3 and ending with a TAG codon at nucleotides 958-960.
  • a putative untranslated region downstream from the termination codon are underlined in Table 5A, and the start and stop codons are in bold letters.
  • NOV5a nucleic acid was identified on chromosome 7 and has 260 of 389 bases (66%) identical to a Homo sapiens (clone pHOM) opioid-binding cell adhesion molecule mRNA (gb:GENBANK-ID:HUMOBCAM
  • acc:L34774.1) (E 3.4e *50 ).
  • a disclosed NOV5a polypeptide (SEQ ID NO:22) encoded by SEQ ID NO:21 is 319 amino acid residues and is presented using the one-letter code in Table 5B.
  • Signal P, Psort and/or Hydropathy results predict that NOV5a does not contain a signal peptide and is likely to be localized in the mitochondrial matrix space with a certainty of 0.4686 and the cytoplasm with a certainty of 0.4500.
  • NOV5a protein may be localized in the mitochondrial matrix space and cytoplasm, the protein predicted here is similar to the Opioid Binding Cell Adhesion Molecule family, some members of which are released extracellularly.
  • SWISSPROT-ACC:Q14982 opioid binding protein/cell adhesion molecule is a type la membrane protein that is localized to the plasma membrane extracellularly. This indicates that the signal peptide ofthe mature protein is cleaved. Therefore it is likely that NOV5a protein is available at the same sub-cellular localization and hence accessible to a diagnostic probe and for various therapeutic applications. It also indicates that the use of a heterologous signal peptide to target the novel protein to the appropriate location, i.e. extracellularly, is appropriate.
  • NOV5a amino acid sequence has 162 of 300 amino acid residues (54%) identical to, and 213 of 00 amino acid residues (71%) similar to, a Homo Sapiens 345 amino acid residue opioid binding protein/cell adhesion molecule precursor (OBCAM) / opioid-binding cell adhesion molecule (OPCML)
  • NOV5a is expressed in at least the following tissues: Brain and Fetal brain. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, genomic clone sources, literature sources, and/or RACE sources. In addition, NOV5a is predicted to be expressed in brain tissues because ofthe expression pattern of a closely related Human (clone pHOM) opioid-binding cell adhesion molecule mRNA homo log (gb:GENBANK- ID:HUMOBCAM
  • a disclosed NOV5b nucleic acid of 1017 nucleotides (also referred to as 139785504_dal) encoding a novel Opioid Binding Cell Adhesion Molecule-like protein is shown in Table 5C.
  • An open reading frame lacking the signal peptide was identified beginning with an GCC at nucleotides 3-5 and ending with a TAG codon at nucleotides 958-960. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 5C, and the start and stop codons are in bold letters.
  • the NOV5b nucleic acid was identified on chromosome 7 and has 261 of 389 bases
  • a disclosed NOV5b polypeptide (SEQ ID NO:24) encoded by SEQ ID NO:23 is 319 amino acid residues and is presented using the one-letter code in Table 5D.
  • Signal P, Psort and/or Hydropathy results predict that NOV5b does not contain a signal peptide and is likely to be localized in the mitochondrial matrix space with a certainty of 0.4686 and the cytoplasm with a certainty of 0.4500.
  • SignalP, Psort and/or hydropathy suggest that NOV5b protein may be localized in the mitochondrial matrix space and cytoplasm, the protein predicted here is similar to the Opioid Binding Cell Adhesion Molecule family, some members of which are released extracellularly.
  • the closest homolog SWISSPROT-ACC.-Q14982 opioid binding protein cell adhesion molecule is a type la membrane protein that is localized to the plasma membrane extracellularly. This indicates that the signal peptide ofthe mature protein is cleaved. Therefore it is likely that NOV5b protein is available at the same sub-cellular localization and hence accessible to a diagnostic probe and for various therapeutic applications. It also indicates that the use of a heterologous signal peptide to target the novel protein to the appropriate location, i.e. extracellularly, is appropriate.
  • Table 5D Encoded NOV5b protein sequence (SEQ ID NO:24).
  • OBCAM opioid binding protein/cell adhesion molecule precursor
  • OPCML opioid-binding cell adhesion molecule
  • NOV5b is expressed in at least the following tissues: Brain and Fetal brain. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, genomic clone sources, literature sources, and/or RACE sources. In addition, NOV5b is predicted to be expressed in brain tissues because ofthe expression pattern of a closely related Homo sapiens (clone pHOM) opioid-binding cell adhesion molecule mRNA homolog (gb:GENBANK- ID:HUMOBCAM
  • clone pHOM Homo sapiens
  • NOV5c A disclosed NOV5c nucleic acid of 1136 nucleotides (also referred to as CG51027-03) encoding a novel Opioid Binding Cell Adhesion Molecule-like protein is shown in Table 5E.
  • An open reading frame lacking a signal peptide was identified beginning with an TCC at nucleotides 2-4and ending with a TAG codon at nucleotides 923-925. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 5E, and the start and stop codons are in bold letters.
  • Table 5E NOV5c Nucleotide Sequence (SEQ ID NO:25)
  • NOV5c nucleic acid was identified on chromosome 7 and has 274 of 389 bases (70%) identical to a Bos taurus opioid binding protein/cell adhesion molecule (OBCAM) mRNA (gb:GENBANK-ID:BTOBCAM
  • acc:X12672.1) (E 1.3e "56 ).
  • OBCAM Bos taurus opioid binding protein/cell adhesion molecule
  • a disclosed NOV5c polypeptide (SEQ ID NO:26) encoded by SEQ ID NO:25 is 307 amino acid residues and is presented using the one-letter code in Table 5F. Signal P, Psort and/or Hydropathy results predict that NOV5c does not contain a signal peptide and is likely to be localized in the mitochondrial matrix space with a certainty of 0.4686 and the cytoplasm with a certainty of 0.4500.
  • NOV5c protein may be localized in the mitochondrial matrix space and cytoplasm, the protein predicted here is similar to the Opioid Binding Cell Adhesion Molecule family, some members of which are released extracellularly.
  • SWISSPROT-ACC:Q14982 opioid binding protein/cell adhesion molecule is a type la membrane protein that is localized to the plasma membrane extracellularly. This indicates that the signal peptide ofthe mature protein is cleaved. Therefore it is likely that NOV5c protein is available at the same sub-cellular localization and hence accessible to a diagnostic probe and for various therapeutic applications. It also indicates that the use of a heterologous signal peptide to target the novel protein to the appropriate location, i.e. extracellularly, is appropriate.
  • NOV5c is expressed in at least the following tissues: Brain and Fetal brain. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, genomic clone sources, literature sources, and/or RACE sources.
  • a disclosed NOV5d nucleic acid of 1169 nucleotides (also referred to as CG51027-05) encoding a novel Opioid Binding Cell Adhesion Molecule- like protein is shown in Table 5G.
