WO2002057453A2 - Polypeptides et acides nucleiques codant ces derniers - Google Patents

Polypeptides et acides nucleiques codant ces derniers Download PDF

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WO2002057453A2
WO2002057453A2 PCT/US2001/050331 US0150331W WO02057453A2 WO 2002057453 A2 WO2002057453 A2 WO 2002057453A2 US 0150331 W US0150331 W US 0150331W WO 02057453 A2 WO02057453 A2 WO 02057453A2
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nucleic acid
amino acid
polypeptide
protein
seq
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PCT/US2001/050331
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WO2002057453A3 (fr
Inventor
Esha A. Gangolli
Meera Patturajan
Corine A. M. Vernet
Uriel M. Malyankar
Ramesh Kekuda
David J. Stone
David Anderson
Richard A. Shimkets
Catherine E. Burgess
Bryan D. Zerhusen
Xiaohong Liu
Kimberly A. Spytek
Stacie J. Casman
Ferenc L. Boldog
Glennda Smithson
Li Li
Weizhen Ji
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Curagen Corporation
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Priority to JP2002558505A priority Critical patent/JP2005508601A/ja
Priority to CA002433313A priority patent/CA2433313A1/fr
Priority to EP01993342A priority patent/EP1352065A2/fr
Publication of WO2002057453A2 publication Critical patent/WO2002057453A2/fr
Publication of WO2002057453A3 publication Critical patent/WO2002057453A3/fr

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    • 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
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • the invention generally relates to nucleic acids and polypeptides encoded thereby.
  • the epidermal growth factor (EGF) superfamily comprises a diverse group of proteins that function as secreted signaling molecules, growth factors, and components of the extracellular matrix, many with a role in vertebrate development.
  • EGF -related proteins with Cls-li e (CUB) domains have been reported.
  • the CUB domain is found in 16 functionally diverse proteins such as the dorso-ventral patterning protein tolloid, bone niorphogenetic protein- 1, a family of spermadhesins, complement subcomponents Cls/Clr and the neuronal recognition molecule A5. Most of these proteins are known to be involved in developmental processes.
  • the second domain is found mostly among developmentally-regulated proteins and spermadhesins.
  • ACRP3 The adipocyte complement related protein-3 (AC P3), is a 30 kDa serum protein made and secreted exclusively from adipocyte cells, which is implicated in energy homeostasis and obesity.
  • ACRP3 is structurally similar to complement factor Clq and to a hibernation-specific protein isolated from the plasma of Siberian chipmunks; it forms large homo-oligomers that undergo a series of post-translational modifications (see, Scherer PE, et al, J Biol Chem 1995 Nov 10;270(45):26746-9).
  • ACRP30 is a close homologue of the complement protein Clq,
  • Clq is the first subcomponent of the Cl complex of the classical pathway of complement activation.
  • Several functions have been assigned to Clq, which include antibody- dependent and independent immune functions, and are considered to be mediated by Clq receptors present on the effector cell surface.
  • Clq receptors present on the effector cell surface.
  • the problem of identifying receptor proteins with complementary binding sites for Clq has been compounded by the highly charged nature of the different domains in Clq.
  • the first component of complement is a calcium-dependent complex of the 3 subcomponents Clq, Clr, and Cls.
  • Subcomponent Clq binds to immunoglobulin complexes with resulting serial activation of Clr (enzyme), Cls (proenzyme) and the other 8 components of complement.
  • Clq is composed of 3 different species of chains, called A, B, and C. Fragments of the A chain of Clq have been sequenced. The total A chain contains 190 amino acids. Clq shares with collagen the presence of hydroxyproline in its amino acid sequence.
  • Beta-adrenergic receptor kinase (beta-ARKl) phosphorylates the beta-2-adrenergic receptor and appears to mediate agonist-specific desensitization observed at high agonist concentrations.
  • Beta-ARKl is an ubiquitous cytosolic enzyme that specifically phosphorylates the activated form of the beta-adrenergic and related G-protein-coupled receptors.
  • the beta-ARKl gene spans approximately 23 kb and is composed of 21 exons.
  • Beta-AR kinase (beta-ARKl) is known to be elevated in failing human heart tissue and its activity resulting in rapid desensitization via the abnormal coupling or uncoupling of beta- adrenergic receptor to G protein, receptor down-regulation, internalization and degradation, may account for some of the abnormalities of contractile function in the heart disease (see, Post, S. R., Hammond, H.K., Drei, P. A., 1999, Annu. Rev. Pharmacol. Vol. 39: 343-360) inco ⁇ orated by reference.
  • the TEN-M4 protein belongs to the ODZ/TENM family of proteins. This family was first identified in Drosophila as being a pair-rule gene affecting segmentation of the early embryo. It was the first pair-rule gene identified that was not a transcription factor, but a type II transmembrane protein. Vertebrate homologs of the TENM family have been identified in mouse and zebrafish. In the mouse, TEN-M4 expression was found to be on the cell surface, in the brain, trachea as well as developing limb and bone. Analysis of the TEN-MI protem reveals that it can bind to itself, making it likely that TEN-M4 may be a dimeric moiety as well.
  • fragments of the TEN-M proteins can bind the Drosophila PS2 integrins.
  • members of the TEN-M family have been identified to be downstream of the endoplasmic reticulum stress response pathway, which alters the response of cells to their environment. This suggests that the ODZ/TENM family may be involved in cell adhesion, spreading and motility. Translocations leading to the fusion of this gene with the NRG1/HGL gene from chromosome 8 have been found to generate a paracrine growth factor for one mammary carcinoma cell line, termed gamma-heregulin.
  • the protein is known to be expressed in spleen and liver.
  • Glucose tranporter 4 (GLUT4) is critical to insulin-sensitive glucose uptake.
  • Mouse EphA6 (also known as m-ehk2) belongs to the superfamily of receptor tyrosine kinases, which constitute the largest family of oncogenes. This family includes prominent growth factor receptors such as those for epidermal growth factor, platelet-derived growth factor etc. Members of this superfamily influence cell shape, mobility, differentiation and proliferation. Within this superfamily, the Ephrin (Eph) receptors constitute the largest subfamily. Eph receptors and their ligands, ephrins, are known to be involved in several normal developmental processes, including formation of segmented structures, axon guidance, cell adhesion and development of vasculature.
  • Ephrin receptors are classified into two main subtypes: EphA receptors bind to GPI-anchored ephrin-A ligands, while EphB receptors bind to ephrin-B proteins that have a transmembrane and cytoplasmic domain.
  • EphA6 receptor is highly expressed in the mouse brain and inner ear, including the cochlea. This receptor is also differentially expressed relative to the other ephrin receptors in certain regions of the primate neocortex during development. In addition, it is found in the developing retina and optic tectum in the chicken.
  • the present invention is based in part on nucleic acids encoding proteins that are members of the following protein families: EGF related SCUBEl-like proteins, Adipocyte Complement Related proteins, complement Clq tumor necrosis factor-like proteins, ⁇ - Adrenergic Receptor Kinase-like proteins, TENM4-like proteins, Out At First-like proteins, EphA6-ehk2-like proteins, Glucose Transporter-like proteins, Type la Membrane Sushi- Containing Domain-like proteins, Type la Membrane Sushi-Containing Domain proteins, Butyrophilin-like proteins, and Butyrophilin Precursor B7-DC-like proteins.
  • novel polynucleotides and polypeptides are referred to herein as NOV1, NOV2a, NOV2b, NOV2c, NOV2d, NOV3, NOV4, NOV5a, NOV5b, NOV6a, NOV6b, NOV7, NOV8, NOV9, NOVlOa, NOVlOb and NOV11.
  • 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, 23, 25, 27, 29, 31 and 33.
  • 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 and 34.
  • 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 D NOS:l, 3, 5, 1, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33.
  • an oligonucleotide e.g., an oligonucleotide which includes at least 6 contiguous nucleotides of a NOVX nucleic acid (e.g., SEQ ID NOS:l, 3, 5, 1, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33) or a complement of said oligonucleotide.
  • a NOVX nucleic acid e.g., SEQ ID NOS:l, 3, 5, 1, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31 and 33
  • substantially purified NOVX polypeptides SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34.
  • 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., Von Hippel- Lindau (VHL) syndrome, cirrhosis, transplantation disorders, pancreatitis, obesity, diabetes, autoimmune disease, renal artery stenosis, interstitial nepliritis, glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy, hypercalcemia, Lesch-Nyhan syndrome, developmental defects, cataract, spinal cord injury, Alzheimer's disease, muscular dystrophy, acoustic trauma, cancer, learning and memory defects, infertility, cardiomyopathies, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect, atrioventricular canal defect, ductus arteriosus, pulmonary stenosis, subaortic nephropathy, glomerular acido
  • 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.
  • compositions of the present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the polypeptides can be used as immunogens to produce antibodies specific for the invention, and as vaccines. They can also be used to screen for potential agonist and antagonist compounds.
  • a cDNA encoding NOVX may be useful in gene therapy, and NOVX may be useful when administered to a subject in need thereof.
  • the compositions of the present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the invention further includes a method for screening for a modulator of disorders or syndromes including, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the method includes contacting a test compound with a NOVX polypeptide and determining if the test compound binds to said NOVX polypeptide. Binding of the 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 of the invention is a method for screening for a modulator of activity, or of latency or predisposition to disorders or syndromes including, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like by administering a test compound to a test animal at increased risk for the aforementioned disorders or syndromes.
  • the test animal expresses a recombinant polypeptide encoded by a NOVX nucleic acid.
  • Expression or activity of NOVX polypeptide is then measured in the test animal, as is expression or activity of the 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 of the disorder or syndrome.
  • the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide, a NOVX nucleic acid, or both, in a subject (e.g., a human subject).
  • the method includes measuring the amount of the NOVX polypeptide in a test sample from the subject and comparing the amount of the polypeptide in the test sample to the amount of the NOVX polypeptide present in a control sample.
  • An alteration in the level of the NOVX polypeptide in the test sample as compared to the control sample indicates the presence of or predisposition to a disease in the subject.
  • the predisposition includes, e.g., the diseases and disorders disclosed above and/or other pathologies and disorders of the like.