  • An open reading frame was identified beginning with an ATG codon at nucleotides 71-73 and ending with a TAG codon at nucleotides 1079-1081.
  • Putative untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 5G, and the start and stop codons are in bold letters.
  • NOV5d nucleic acid was identified on chromosome 7 and has 257 of 389 bases (66%) identical to a Homo sapiens (clone pHOM) opioid-binding cell adhesion molecule mRNA (gb:GENBANK-ID:HUMOBCAM
  • acc:L34774.1) (E 2.0e "46 ).
  • a disclosed NOV5d polypeptide (SEQ ID NO:28) encoded by SEQ ID NO:27 is 336 amino acid residues and is presented using the one-letter code in Table 5H.
  • Signal P, Psort and/or Hydropathy results predict that NOV5d contains a signal peptide and is likely to be localized extracellularly with a certainty of 0.6329.
  • the most likely cleavage site for a NOV5d peptide is between amino acids 30 and 31, at: LLS-QR.
  • NOV5d is expressed in at least the following tissues: Brain and Fetal brain. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, genomic clone sources, literature sources, and/or RACE sources. In addition, NOV5d is predicted to be expressed in occipital cortex tissues because ofthe expression pattern of a closely related Homo sapiens (clone pHOM) opioid-binding cell adhesion molecule mRNA homolog (GENBANK-ID: gb:GENBANK-ID:HUMOBCAM
  • clone pHOM Homo sapiens
  • SNPs small nucleotide polymorphisms
  • NOV5a - NOV5d are very closely homologous as is shown in the amino acid alignment in Table 5J.
  • NOV5 Homologies to any ofthe above NOV5 proteins will be shared by the other NOV5 proteins insofar as they are homologous to each other as shown above. Any reference to NOV5 is assumed to refer to both ofthe NOV5 proteins in general, unless otherwise noted.
  • NOV5a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 5K.
  • OBCAM opioid binding protein cell adhesion molecule precursor
  • OPCML opioid binding protein cell adhesion molecule precursor
  • OBCAM opioid binding protein/cell adhesion molecule precursor
  • OPCML opioid binding cell adhesion molecule [Rattus norvegicus]
  • Tables 5M - 5R list the domain description from DOMAIN analysis results against NOV5a. This indicates that the NOV5a sequence has properties similar to those of other proteins known to contain these domains.
  • Length 86 residues, 100.0% aligned
  • Length 86 residues, 87.2% aligned
  • Length 86 residues, 97.7% aligned
  • NOV5a 24 NYTVCEGDNATLSCFIDEHVT-RVA LNRSNILYAGNDRWTSDPRVRLLINTPEEFSILI 82
  • Length 63 residues, 100.0% aligned
  • NOV5a 128 NEGGNVNLLCLAVGRPEPTVT R QLRDG-FTSEGEILEISDIQRGQAGEYECVTHN 182
  • Length 63 residues, 96.8% aligned
  • NOV5a 214 GRTALLRCEAMAVPPADFQWYKDDRLLSSGTAEGLKVQTERTRSMLLFANVSARHYGNYT 273 l + l l l l + l l + + I I I I I I I I I
  • Immunoglobulin domain Members of the immunoglobulin superfamily are found in hundreds of proteins of different functions. Examples include antibodies, the giant muscle kinase titin and receptor tyrosine kinases. Immunoglobulin-like domains may be involved in protein-protein and protein-ligand interactions. The Pfam alignments do not include the first and last strand of the immunoglobulin-like domain.
  • Opioid-binding cell adhesion molecule a neuron-specific protein, consists of three immunoglobulin (Ig)-like domains anchored to the membrane through a glycosylphosphatidylinositol (GPI)-tail.
  • Ig immunoglobulin
  • GPI glycosylphosphatidylinositol
  • OBCAM has been presumed to play a role as a cell adhesion/recognition molecule, but its function has not been fully elucidated and may also play a role in early neuronal development (Hachisuka et al., Developmental expression of opioid-binding cell adhesion molecule (OBCAM) in rat brain. J Brain Res Dev Brain Res 122(2):183-91, 2000).
  • opioid binding cell adhesion molecule antibodies inhibit opioid binding by opioid binding cell adhesion molecule antibodies
  • down-regulation of opioid binding cell adhesion molecule by chronic opioid agonist treatment of cultured NG108- 15 cells
  • reduction of opioid binding in NG108-15 cells by transfection of opioid binding cell adhesion molecule antisense cDNA
  • opioid binding protein is specifically down-regulated by chronic morphine treatment in dorsal root and trigeminal ganglia. Neuroscience 66(4):943-9, 1995).
  • OBCAM central nervous system
  • NOV5 may function as a member of a Opioid Binding Cell Adhesion Molecule-like protein family. Therefore, the ⁇ OV5 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the NOV5 compositions of the present invention will have efficacy for treatment of patients suffering from Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, Lesch-Nyhan syndrome, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neurodegeneration.
  • VHL Von Hippel-Lindau
  • Molecule-like protein, and the Opioid Binding Cell Adhesion Molecule-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV6 NOV6 includes two novel triacylglycerol lipase-like proteins disclosed below. The disclosed proteins have been named NOV6a and NOV6b.
  • a disclosed NOV6a nucleic acid of 1377 nucleotides (also referred to as SCI 22982104_A) encoding a novel triacylglycerol lipase-like protein is shown in Table 6A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 91-93 and ending with a TAA codon at nucleotides 1243-1245. Putative untranslated regions upstream from the start codon and downstream from the termination codon are underlined in Table 6A, and the start and stop codons are in bold letters.
  • the NOV6a nucleic acid was identified on chromosome 10 and has 367 of 543 bases (67%) identical to a rabbit gastric lipase precursor coding sequence mRNA (gb:GENBANK- ID:A26689
  • acc:A26689.1) (E 9.1e "81 ).
  • a disclosed NOV6a polypeptide (SEQ ID NO:30) encoded by SEQ ID NO:29 is 390 amino acid residues and is presented using the one-letter code in Table 6B.
  • Signal P, Psort and/or Hydropathy results predict that NOV6a contains a signal peptide and is likely to be localized in the microbody (peroxisome) with a certainty of 0.7480.
  • the most likely cleavage site for a NOV6a peptide is between amino acids 19 and 20, at: THG-VF.
  • the NOV6a amino acid sequence has 218 of 396 amino acid residues (55%) identical to, and 288 of 396 amino acid residues (72%) similar to, a Homo sapiens 398 amino acid residue (triacylglycerol lipase, gastric precursor (ec 3.1.1.3) (gastric lipase) protein
  • NOV6a is expressed in at least the following tissues: Whole Organism , fetal lung.
  • SeqCalling sources Whole Organism
  • PublicEST sources fetal lung NbHL19W, testis NHT, and B-cell, pooled germ cell.