  • the expression levels of the new polypeptides of the invention can be used in a method to screen for various cancers as well as to determine the stage of cancers.
  • the invention includes a method of treating or preventing a pathological condition associated with a disorder in a mammal by administering to the subject a NOVX polypeptide, a NOVX nucleic acid, or a NOVX-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 of the like.
  • the invention can be used in a method to identity the cellular receptors and downstream effectors of the invention by any one of a number of techniques commonly employed in the art. These include but are not limited to the two-hybrid system, affinity purification, co-precipitation with antibodies or other specific-interacting molecules.
  • NOVX nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOVX substances for use in therapeutic or diagnostic methods.
  • NOVX antibodies may be generated according to methods l ⁇ iown in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOVX proteins have multiple hydrophilic regions, each of which can be used as an immunogen. These NOVX proteins can be used in assay systems for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.
  • the NOVX nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below.
  • the potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.
  • the present invention provides novel nucleotides and polypeptides encoded thereby.
  • NOV1 novel nucleic acid sequences and their encoded polypeptides referred to herein as NOV1, NOV2a, NOV2b, NOV2c, NOV2d, NOV3, NOV4, NOV5a,
  • NOVX nucleic acids or “NOVX polynucleotides” and the corresponding encoded polypeptides are referred to as “NOVX polypeptides” or “NOVX proteins.” Unless indicated otherwise, “NOVX” is meant to refer to any of the novel sequences disclosed herein. Table A provides a summary of the NOVX nucleic acids and their encoded polypeptides.
  • 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 of the 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 of the family to which the NOVX polypeptides belong.
  • NOV1 is homologous to an EGF-Related SCUBEl-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, obesity, endometriosis, trauma, viral, bacterial, or parasitic infections, allergy, asthma, endocrine disfunctions, diabetes, growth and reproductive disorders, and other diseases, disorders and conditions of the like.
  • NOV2 is homologous to the adipocyte complement Clq Tumor Necrosis Factor-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; cancer, inflammation, neurological disorders, neuropsychiatric disorders, obesity, diabetes, viral'bacterial/parasitic infections, autoimmune diseases, renal artery stenosis, renal tubular acidosis, hypercalcemia, IgA nephropathy, Lesch-Nyhan syndrome, glomerulonephritis, interstitial nephritis, polycystic kidney disease, trauma, regeneration, Alzheimer's disease, allergies, addiction, anxiety, ataxia-telangiectasia, asthma, ARDS, atherosclerosis, behavioral disorders, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, allergy, cerebral palsy, con
  • NOV3 is homologous to a family of beta-adrenergic receptor kinase-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: cardiac disorders and disorders of myocontractility and the like.
  • NOV4 is homologous to the TEN-M4-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 in, for example: cancer, inflammation, neurological disorders, neuropsychiatric disorders, obesity, diabetes, viral/bacterial/parasitic infections, autoimmune diseases, renal artery stenosis, renal tubular acidosis, hypercalcemia, IgA nephropathy, Lesch-Nyhan syndrome, glomerulonephritis, interstitial nephritis, polycystic kidney disease, trauma, regeneration, Alzheimer's disease, allergies, addiction, anxiety, ataxia-telangiectasia, asthma, ARDS, atherosclerosis, behavioral disorders, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, allergy, cerebral palsy, congenital adrenal hyperplasia, cir
  • NOV5 is homologous to the Out At First (OAF)-like family of proteins.
  • OAF Out At First
  • NOV5 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in central nervous system diseases, disorders and conditions of the like.
  • NOV6 is homologous to the EphA6/ehk-2-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: cancer, inflammation, neurological disorders, neuropsychiatric disorders, obesity, diabetes, viral/bacterial/parasitic infections, autoimmune diseases, renal artery stenosis, renal tubular acidosis, hypercalcemia, IgA nephropathy, Lesch-Nyhan syndrome, glomerulonephritis, interstitial nephritis, polycystic kidney disease, trauma, regeneration, Alzheimer's disease, allergies, addiction, anxiety, ataxia-telangiectasia, asthma, ARDS, atherosclerosis, behavioral disorders, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, allergy, cerebral palsy, congenital adrenal hyperplasi
  • NOV7 is homologous to members of the glucose transporter-like family of proteins.
  • the NOV7 nucleic acids, polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; obesity, diabetes, cancer, inflammation, CNS diseases and other diseases, disorders and conditions of the like.
  • NOV8 is homologous to the Type la Membrane Sushi-Containing Domain-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; cancer, inflammation, neurological disorders, neuropsychiatric disorders, obesity, diabetes, viral/bacterial/parasitic infections, autoimmune diseases, renal artery stenosis, renal tubular acidosis, hypercalcemia, IgA nephropathy, Lesch-Nyhan syndrome, glomerulonephritis, interstitial nephritis, polycystic kidney disease, trauma, regeneration, Alzheimer's disease, allergies, addiction, anxiety, ataxia-telangiectasia, asthma, ARDS, atherosclerosis, behavioral disorders, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, allergy, cerebral palsy, congen
  • NOV9 is homologous to the Type la Membrane Sushi-Containing Domain-like family of proteins.
  • NOV9 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example: cancer, inflammation, neurological disorders, neuropsychiatric disorders, obesity, diabetes, viral/bacterial/parasitic infections, autoimmune diseases, renal artery stenosis, renal tubular acidosis, hypercalcemia, IgA nephropathy, Lesch-Nyhan syndrome, glomerulonephritis, interstitial nephritis, polycystic kidney disease, trauma, regeneration, Alzheimer's disease, allergies, addiction, anxiety, ataxia-telangiectasia, asthma, ARDS, atherosclerosis, behavioral disorders, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, allergy, cerebral palsy, congen
  • NOV10 is homologous to the butyrophilin-like family of proteins.
  • NOV10 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; cancer, inflammation, neurological disorders, neuropsychiatric disorders, obesity, diabetes, viral/bacterial/parasitic infections, autoimmune diseases, renal artery stenosis, renal tubular acidosis, hypercalcemia, IgA nephropathy, Lesch-Nyhan syndrome, glomerulonephritis, interstitial nephritis, polycystic kidney disease, trauma, regeneration, Alzheimer's disease, allergies, addiction, anxiety, ataxia-telangiectasia, asthma, ARDS, atherosclerosis, behavioral disorders, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, allergy, cerebral palsy, congenital adrenal hyperplasia, cir
  • NOV11 is homologous to the cysteine sulfinic acid decarboxylase-like family of proteins.
  • NOV11 nucleic acids and polypeptides, antibodies and related compounds according to the invention will be useful in therapeutic and diagnostic applications implicated in, for example; cancer, inflammation, neurological disorders, neuropsychiatric disorders, obesity, diabetes, viral/bacterial/parasitic infections, autoimmune diseases, renal artery stenosis, renal tubular acidosis, hypercalcemia, IgA nephropathy, Lesch-Nyhan syndrome, glomerulonephritis, interstitial nephritis, polycystic kidney disease, trauma, regeneration, Alzheimer's disease, allergies, addiction, anxiety, ataxia-telangiectasia, asthma, ARDS, atherosclerosis, behavioral disorders, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, allergy, cerebral palsy, congen
  • 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.
  • a disclosed NOV1 nucleic acid of 3137 nucleotides (also referred to as CG55758-01) encoding a novel EGF-Related Protein (SCUBEl)-like protein is shown in Table 1 A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 78-80 and ending with a TGA codon at nucleotides 2973-2975.
  • a putative untranslated region upstream from the initiation codon and downstream from the termination codon is underlined in Table 1 A. The start and stop codons are in bold letters.
  • NOVl nucleic acid sequence located on chromosome 22ql3, demonstrates 88% identity to Mus Musculus EGF-related protein SCUBEl (Genbank AF276425).
  • Public nucleotide databases include all GenBank databases and the GeneSeq patent database.
  • the "E- value” or “Expect” value is a numeric indication of the 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 NOVl BLAST analysis, e.g., Mus Musculus EGF-related protein SCUBEl, matched the Query NOVl sequence purely by chance is Lie -17.
  • 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 of the P value (probability) to report the significance of matches.
  • P value probability
  • an E value of one assigned to a hit can be interpreted as meaning that in a database of the 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/.
  • NOVl polypeptide (SEQ ID NO:2) encoded by SEQ ID NO:l has 965 amino acid residues and is presented in Table IB using the one-letter amino acid codes.
  • Signal P, Psort and/or Hydropathy results predict that NOVl has a signal peptide and is likely to be localized outside the cell with a certainty of 0.3700.
  • NOVl may also be localized to the lysosome (lumen) with a certainty of 0.1900, the nucleus with a certainty of 0.1800, or in the endoplasmic reticulum (membrane) with a certainty of 0.1000.
  • the most likely cleavage site for a NOVl signal peptide is between amino acids 23 and 24, at: RLA-GG.
  • NOVl amino acid sequence has 145 of 489 amino acid residues (29%) identical to, and 216 of 489 amino acid residues (44%) similar to, the 2489 amino acid residue ptnr:SPTREMBL-ACC:Q16744 protein from Homo sapiens (Human) (COMPLEMENT RECEPTOR 1).
  • Public amino acid databases include the GenBank databases, SwissProt, PDB and PIR.
  • NOVl is expressed in at least the pituitary gland, the ovaries, and the trachea. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.
  • NOVl polypeptide has homology to the amino acid sequences shown in the BLASTP data listed in Table lC.
  • NOVl The presence of identifiable domains in NOVl, 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 NOVl as disclosed in Table IE 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.
  • the "strong” group of conserved amino acid residues may be any one of the following groups of amino acids: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW.
  • Table IE lists the domain description from DOMAIN analysis results against NOVl. This indicates that the NOVl sequence has properties similar to those of other proteins known to contain this domain. Table IE. Domain Analysis of NOVl
  • smart00042 CUB, Domain first found in Clr, Cls, uEGF, and bone mo ⁇ hogenetic protein; This domain is found mostly among developmentally-regulated proteins. Spermadhesins contain only this domain.
  • the epidermal growth factor (EGF) superfamily comprises a diverse group of proteins that function as secreted signaling molecules, growth factors, and components of the extracellular matrix, many with a role in vertebrate development.