  • NOV6a is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related precursor of rabbit gastric lipase coding sequence homolog in species synthetic construct (gb:GENBANK-ID:A26689
  • a disclosed NOV6b nucleic acid of 1260 nucleotides (also referred to as CG58608-02) encoding a novel triacylglycerol lipase-like protein is shown in Table 6C.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 31-33 and ending with a TAA codon at nucleotides 1234-1236. Putative untranslated regions upstream from the start codon and downstream from the termination codon are underlined in Table 6C, and the start and stop codons are in bold letters.
  • NOV6b nucleic acid was identified on chromosome 1 and has 711 of 997 bases (71%) identical to a Homo sapiens gastric lipase mRNA (gb:GENBANK- ID:A01046
  • acc:A01046.1) (E 1.3e "117 )
  • a disclosed NOV6b polypeptide (SEQ ID NO:32) encoded by SEQ ID NO:31 is 401 amino acid residues and is presented using the one-letter code in Table 6D.
  • Signal P, Psort and/or Hydropathy results predict that NOV6b contains a signal peptide and is likely to be localized in the lysosome (lumen) with a certainty of 0.5078.
  • the most likely cleavage site for a NOV6b peptide is between amino acids 19 and 20, at: MYG-YD.
  • Table 6D Encoded NOV6b protein sequence (SEQ ID NO:32).
  • NOV6b is expressed in at least the following tissues: Mammalian Tissue. This information was derived by determining the tissue sources ofthe 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
  • NOV6a and NOV6b are very closely homologous as is shown in the amino acid alignment in Table 6F.
  • NOV6a IGSKLCPLQIFDKICLNILFM FGYDPKNLNMSRLDVYFSHNPAGTSVQN NOV6b IGSKLCPLQIFDKICLNILFMMFGYDPKNLNMSRLDVYFSHNPAGTSVON
  • NOV6a ⁇ .YDWGSPDLNLVHYNQ r ⁇ PLYNMTNMNVATAIWNG NOV6b SLLNSTHL] AYDWGSPDLNLVHYNQ' 5PLYNMTNMNVATA1WNG
  • NOV6 Homologies to any ofthe 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 ofthe NOV6 proteins in general, unless otherwise noted.
  • NOV6a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 6G.
  • Hepatic lipase plays a role in the metabolism of several lipoproteins (Jansen et al., Role of lipoprotein lipases in postprandial lipid metabolism. Atherosclerosis 141 Suppl l :S31-4, 1998).
  • Hepatic lipase (HL) is an enzyme that is made primarily by hepatocytes (and also found in adrenal gland and ovary) and hydrolyzes phospholipids and triglycerides of plasma lipoproteins. It is secreted and bound to the hepatocyte surface and readily released by heparin.
  • the enzyme can be divided into an NH2 -terminal domain containing the catalytic site joined by a short spanning region to a smaller COOH-terminal domain.
  • the NH2-terminal portion contains an active site serine in a pentapeptide consensus sequence, Gly-Xaa-Ser-Xaa- Gly, as part of a classic Ser-Asp-His catalytic triad, and a putative hinged loop structure covering the active site.
  • the COOH-terminal domain contains a putative lipoprotein-binding site.
  • the heparin-binding sites may be distributed throughout the molecule, with the characteristic elution pattern from heparin-sepharose determined by the COOH-terminal domain. Ofthe three N-linked glycosylation sites, Asn-56 is required for efficient secretion and enzymatic activity.
  • HL is hypothesized to directly couple HDL lipid metabolism to tissue/cellular lipid metabolism. The potential significance ofthe HL pathway is that it provides the hepatocyte with a mechanism for the uptake of a subset of phospholipids enriched in unsaturated fatty acids and may allow the uptake of cholesteryl ester, free cholesterol, and phospho lipid without catabolism of HDL apolipoproteins.
  • HL can hydro lyze triglyceride and phospholipid in all lipoproteins, but is predominant in the conversion of intermediate density lipoproteins to LDL and the conversion of post-prandial triglyceride-rich HDL into the postabsorptive triglyceride-poor HDL.
  • HL plays a secondary role in the clearance of chylomicron remnants by the liver.
  • a rare family with HL deficiency has been described.
  • Affected patients are compound heterozygotes for a mutation of Ser267 to Phe that results in an inactive enzyme and a mutation of Thr383 to Met that results in impaired secretion and reduced specific activity.
  • NOV6 may function as a member of a triacylglycerol lipase family. Therefore, the NOV6 nucleic acids and proteins of the invention are useful in potential therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the NOV6 compositions of the present invention will have efficacy for treatment of patients suffering from Adrenoleukodystrophy , Congenital Adrenal Hyperplasia, Diabetes, Von Hippel-Lindau (VHL) syndrome , Pancreatitis, Obesity ,Endometriosis, Xerostomia, Scleroderma, Hypercalceimia, Ulcers Von Hippel-Lindau (VHL) syndrome, Cirrhosis, Transplantation, Inflammatory bowel disease, Diverticular disease, Hirschsprung's disease , Crohn's Disease, Appendicitis, Hypercalceimia, Arthritis, Ankylosing spondylitis, Arthritis, Tendinitis on Hippel-Lindau (VHL) syndrome , Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington's disease, Endocrine dysfunctions, Diabetes, Growth and reproductive disorders, Multiple sclerosis, Leukodys, Le
  • the NOV6 nucleic acid encoding triacylglycerol lipase-like protein, and the triacylglycerol lipase-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV7 NOV7 includes two novel IGE receptor beta subunit-like proteins disclosed below.
  • the disclosed proteins have been named NOV7a and NOV7b.
  • a disclosed NOV7a nucleic acid of 691 nucleotides (also referred to SC126624027_A) encoding a novel IGE receptor beta subunit-like protein is shown in Table 7A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 52-54 and ending with a TGA codon at nucleotides 652-654. Putative untranslated regions are found upstream from the initiation codon and downstream from the termination codon in Table 7A, and the start and stop codons are in bold letters.
  • the disclosed NOV7a nucleic acid sequence, localized to chromosome 15, has 325 of 560 bases (58%) identical to a Mus musculus mast cell high affinity IgE receptor (Fc-epsilon- RI) beta subunit mRNA (gb:GENBANK-ID:MUSFCERB
  • acc:J05019.1) (E 2.2e "05 ).
  • a disclosed NOV7a polypeptide (SEQ ID NO:34) encoded by SEQ ID NO:33 is 200 amino acid residues and is presented using the one-letter amino acid code in Table 7B.
  • Signal P, Psort and/or Hydropathy results predict that NOV7a contains a signal peptide and is likely to be localized in the plasma membrane with a certainty of 0.6000.
  • the most likely cleavage site for a NOV7a peptide is between amino acids 20 and 21, at: ITA-SE.
  • Table 7B Encoded NOV7a protein sequence (SEQ ID NO:34).