  • a novel mammalian gene encoding an EGF-related protein with a CUB (Cls-like) domain that defines a new mammalian gene family.
  • the SCUBEl (signal peptide-CUB domain-EGF-related 1) gene was isolated from a developing mouse urogenital ridge cDNA library and is expressed prominently in the developing gonad, nervous system, somites, surface ectoderm, and limb buds.
  • Mouse SCUBEl was mapped to chromosome 15 and shown that it is orthologous to a human gene in the syntenic region of chromosome 22ql 3.
  • EGF-related proteins with Cls-like (CUB) domains have been reported.
  • the CUB domain is found in 16 functionally diverse proteins such as the dorso-ventral patterning protein tolloid, bone morphogenetic protein-1, a family of spermadhesins, complement subcomponents Cls/Clr and the neuronal recognition molecule A5. Most of these proteins are known to be involved in developmental processes.
  • the second domain is found mostly among developmentally-regulated proteins and spermadhesins.
  • the disclosed NOVl nucleic acid of the invention encoding an EGF-Related Protein
  • SCUBEl-like protein includes the nucleic acid or a fragment thereof whose sequence is provided in Table 1 A.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 1 A while still encoding a protein that maintains its EGF-Related Protein (SCUBEl)-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any of the nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject. In the mutant or variant nucleic acids, and their complements, up to about 30% percent of the bases may be so changed.
  • the disclosed NOVl protein of the invention includes an EGF-Related Protein (SCUBEl)-like protein whose sequence is provided in Table IB.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table IB while still encoding a protein that maintains its EGF-Related Protein (SCUBEl)-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 12% percent of the residues may be so changed.
  • the invention further encompasses antibodies and antibody fragments, such as F a or (F ab ) 2, that bind immunospecifically to any of the proteins of the invention.
  • NOVl EGF-Related Protem
  • SCUBEl EGF-Related Protein
  • SCUBEl EGF-Related Protein
  • the NOVl 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.
  • NOVl nucleic acids and proteins of the invention are useful in potential therapeutic applications implicated in cancer including but not limited to various pathologies and disorders as indicated below.
  • a cDNA encoding EGF-Related Protein (SCUBEl)-like protein (NOVl) may be useful in gene therapy, and the EGF-Related Protein (SCUBEl)-like protein (NOVl) may be useful when administered to a subject in need thereof.
  • the compositions of the present invention will have efficacy for treatment of patients suffering from cancer, trauma, viral/bacterial/parasitic infections, endometriosis, fertility, astlima, allergy, endocrine dysfunctions, diabetes, obesity, growth and reproductive disorders and other diseases, disorders and conditions of the like.
  • NOVl nucleic acid encoding the EGF-Related Protein (SCUBEl)-like protein of the invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • SCUBEl EGF-Related Protein
  • NOVl nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOVl substances for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOVl proteins have multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOVl epitope is from about amino acids 400 to 450.
  • a NOVl epitope is from about amino acids 500 to 600, from about 1000-1100, from about 1500-1600 and 2500-2800.
  • NOV2 includes four adipocyte complement-related Clq Tumor Necrosis Factor-like proteins and nucleic acids encoding the same.
  • the disclosed sequences are identified herein as NOV2a, NOV2b, NOV2c, and NOV2d.
  • a disclosed NO V2a nucleic acid of 874 nucleotides identified as SEQ IDNO:3 also referred to as CG55724-01 encoding an adipocyte complement-related Clq Tumor Necrosis Factor-like protein is shown in Table 2A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 11-13 and ending with a TGA codon at nucleotides 674-676. Putative upstream and downstream untranslated regions are underlined.
  • the disclosed NOV2a nucleic acid sequence, localized to chromosome 11, has 294 of 485 bases (60%) identical to a gb:GENBANK-ID:AF192499
  • a NOV2a polypeptide (SEQ ID NO:4) encoded by SEQ ID NO:3 has 221 amino acid residues and is presented using the one-letter code in Table 2B.
  • Signal P, Psort and/or Hydropathy results predict that NOV2b does not have a signal peptide and the NOV2a polypeptide is likely to be localized to the cytoplasm with a certainty of 0.4500.
  • NOV2a may also be localized to peroxisomal microbodies with a certainty of 0.2688, lysosomes with a certainty of 0.1937, or the mitochondrial matrix space with a certainty of 0.1000.
  • the disclosed NO V2a amino acid sequence has 55 of 158 amino acid residues (34%) identical to, and 84 of 158 amino acid residues (53%) identity to the 244 amino acid residue pntr:SWISSPROT ACC:Q15848 protein from Homo sapiens (Human) (30 kDa adipocyte complement related protein precursor, ACRP30).
  • the NOV2a adipocyte complement-related protein precursor disclosed in this invention is expressed in at least the following tissues: testis, kidney, whole embryo. This information was derived by determining the tissue sources of the sequences that were included in the invention including but not limited to SeqCalling sources, public EST sources, literature sources, and/or RACE sources.
  • sequence is predicted to be expressed in the following tissues because of the expression pattern of (GENBANK-ID: gb:GENBANK-ID:AF192499
  • a disclosed NOV2b nucleic acid of 1277 nucleotides (also referred to as CG55724-03) encoding a complement related Clq Tumor Necrosis Factor-like protein is shown in Table 2C as SEQ ID NO:5.