  • NOV7a is expressed in at least the following tissues: Testis Whole Organism Male
  • SeqCalling_celltypes testis liver spleen parathyroid tumor. This information was derived by determining the tissue sources ofthe sequences that were included in the invention. SeqCalling sources: Testis Whole Organism Male Reproductive System,
  • NOV7a is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Mus musculus mast cell high affinity IgE receptor (Fc-epsilon-RI) beta subunit homolog mRNA
  • a disclosed NOV7b nucleic acid of 500 nucleotides (also referred to CG55760-02) encoding a novel IGE receptor beta subunit-like protein is shown in Table 7C.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 26-28 and ending with a TGA codon at nucleotides 473-475. Putative untranslated regions are found upstream from the initiation codon and downstream from the termination codon in Table 7C, and the start and stop codons are in bold letters.
  • a disclosed NOV7b polypeptide (SEQ ID NO: 36) encoded by SEQ ID NO:35 is 149 amino acid residues and is presented using the one-letter amino acid code in Table 7D.
  • Signal P, Psort and/or Hydropathy results predict that NOV7b contains a signal peptide and is likely to be localized in the plasma membrane with a certainty of 0.6000.
  • the most likely cleavage site for a NOV7b peptide is between amino acids 20 and 21, at: ITA-SE.
  • Table 7D Encoded NOV7b protein sequence (SEQ ID NO:36).
  • NOV 7b is expressed in at least the following tissues: testis. This information was derived by determining the tissue sources ofthe 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
  • NOV7a and NOV7b are very closely homologous as is shown in the amino acid alignment in Table 7F.
  • NOV7 Homologies to any ofthe above NOV7 proteins will be shared by the other NOV7 proteins insofar as they are homologous to each other as shown above. Any reference to NOV7 is assumed to refer to both ofthe NOV7 proteins in general, unless otherwise noted.
  • NOV7a also has homology to the amino acid sequence shown in the BLASTP data listed in Table 7G.
  • the IgE receptor plays a central role in allergic disease, coupling allergen and mast cell to initiate the inflammatory and immediate hypersensitivity responses that are characteristic of disorders such as hay fever and asthma.
  • the allergic response occurs when 2 or more high- affinity IgE receptors are crosslinked via IgE molecules that in turn are bound to an allergen (antigen) molecule.
  • a perturbation occurs that brings about the release of histamine and proteases from the granules in the cytoplasm ofthe mast cell and leads to the synthesis of prostaglandins and leukotrienes-potent effectors ofthe hypersensitivity response.
  • the IgE receptor consists of 3 subunits: alpha, beta (147138), and gamma (147139); only the alpha subunit is glycosylated.
  • the human and rat alpha subunits share similarities with each other and with the immunoglobulin gene family, suggesting origin from a common ancestral gene, and share structural homology with their ligands. Liu et al.
  • Garman et al. (1990) assigned genes for both the alpha and the gamma subunits to lq23.
  • Garman et al. (1998) determined the x-ray crystal structure ofthe antibody-binding domains ofthe human IgE receptor alpha subunit at 2.4- angstrom resolution. The structure revealed a highly bent arrangement of immunoglobulin domains that form an extended convex surface of interaction with IgE. A prominent loop that confers specificity for IgE molecules extends from the receptor surface near an unusual arrangement of 4 exposed tryptophans.
  • the crystal structure ofthe IgE receptor provides a foundation for the development of new therapeutic approaches to allergy treatment.
  • Garman et al. solved the crystal structure ofthe human IgE-Fc-FCERl A complex to 3.5-angstrom resolution.
  • NOV7 may function as a member of a IGE receptor beta subunit protein family. Therefore, the NOV7 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the NOV7 compositions ofthe present invention will have efficacy for treatment of patients suffering from 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, leukemia or pancreatic cancer.; blood disorders; asthma; psoriasis; inflammatory skin disordersvascular disorders, hypertension, skin disorders, renal disorders including Alport syndrome, immunological disorders, inflammation including irritable bowel disease, and tissue injury, cancers, fibrosis disorders, bone diseases, Ehlers-Danlos syndrome type VI, VII, type IV, S-linked cutis laxa and Ehlers- Danlos syndrome type V, osteogenesis imperfecta.Immuno therapy of inflammatory and infectious diseases such as AIDS, cancer therapy, treatment of Neurologic diseases, Brain and/or autoimmune disorders like encephalomyelitis, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematop
  • the NOV7 nucleic acid encoding IGE receptor beta subunit-like protein, and the IGE receptor beta subunit-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • a disclosed NOV8 nucleic acid of 1386 nucleotides (also referred to SC138745558_A) encoding a novel Muncl8-like protein is shown in Table 8 A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 36-38 and ending with a TGA codon at nucleotides 1350-1352.
  • Putitive untranslated regions upstream from the initiation codon and downstream from the termination codon are underlined in Table 8A, and the start and stop codons are in bold letters.
  • the disclosed NOV8 nucleic acid sequence is localized to chromosome 16.
  • a disclosed NOV8 polypeptide (SEQ ID NO:38) encoded by SEQ ID NO:37 is 438 amino acid residues and is presented using the one-letter amino acid code in Table 8B.
  • Signal P, Psort and/or Hydropathy results predict that NOV8 does not contain a signal peptide and is likely to be localized to the mitochondrial matrix space with a certainty of 0.4363.
  • Table 8B Encoded NOV8 protein sequence (SEQ ID NO:38).
  • NOV8a is expressed in at least the following tissues: Adrenal Gland/Suprarenal gland, Amygdala, Cervix, Pituitary Gland, Thymus, Tonsils, Whole Organism, SeqCalling_celltypes: liver, spleen, testis, tumor. This information was derived by determining the tissue sources of the sequences that were included in the invention. SeqCalling sources: Adrenal Gland/Suprarenal gland, Amygdala, Cervix, Pituitary Gland, Thymus, Tonsils, Whole Organism, SeqCalling_celltypes: liver, spleen, testis, tumor. This information was derived by determining the tissue sources of the sequences that were included in the invention. SeqCalling sources: Adrenal
  • Gland/Suprarenal gland Amygdala, Cervix, Pituitary Gland, Thymus, Tonsils, Whole Organism; PublicEST sources: liver, spleen, testis, tumor.
  • the disclosed NOV8 polypeptide has homology to the amino acid sequences shown in the BLASTP data listed in Table 8C.
  • Muncl8-2 function in apical membrane trafficking involves aspects independent ofthe syntaxin 3 interaction (Riento et al., Muncl8-2, a functional partner of syntaxin 3, controls apical membrane trafficking in epithelial cells. J Biol Chem 275(18): 13476-83, 2000).
  • the Q-SNARE syntaxin 1 is a central component ofthe synaptic membrane fusion machinery. Syntaxin probably interacts with multiple proteins during synaptic vesicle exocytosis. In vitro, the tightest binding partners for syntaxin 1 are other SNAREs (synaptobrevin/VAMP and SNAP-25) and muncl8-l (also known as rbsecl/nsecl) (Matos et al., The relation of protein binding to function: what is the significance of muncl ⁇ and synaptotagmin binding to syntaxin 1, and where are the corresponding binding sites? Eur J Cell Biol 79(6):377-82, 2000).
  • Mintl (XI 1 /human Lin- 10) and Mint2 are neuronal adaptor proteins that bind to Muncl8-1 (n/rb-secl), a protein essential for synaptic vesicle exocytosis.
  • Mintl has previously been characterized in a complex with CASK, another adaptor protein that in turn interacts with neurexins.
  • Neurexins are neuron-specific cell surface proteins that act as receptors for the excitatory neurotoxin -latrotoxin.
  • one possible function for Mintl is to mediate the recruitment of Muncl ⁇ to neurexins.
  • NOV8 may function as a member of a Muncl ⁇ protein family. Therefore, the NOV8 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the NOV8 compositions of the present invention will have efficacy for treatment of patients suffering from 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, leukemia or pancreatic cancer.; blood disorders; asthma; psoriasis; inflammatory skin disordersvascular disorders, hypertension, skin disorders, renal disorders including Alport syndrome, immunological disorders, tissue injury, cancers, fibrosis disorders, bone diseases, Ehlers-Danlos syndrome type VI, VII, type IV, S-linked cutis laxa and Ehlers- Danlos syndrome type V, osteogenesis imperfecta, Immuno therapy of inflammatory and infectious diseases such as AIDS, treatment of Neurologic diseases, Brain and/or autoimmune disorders like encephalomyelitis, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, endocrine diseases, muscle disorders, wound
  • the NOV8 nucleic acid encoding Muncl 8-like protein, and the Muncl 8-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV9 includes two novel Immunoglobulin-like proteins disclosed below. The disclosed proteins have been named NOV9a and NOV9b.
  • NOV9a nucleic acid of 1514 nucleotides also referred to SC138673511_A
  • Table 9A An open reading frame was identified beginning with an ATG initiation codon at nucleotides 29- 31 and ending with a TGA codon at nucleotides 1319-1321. Putative untranslated regions upstream from the initiation codon and downstream from the termination codon is underlined in Table 9A, and the start and stop codons are in bold letters.
  • Table 9A NOV9a Nucleotide Sequence (SEQ ID NO:39)
  • NOV9a nucleic acid sequence maps to chromosome 19, has 510 of 852 bases (59%) identical to a Mus musculus immunosuperfamily protein B12 mRNA from (gb:GENBANK-ID:AF061260
  • acc:AF061260) (E 7.6e "21 ).
  • a disclosed NOV9a polypeptide (SEQ ID NO:40) encoded by SEQ ID NO:39 is 430 amino acid residues and is presented using the one-letter amino acid code in Table 9B.
  • Signal P, Psort and/or Hydropathy results predict that NOV9a contains a signal peptide and is likely to be localized in the plasma membrane with a certainty of 0.7300.
  • the most likely cleavage site for a NOV9a peptide is between amino acids 66 and 67, at: GAG-QE.
  • Table 9B Encoded NOV9a protein sequence (SEQ ID NO:40).
  • NOV9a is expressed in at least the following tissues: Amygdala, Brain, Coronary Artery, Heart, Hippocampus, Hypothalamus, Kidney, Lung, Pituitary Gland, Spinal Chord, Substantia Nigra, Thalamus, Whole Organism, SeqCalling_celltypes: glioblastoma total_fetus schizo brain brain oligodendroglioma Fetal brain. This information was derived by determining the tissue sources ofthe sequences that were included in the invention.
  • SeqCalling sources Amygdala, Brain, Coronary Artery, Heart, Hippocampus, Hypothalamus, Kidney, Lung, Pituitary Gland, Spinal Chord, Substantia Nigra, Thalamus, Whole Organism, PublicEST sources: glioblastoma total_fetus schizo brain brain oligodendroglioma Fetal brain.
  • NOV9a is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Mus musculus immunosuperfamily protein B12 mRNA (GENBANK-ID: gb:GENBANK-ID:AF061260
  • a closely related Mus musculus immunosuperfamily protein B12 mRNA GENE-ID: gb:GENBANK-ID:AF061260
  • a disclosed NOV9b nucleic acid of 1161 nucleotides (also referred to CG106625-02) encoding a novel Immunoglobulin-like protein is shown in Table 9C.
  • An open reading frame lacking the signal peptide was identified beginning with an GCC codon at nucleotides 2-4 and ending with a TGA codon at nucleotides 1157-1159.
  • Putative untranslated regions upstream from the initiation codon and downstream from the termination codon is underlined in Table 9C, and the start and stop codons are in bold letters.
  • NOV9b nucleic acid sequence maps to chromosome 19, has 557 of 931 bases (59%) identical to a Mus musculus sgigsf mRNA for spermatogenic immunoglobulin superfamily protein (gb:GENBANK-ID:AB052293
  • acc:AB052293.1) (E 2.1e "26 ).
  • a disclosed NOV9b polypeptide (SEQ ID NO:42) encoded by SEQ ID NO:41 is 385 amino acid residues and is presented using the one-letter amino acid code in Table 9D.
  • Signal P, Psort and/or Hydropathy results predict that NOV9b contains a signal peptide and is likely to be localized in the plasma membrane with a certainty of 0.4600.
  • the most likely cleavage site for a NOV9b peptide is between amino acids 21 and 22, at: GAG-QE.
  • Table 9D Encoded NOV9b protein sequence (SEQ ID NO:42).
  • NOV9b is expressed in at least the following tissues: Amygdala, Brain, Coronary Artery, Heart, Hippocampus, Hypothalamus, Kidney, Lung, Pituitary Gland, Spinal Chord, Substantia Nigra, Thalamus, Whole Organism. This information was derived by determining the tissue sources ofthe sequences that were included in the invention. SeqCalling sources: Amygdala, Brain, Coronary Artery, Heart, Hippocampus, Hypothalamus, Kidney, Lung, Pituitary Gland, Spinal Chord, Substantia Nigra, Thalamus, Whole Organism, PublicEST sources: glioblastoma total_fetus schizo brain brain oligodendroglioma Fetal brain.
  • NOV9b is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Mus musculus sgigsf mRNA for spermatogenic immunoglobulin superfamily protein (gb:GENBANK-ID:AB052293
  • NOV9a and NOV9b are very closely homologous as is shown in the amino acid alignment in Table 9E.
  • NOV9a GVLDA MGPEVWVPQGAGAKGPDPPSPVRAVGIGLGEDN GKAR NOV9b
  • NOV9 Homologies to any ofthe above NOV9 proteins will be shared by the other NOV9 proteins insofar as they are homologous to each other as shown above. Any reference to NOV9 is assumed to refer to both ofthe NOV9 proteins in general, unless otherwise noted.
  • NOV9a also has homology to the amino acid sequences shown in the BLASTP data listed in Table 9F.