  • SEQ ID NO:5 An open reading frame was identified beginning with an ATG initiation codon at nucleotides 225-227 and ending with a TGA codon at nucleotides 1077-1079. Putative upstream and downstream untranslated regions are underlined.
  • NOV2b nucleic acid sequence localized to chromosome 11, has 767 of 814 bases (94%) identical to a gb:GENBANK-ID:AF329838
  • a NOV2b polypeptide (SEQ ID NO:6) encoded by SEQ ID NO:5 has 284 amino acid residues and is presented using the one-letter code in Table 2D.
  • Signal P, Psort and/or Hydropathy results predict that NOV2b has a signal peptide and is likely to be localized outside the cell with a certainty of 0.4801.
  • NOV2b may also be localized to microsomal bodies with a certainty of 0.2178, the endoplasmic reticulum (membrane or lumen) with a certainty of 0.1000.
  • the most likely cleavage site for a NOV2b signal peptide is between amino acids 16 and 17, at: CWA-LG.
  • the disclosed NOV2b amino acid sequence has 55 of 158 amino acid residues (34%) identical to, and 84 of 158 amino acid residues (53%) identity to the 244 amino acid residue pntr:SPTREMBL ACC:Q9BXJ3 protein from Homo sapiens (Human) (complement Clq Tumor Necrosis Factor-related protein).
  • the NOV2b complement-Clq tumor necrosis factorlike gene disclosed in this invention is expressed in at least the following tissues: brain, germ cell, kidney, pooled, testis, whole embryo. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence of CuraGen Ace. No. CG55724-03, CG55724-04, or CG55724-06.
  • a disclosed NOV2c nucleic acid of 1322 nucleotides (also referred to as CG55724-04) encoding a complement related Clq Tumor Necrosis Factor-like protein is shown in Table 2E as SEQ ID NO:7.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 225-227 and ending with a TGA codon at nucleotides 1122-1124. Putative upstream and downstream untranslated regions are underlined.
  • the disclosed NO V2c nucleic acid sequence, localized to chromosome 11, has 949 of 1136 bases (83%) identical to a gb:GENBANK-ID:AF329838
  • a NOV2c polypeptide (SEQ ID NO:8) encoded by SEQ ID NO:7 has 299 amino acid residues and is presented using the one-letter code in Table 2F.
  • Signal P, Psort and/or Hydropathy results predict that NOV2c has a signal peptide and is likely to be localized outside the cell with a certainty of 0.4801.
  • NOV2c may also be localized to microsomal bodies with a certainty of 0.2178, the endoplasmic reticulum (membrane or lumen) with a certainty of 0.1000.
  • the most likely cleavage site for aNOV2c signal peptide is between amino acids 16 and 17, at: CWA-LG.
  • the disclosed NOV2c amino acid sequence has 164 of 170 amino acid residues (96%) identical to, and 164 of 170 amino acid residues (96%) identity to the 329 amino acid residue pntr:SPTREMBL ACC:Q9BXJ3 protein from Homo sapiens (Human) (complement Clq Tumor Necrosis Factor-related protein).
  • the NOV2c complement-Clq tumor necrosis factorlike gene disclosed in this invention is expressed in at least the following tissues: brain, germ cell, kidney, pooled, testis, whole embryo. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence of CuraGen Ace. No. CG55724-03, CG55724-04, or CG55724-06.
  • NOV2d A disclosed NO V2d nucleic acid of 409 nucleotides (also referred to as CG55724-06) encoding a complement related Clq Tumor Necrosis Factor-like protein is shown in Table 2G as SEQ ID NO:X. An open reading frame was identified beginning with an ATG initiation codon at nucleotides 4-6 and ending with a TGA codon at nucleotides 403-405. Putative upstream and downstream untranslated regions are underlined.
  • the disclosed NOV2d nucleic acid sequence localized to chromosome 11, has 239 of 260 bases (91%) identical to a gb:GENBANK-ID:AF329838
  • a NOV2d polypeptide (SEQ ID NO: 10) encoded by SEQ ID NO:9 has 133 amino acid residues and is presented using the one-letter code in Table 2H.
  • Signal P, Psort and/or Hydropathy results predict that NOV2d has a signal peptide and is likely to be localized outside the cell with a certainty of 0.4801.
  • NOV2d may also be localized to microsomal bodies with a certainty of 0.1972, the endoplasmic reticulum (membrane or lumen) with a certainty of 0.1000.
  • the most likely cleavage site for a NOV2d signal peptide is between amino acids 16 and 17, at: CWA-LG.
  • the disclosed NOV2d amino acid sequence has 164 of 170 amino acid residues (96%) positives to, and 164 of 170 amino acid residues (96%) positives to the 329 amino acid residue pnt ⁇ SPTREMBL ACC:Q9BXJ3 protein from Homo sapiens (Human) (complement Clq Tumor Necrosis Factor-related protein).