  • IAF 132811 1 (AF 132811) nectin-hke protein 2 [Homo sapiens] (SEQ ID NO.110)
  • Tables 9H - 9P list the domain description from DOMAIN analysis results against NOV9. This indicates that the NOV9 sequence has properties similar to those of other proteins known to contain these domains.
  • Length 63 residues, 100.0% aligned
  • NOV9a 278 REGDTLVLTCAVTGNPRPNQIRWNRGNESLPE-RAEAVGETLTLPGLVSADNGTYTCEAS 336
  • Length 63 residues, 96.8% aligned
  • NOV9a 179 EGGEVELSCLVPRSRPAATLRWYRDRKELKGVSSSQENGKVWSVASTVRFRVDRKDDGGI 238
  • Length 86 residues, 98.8% aligned
  • NOV9a 326 ADNGTYTCEASNKHGHARALYVLVVY 351 l + l I I I I l + l 1 1 + I I 00409 61 EDSGTYTCAATNSSGSASSGTTLTVL 86
  • Length 86 residues, 98.8% aligned
  • Length 86 residues, 77.9% aligned
  • Length 68 residues, 100.0% aligned
  • NOV9a 280 GDTLVLTCAVTGNPRPNQIRWNRGNE SLPERAEAVGETLTLPGLVSAD 327
  • Length 80 residues, 97.5% aligned
  • NOV9a 82 AEITCRLHQYDGSIVVI QNPARQTLFF NGTRALKDERFQL-EEFSPRRV 129
  • rIL-4 The effect of rIL-4 on the expression of low affinity receptor for the Fc part of IgE (Fc epsilon R2/CD23) and class II MHC antigens on Burkitt's lymphoma (BL) cell lines was investigated. Some ofthe BL lines contained low percentages of CD23 and HLA-DQ-positive cells, but virtually all cells expressed HLA-DR. IL-4 induced CD23 and class II MHC Ag expression on 7 of 9 BL. Optimal CD23 and class II MHC expression was observed after 48- 72 h of incubation. Induction of CD23 and class II MHC Ag in the BL cell line BL2 by IL-4 was confirmed at the specific mRNA level.
  • HLA-DQ mRNA Significant activation of HLA-DQ mRNA was obtained after 6 h of incubation with IL-4 and gradually increased during prolonged incubation. Maximal induction of mRNA transcription occurred after 48 to 72 h. Optimal induction of HLA-DR and CD23 transcription in BL2 was also observed after 48 to 72 h. The induction of CD23 and class II MHC Ag seems to be specific for IL-4, because rIL-1, rIL-2, rIFN-gamma, recombinant granulocyte-macrophage-CSF, and a commercial source of low m.w. B cell growth factor were ineffective.
  • CD40L blocking Abs on somatic mutation and 2) the ability of a CD40L-def ⁇ cient T cell clone (isolated from an X-linked hyper-IgM syndrome patient) to induce somatic mutation in B cell receptor-engaged BL2 cells.
  • the in vitro model reveals that T-B cell membrane interactions through surface molecules different from CD40-CD40L can trigger somatic hypermutation (Denepoux et al., T cells can induce somatic mutation in B cell receptor- engaged BL2 Burkitt's lymphoma cells independently of CD40-CD40 ligand interactions. J Immunol 164(3):1306-13, 2000).
  • BL2 68,000 dalton surface membrane protein
  • peripheral blood B cells which is absent from thymocytes, T cells, and granulocytes.
  • Indirect immunofluorescent assay with this monoclonal antibody demonstrated that BL2 is expressed by cells within the fetal liver and by a variable proportion of lymph node, tonsil, and spleen B cells, but not by T cells.
  • BL2 The neoplastic cells isolated from 18 T-cell malignancies were BL2- .
  • BL2 was was hetero geneously expressed by a variable proportion ofthe malignant cells in 29/32 cases of B-chronic lymphocytic leukemia and 33/38 cases of B-cell lymphomas, but appeared to be lost in the terminal stages of B-cell differentiation, as myeloma plasma cells were BL2- .
  • BL2 expression was not limited to B cells of a particular surface immunoglobulin isotype. Immunofluorescent staining for BL2 in cryostat tissue sections demonstrated that the majority, but not all, germinal center and interfollicular Ia+ (non-T) cells are BL2+.
  • BL2 is a B-cell lineage-specific differentiation marker that may be useful in the study of B-cell ontogeny and in defining subgroups ofthe B-cell malignancies (Knowles et al., A new human B-lymphocyte surface antigen (BL 2) detectable by a hybridoma monoclonal antibody: distribution on benign and malignant lymphoid cells. Blood 1983 Jul;62(l):191-9, 1983).
  • NOV9 may have important structural and/or physiological functions characteristic ofthe Immunoglobulin protein family. Therefore, the NOV9 nucleic acids and proteins ofthe invention are useful in potential therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the NOV9 compositions of the present invention will have efficacy for treatment of patients suffering from 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, leukemia or pancreatic cancer.; blood disorders; asthma; psoriasis; inflammatory skin disordersvascular disorders, hypertension, skin disorders, renal disorders including Alport syndrome, immunological disorders, tissue injury, cancers, fibrosis disorders, bone diseases, Ehlers-Danlos syndrome type VI, VII, type IV, S-linked cutis laxa and Ehlers- Danlos syndrome type V, osteogenesis imperfecta, Immuno therapy of inflammatory and infectious diseases such as AIDS, treatment of Neurologic diseases, Brain and/or autoimmune disorders like encephalomyelitis, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, endocrine diseases, muscle disorders, wound
  • the NOV9 nucleic acid encoding Immunoglobulin-like protein, and the Immunoglobulin-like protein ofthe invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.
  • NOV 10 includes three novel Type II Cytokeratin-like proteins disclosed below. The disclosed proteins have been named NOV 10a, NOV 10b and NOV 10c.
  • NOVlOa A disclosed NOV 10a nucleic acid of 1782 nucleotides (also referred to
  • GSAC055715.12_D encoding a Type II Cytokeratin-like protein is shown in Table 10A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 63- 65 and ending with a TAA codon at nucleotides 1710-1712.
  • Putative untranslated regions upstream from the intiation codon and downstream from the termination codon are underlined in Table IOA, and the start and stop codons are in bold letters.
  • the disclosed NOVlOa nucleic acid sequence, localized to chromosome 12, has 1255 of 1478 bases (84%) identical Mus musculus type II cytokeratin mRNA (gb:GENBANK- ID:AB033744
  • acc:AB033744.1) (E 5.2e "231 ).
  • a disclosed NOVlOa polypeptide (SEQ ID NO:44) encoded by SEQ ID NO:43 is 549 amino acid residues and is presented using the one-letter amino acid code in Table 10B.
  • Signal P, Psort and/or Hydropathy results predict that NOVlOa does not contain a signal peptide and is likely to be localized in the cytoplasm with a certainty of 0.4500.