  • the NOV2d complement-Clq tumor necrosis factorlike gene disclosed in this invention is expressed in at least the following tissues: brain, germ cell, kidney, pooled, testis, whole embryo. Expression information was derived from the tissue sources of the sequences that were included in the derivation of the sequence of CuraGen Ace. No. CG55724-03, CG55724-04, or CG55724-06.
  • the disclosed NOV2 nucleic acids of the present invention are expressed in at least bone marrow, brain, thalamus, testis, lung, kidney, and germ cells. 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, Bone, Bone Marrow, Brain, Colon, Coronary Artery, Dennis, Epidermis, Foreskin, Hair Follicles, Heart, Hippocampus, Hypothalamus, Kidney, Liver, Lung, Lymph node, Lymphoid tissue, Mammary gland/Breast, Esophagus, Ovary, Pancreas, Parathyroid Gland, Peripheral Blood, Pineal Gland, Pituitary Gland, Placenta, Prostate, Retina, Salivary Glands, Small Intestine, Spleen, Stomach, Testis, Thalamus, Thymus, Tonsils, Trachea, Umbilical
  • NOV2 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 21.
  • NOV2d gi 113994273 I .
  • Tables 2K list the domain description from DOMAIN analysis results against NOV2. This indicates that the NOV2 sequence has properties similar to those of other proteins known to contain this domain.
  • Table 2K Domain Analysis of NOV2 gnllSmartlsmartOOllO, C1Q, Complement component Clq domain.; Globular domain found in many collagens and eponymously in complement Clq. When part of full length proteins these domains form a 'bouquet' due to the multimerization of heterotrimers. The Clq fold is similar to that of tumour necrosis factor.
  • Clq is the first subcomponent of the Cl complex of the classical pathway of complement activation.
  • Several functions have been assigned to Clq, which include antibody- dependent and independent immune functions, and are considered to be mediated by Clq receptors present on the effector cell surface.
  • Clq receptors present on the effector cell surface.
  • the problem of identifying receptor proteins with complementary binding sites for Clq has been compounded by the highly charged nature of the different domains in Clq.
  • ACRP3 adipocyte complement related protein 3
  • the ACRP3 protein is made exclusively in adipocytes and its mRNA is induced over 100-fold during adipocyte differentiation.
  • ACRP3 is structurally similar to complement factor Clq and to a hibernation-specific protein isolated from the plasma of Siberian chipmunks; it forms large homo-oligomers that undergo a series of post-translational modifications.
  • a similar protein has a cluster of aromatic residues near the C terminus having high local similarity with collagens X and VIII and complement factor Clq.
  • Clq is a subunit of the Cl enzyme complex that activates the serum complement system. Clq comprises 6 A, 6 B and 6 C chains.
  • the Clq protein is produced by collagen- producing cells and shows sequence and structural similarity to collagens VIII and X, (see, Scherer PE, et al., J Biol Chem 1995 Nov 10;270(45):26746-9 and Maeda K, et al., Biochem Biophys Res Commun 1996 Apr 16;221(2):286-9), incorporated herein by reference.
  • the present invention includes chimeric or fusion proteins of the complement-Clq tumor necrosis factor-like protein, in which the complement-Clq tumor necrosis factor-like protein of the present invention is joined to a second polypeptide or protein that is not substantially homologous to the present novel protein.
  • the second polypeptide can be fused to either the amino-terminus or carboxyl-terminus of the present CG55724-01, CG55724-03, CG55724-04, or CG55724-06 polypeptide.
  • a third nonhomologous polypeptide or protein may also be fused to the novel complement-Clq tumor necrosis factorlike protein such that the second nonhomologous polypeptide or protein is joined at the amino terminus, and the third nonhomologous polypeptide or protein is joined at the carboxyl terminus, of the CG55724-01, CG55724-03, CG55724-04, or CG55724-06 polypeptide.
  • nonhomologous sequences that may be incorporated as either a second or third polypeptide or protein include glutathione S-transferase, a heterologous signal sequence fused at the amino terminus of the complement-Clq tumor necrosis factor-like protein, an immunoglobulin sequence or domain, a serum protein or domain thereof (such as a serum albumin), an antigenic epitope, and a specificity motif such as (His) 6 .
  • the invention further includes nucleic acids encoding any of the chimeric or fusion proteins described above.
  • the disclosed NOV2 nucleic acids of the invention encoding a complement-related Clq Tumor Necrosis Related Protein-like protein includes the nucleic acidswhose sequence is provided in Table 2A, 2C, 2E and 2G or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 2A, 2C, 2E and 2G while still encoding a protein that maintains its complement-related Clq Tumor Necrosis Related Protein-like protein activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any of the nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.
  • up to about 40% (NOV2a), 6% (NOV2b), 6% (NOV2c) and 9% (NOV2d) of the bases may be so changed.
  • the disclosed NON2 protein of the invention includes the complement-related Clq Tumor Necrosis Related Protein-like protein whose sequence is provided in Table 2B, 2D, 2F and 2G.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 2B, 2D, 2F and 2G while still encoding a protein that maintains its the complement-related Clq Tumor Necrosis Related Protein-like activities and physiological functions, or a functional fragment thereof.
  • up to about 66% (NOV2a), 2% (NON2b, ⁇ ON2c), and 9% ( ⁇ OV2d) of the residues may be so changed.