  • NOVlOa is expressed in at least the following tissues: skin, muscle, bone, cartilage, Colon carcinoma, lung. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Genomic Clone sources, Literature sources, and/or RACE sources. In addition, NOVlOa is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Mus musculus mRNA for type II cytokeratin (GENBANK-ID: gb:GENBANK-ID:AB033744
  • a disclosed NOV 10b nucleic acid of 1601 nucleotides (also referred to GSAC055715 C) encoding a Type II Cytokeratin-like protein is shown in Table IOC.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 66- 68 and ending with a TGA codon at nucleotides 1599-1601.
  • a putative untranslated region upstream from the intiation codon is underlined in Table 10C, and the start and stop codons are in bold letters.
  • the disclosed NOVlOb nucleic acid sequence, localized to chromosome 12, has 1004 of 1224 bases (82%) identical Mus musculus type II cytokeratin mRNA (gb:GENBANK- ID:AB033744
  • acc:AB033744.1) (E 4.8e "176 ).
  • a disclosed NOVlOb polypeptide (SEQ ID NO:46) encoded by SEQ ID NO:45 is 511 amino acid residues and is presented using the one-letter amino acid code in Table 10D. Signal P, Psort and/or Hydropathy results predict that NOVlOb does not contain a signal peptide and is likely to be localized in the cytoplasm with a certainty of 0.4500.
  • Table 10D Encoded NOVlOb protein sequence (SEQ ID NO:46).
  • NOVlOb is expressed in at least the following tissues: skin, muscle, bone, cartilage, Colon carcinoma, lung. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Genomic Clone sources, Literature sources, and/or RACE sources. In addition, NOVlOb is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Mus musculus mRNA for type II cytokeratin (GENBANK-ID: gb:GENBANK- ⁇ D:AB033744
  • GENE-ID gb:GENBANK- ⁇ D:AB033744
  • a disclosed NOV 10c nucleic acid of 1606 nucleotides (also referred to GSAC055715 B) encoding a Type II Cytokeratin-like protein is shown in Table 10E.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TAG codon at nucleotides 1515-1517.
  • a putative untranslated region downstream from the termination codon is underlined in Table 10E, and the start and stop codons are in bold letters.
  • a disclosed NOVlOc polypeptide (SEQ ID NO:48) encoded by SEQ ID NO:47 is 521 amino acid residues and is presented using the one-letter amino acid code in Table 10F.
  • Signal P, Psort and/or Hydropathy results predict that NOVlOc does not contain a signal peptide and is likely to be localized in the cytoplasm with a certainty of 0.4500.
  • Table 10F Encoded NOVlOc protein sequence (SEQ ID NO:48). SRQFTYKSGAAAKGGFSGCSAVLSGGSSSSYRAGGKGLSGGFSSRSLYSLGGARSISFNVASGSG AGGYGFGRGRASG FAGSMFGSVALGSVCPSLCPPGGIHQVTINKSLLAPLNVELDPEIQKVRAQEREQIKVLNNKFASFIDKVRFLEQQNQVL ETKWELLQQLDLNNCKNNLEPILEGYISNLRKQLETLSGDRVRLDSELRSVREVVEDYKKRYEEEINKRTTAENEFVVLK KDVDAAYTSKVELQAKVDALDGEIKFFKCLYEGETAQIQ ⁇ HISDTSIILSMDNNRNLDLDSIIAEVRAQYEEIARKSKAE AEALYQTKFQELQLAAGRHGDDLKHTKNEISELTRLIQRLRSEIESVKKQCANLETAIADAEQRGDCALKDARAKLDELE GALQQAKEELARMLREY
  • NOVlOc is expressed in at least the following tissues: skin, mammary gland, and lung. This information was derived by determining the tissue sources ofthe sequences that were included in the invention including but not limited to SeqCalling sources, Public EST sources, Genomic Clone sources, Literature sources, and/or RACE sources. In addition, NOVlOc is predicted to be expressed in the following tissues because ofthe expression pattern of a closely related Mus musculus mRNA for type II cytokeratin (GENBANK-ID: gb:GENBANK- ID:AB033744
  • NOVlOa, NOVlOb and NOVlOc are very closely homologous as is shown in the amino acid alignment in Table 10G.
  • NOVlOa I 11 ID NOVlOb NOVlOb
  • NOV 10 Homologies to any ofthe above NOV 10 proteins will be shared by the other NOV 10 proteins insofar as they are homologous to each other as shown above. Any reference to NOV 10 is assumed to refer to both ofthe NOV 10 proteins in general, unless otherwise noted.
  • the disclosed NOVlOa polypeptide has homology to the amino acid sequences shown in the BLASTP data listed in Table 10H.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Wood Science & Technology (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Immunology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne des séquences d'acide nucléique qui codent pour de nouveaux polypeptides. L'invention concerne également les polypeptides codés par ces séquences d'acide nucléique, et des anticorps qui se lient de manière immunospécifique avec ces polypeptides, ainsi que des dérivés, des variants, des mutants ou des fragments des poylpeptides, polynucléotides ou anticorps décrits. L'invention concerne en outre des méthodes de traitement, de diagnostic et de recherche destinées au diagnostic, au traitement et à la prévention de troubles associés à l'un de ces nouveaux acides nucléiques et protéines humains.