  • the NOV2 nucleic acids and proteins of the invention are useful in potential therapeutic applications implicated in cancers, adrenoleukodystrophy , Alzheimer's disease, autoimmune disease, allergies, addiction, anxiety, ataxia-telangiectasia, asthma, ARDS, atherosclerosis, behavioral disorders, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, allergy, cerebral palsy, congenital adrenal hyperplasia, cirrhosis, cardiomyopathy, congenital heart defects, diabetes, diverticular disease, epilepsy, emphysema, endometriosis, endocrine dysfunctions, graft versus host disease, glomerulonephritis, graft versus host disease (GVHD), growth and reproductive disorders, hemophilia, hypercoagulation, hypercalceimia, Huntington's disease, hypertension, hypogonadism, fertility, idi
  • the NOV2 nucleic acid encoding the complement-related Clq Tumor Necrosis Related Protein-like protein, and the protein of the invention, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • NOV2 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies” section below. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies” section below.
  • the disclosed NOVa, NOV2b, NOV2c, and NOV2d proteins have multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV2a epitope is from about amino acids 25 to 100.
  • a contemplated NOV2a epitope is from about amino acids 110 to 275.
  • contemplated NOVl epitopes are from about amino acids 280 to 325, 350 to 425, 450 to 625, 650 to 690, 700 to 825, and 850 to 965.
  • a contemplated NOV2b epitope is from about amino acids 20 to 50.
  • a contemplated NOV2b epitope is from about amino acids 55 to 65.
  • contemplated NO V2b epitopes are from about amino acids 90 to 145, 195 to 235, and 240 to 260.
  • a contemplated NOV2c epitope is from about amino acids 20 to 50.
  • a contemplated NOV2c epitope is from about amino acids 55 to 65.
  • contemplated NOV2c epitopes are from about amino acids 90 to 145, 195 to 235, and 240 to 260.
  • a contemplated NOV2d epitope is from about amino acids 18 to 40.
  • a contemplated NOV2d epitope is from about amino acids 42 to 47.
  • contemplated NOV2d epitopes are from about amino acids 60 to 80, 85 to 105, and 106 to 110.
  • a disclosed NO V3 nucleic acid of 3073 nucleotides is set forth as SEQ ID NO: 11 (also referred to as CG50345-01) encoding a beta adrenergic receptor kinase-like protein is shown in Table 3A.
  • SEQ ID NO: 11 also referred to as CG50345-01
  • Table 3A An open reading frame was identified beginning with an ATG initiation codon at nucleotides 108-110 and ending with a TGA codon at nucleotides 2112-2114.
  • NOV3 nucleic acid sequence maps to chromosome 1 lql3 and has 1638 of 1666 bases (98%) identical to a gb:GENBANK-ID:HSBARK
  • a disclosed NOV3 protein (SEQ ID NO: 12) encoded by SEQ ID NO:ll has 668 amino acid residues, and is presented using the one-letter code in Table 3B.
  • Signal P, Psort and/or Hydropathy results predict that NOV3 does have a signal peptide, and is likely to be localized to the nucleus with a certainty of 0.8800.
  • NOV3 is also likely to be localized to perioxisomal microbodies with a certainty of 0.1582, mitochondrial matrix space with a certainty of 0.1000, to the lysosomal lumen with a certainty of 0.1000.
  • the disclosed NOV3 amino acid has 359 of 642 amino acid residues (55%) identical to, and 497 of 497 amino acid residues (100%) similar to 497 of the 689 amino acid residue ptnr:SWISSNEW ACC:P25098 protein from Homo sapiens (Human) beta-adrenergic receptor kinase 1 (beta-ARKl, G-Protein Coupled Receptor Kinase 2).
  • the NOV3 sequence is expressed in at least the following tissues: brain-the Adrenal Gland/Suprarenal gland, Amygdala, Aorta, Bone, Bone Marrow, Brain, Cerebellum, Cervix, Chorionic Villus,Cochlea, Colon, Dermis, Epidermis, Epidermis, Foreskin, Hair Follicles, Heart, Hippocampus, Hypothalamus, Kidney, Liver, Lung, Lymph node, Lymphoid tissue, Mammary gland/Breast, Muscle, Myometrium, Ovary, Pancreas, Parotid Salivary glands, Pituitary Gland, Placenta, Prostate, Proximal Convoluted Tubule, Small Intestine, Spinal Chord, Retina, Spleen, Stomach, Substantia Nigra, Testis, Thymus, Thyroid, Tonsils, Umbilical Vein, Urinary Bladder, Uterus.
  • NOV3 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 3C.
  • NOV3 ISIV'idg.raBi- ⁇ syii-l&Wartl. ⁇
  • Table 3E lists the domain description from DOMAIN analysis results against NOV3. This indicates that the NOV3 sequence has properties similar to those of other proteins known to contain this domain.
  • smart00220 S_TKc
  • Serine/Threonine protein kinases catalytic domain
  • Phosphotransferases Serine or threonine-specific kinase subfamily.
  • Beta-adrenergic receptor kinase (beta-ARKl) phosphorylates the beta-2-adrenergic receptor and appears to mediate agonist-specific desensitization