PCT/US2001/048732 2000-11-13 2001-11-13 Proteines, polynucleotides codant pour ces proteines et procedes d'utilisation WO2002066643A2 (fr)

Applications Claiming Priority (15)

Application Number Priority Date Filing Date Title
US60/248,153 2000-11-13
US24959800P 2000-11-17 2000-11-17
US60/249,598 2000-11-17
US26424001P 2001-01-26 2001-01-26
US60/264,240 2001-01-26
US26612701P 2001-02-02 2001-02-02
US60/266,127 2001-02-02
US26956201P 2001-02-16 2001-02-16
US60/269,562 2001-02-16
US30434801P 2001-07-10 2001-07-10
US60/304,348 2001-07-10
US30926101P 2001-07-31 2001-07-31
US60/309,261 2001-07-31
US31328301P 2001-08-17 2001-08-17
US60/313,283 2001-08-17

Publications (2)

Publication Number Publication Date
WO2002066643A2 true WO2002066643A2 (fr) 2002-08-29
WO2002066643A3 WO2002066643A3 (fr) 2003-06-26

Family

ID=27569466

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/048732 WO2002066643A2 (fr) 2000-11-13 2001-11-13 Proteines, polynucleotides codant pour ces proteines et procedes d'utilisation

Country Status (1)

Country Link
WO (1) WO2002066643A2 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1434783A2 (fr) * 2001-03-16 2004-07-07 Eli Lilly And Company Proteines de mammiferes lp et reactifs associes
EP1918299A1 (fr) * 2006-11-03 2008-05-07 Universite De Geneve Modulateurs de molécules d'adhésion cellulaire et leur utilisation
WO2008142693A2 (fr) * 2007-05-22 2008-11-27 Yeda Research And Development Co. Ltd. Régulation de la myélination par des molécules de type nectine (necl)
US7908000B2 (en) 2004-02-20 2011-03-15 Brainsgate Ltd. Transmucosal electrical stimulation
US8420084B2 (en) 2009-03-05 2013-04-16 Medarex, Inc. Fully human antibodies specific to CADM1
US9675796B2 (en) 2013-11-10 2017-06-13 Brainsgate Ltd. Implant and delivery system for neural stimulator
US9903872B2 (en) 2006-08-29 2018-02-27 Oxford Biotherapeutics, Ltd. Identification of protein associated with hepatocellular carcinoma, gliobastoma and lung cancer
US10271907B2 (en) 2015-05-13 2019-04-30 Brainsgate Ltd. Implant and delivery system for neural stimulator

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9233245B2 (en) 2004-02-20 2016-01-12 Brainsgate Ltd. SPG stimulation
US8055347B2 (en) 2005-08-19 2011-11-08 Brainsgate Ltd. Stimulation for treating brain events and other conditions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999004263A1 (fr) * 1997-07-17 1999-01-28 The John Hopkins University School Of Medicine Recepteur de semaphorine
WO2001029215A2 (fr) * 1999-10-19 2001-04-26 Compugen Ltd. Homologues de molecules d'adherence cellulaire neuronale
WO2002038744A2 (fr) * 2000-10-18 2002-05-16 Incyte Genomics, Inc. Protéases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999004263A1 (fr) * 1997-07-17 1999-01-28 The John Hopkins University School Of Medicine Recepteur de semaphorine
WO2001029215A2 (fr) * 1999-10-19 2001-04-26 Compugen Ltd. Homologues de molecules d'adherence cellulaire neuronale
WO2002038744A2 (fr) * 2000-10-18 2002-05-16 Incyte Genomics, Inc. Protéases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OSADA N ET AL: "Macaca fascicularis brain cDNA, clone:QccE-16296" EMBL, XP002173301 cited in the application *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1434783A4 (fr) * 2001-03-16 2006-06-07 Lilly Co Eli Proteines de mammiferes lp et reactifs associes
EP1434783A2 (fr) * 2001-03-16 2004-07-07 Eli Lilly And Company Proteines de mammiferes lp et reactifs associes
US8954149B2 (en) 2004-02-20 2015-02-10 Brainsgate Ltd. External stimulation of the SPG
US7908000B2 (en) 2004-02-20 2011-03-15 Brainsgate Ltd. Transmucosal electrical stimulation
US8010189B2 (en) 2004-02-20 2011-08-30 Brainsgate Ltd. SPG stimulation for treating complications of subarachnoid hemorrhage
US9903872B2 (en) 2006-08-29 2018-02-27 Oxford Biotherapeutics, Ltd. Identification of protein associated with hepatocellular carcinoma, gliobastoma and lung cancer
EP1918299A1 (fr) * 2006-11-03 2008-05-07 Universite De Geneve Modulateurs de molécules d'adhésion cellulaire et leur utilisation
WO2008142693A2 (fr) * 2007-05-22 2008-11-27 Yeda Research And Development Co. Ltd. Régulation de la myélination par des molécules de type nectine (necl)
WO2008142693A3 (fr) * 2007-05-22 2009-01-08 Yeda Res & Dev Régulation de la myélination par des molécules de type nectine (necl)
US8420084B2 (en) 2009-03-05 2013-04-16 Medarex, Inc. Fully human antibodies specific to CADM1
US9675796B2 (en) 2013-11-10 2017-06-13 Brainsgate Ltd. Implant and delivery system for neural stimulator
US10512771B2 (en) 2013-11-10 2019-12-24 Brainsgate Ltd. Implant and delivery system for neural stimulator
US10271907B2 (en) 2015-05-13 2019-04-30 Brainsgate Ltd. Implant and delivery system for neural stimulator

Also Published As

Publication number Publication date
WO2002066643A3 (fr) 2003-06-26

Similar Documents

Publication Publication Date Title
US20040022781A1 (en) Proteins and nucleic acids encoding same
US6974684B2 (en) Therapeutic polypeptides, nucleic acids encoding same, and methods of use
WO2002066643A2 (fr) Proteines, polynucleotides codant pour ces proteines et procedes d'utilisation
WO2002046229A2 (fr) Nouvelles proteines et acides nucleiques codant celles-ci
WO2002079398A2 (fr) Polypeptides therapeutiques, les acides nucleiques les codant et leurs procedes d'utilisation
US20030219823A1 (en) Therapeutic polypeptides, nucleic acids encoding same, and methods of use
WO2002099116A2 (fr) Polypeptides therapeutiques, acides nucleiques codant ces polypeptides et procedes d'utilisation
WO2002057452A2 (fr) Proteines, polynucleotides codant pour elles et leurs procedes d'utilisation
US20030236188A1 (en) Novel human proteins, polynucleotides encoding them and methods of using the same
EP1549671A2 (fr) Polypeptides therapeutiques, acides nucleiques codant ces polypeptides et methodes d'utilisation associees
WO2002083841A2 (fr) Polypeptides therapeutiques, acides nucleiques les codant, et procedes d'utilisation
EP1443913A2 (fr) Polypeptides therapeutiques, acides nucleiques encodant ces polypeptides et leurs procedes d'utilisation
US20060211031A1 (en) Novel proteins and nucleic acids encoding same
WO2002026985A2 (fr) Nouvelles proteines et acides nucleiques codant ces proteines
US20030229016A1 (en) Novel human proteins, polynucleotides encoding them and methods of using the same
US20030207800A1 (en) Proteins, polynucleotides encoding them and methods of using the same
WO2002081629A2 (fr) Nouvelles proteines humaines, polynucleotides codant celles-ci et procede d'utilisation de ceux-ci
CA2471480A1 (fr) Polypeptides therapeutiques, acides nucleiques codant ces polypeptides et procedes d'utilisation
WO2003064589A2 (fr) Polypeptides therapeutiques, acides nucleiques les codant et leurs methodes d'utilisation
US20030165858A1 (en) Novel GPCR-like proteins and nucleic acids encoding same
AU2003232034A1 (en) Therapeutic polypeptides, nucleic acids encoding same, and methods of use
WO2003004617A2 (fr) Nouvelles proteines humaines, polynucleotides codant pour ces proteines et procedes d'utilisation associes
US20060210559A1 (en) Novel antibodies that bind to antigenic polypeptides, nucleic acids encoding the antigens, and methods of use
CA2448256A1 (fr) Nouvelles proteines humaines, polynucleotides les codant et methodes d'utilisation associees
CA2478032A1 (fr) Polypeptides therapeutiques, acides nucleiques codant pour eux et leur procede d'utilisation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP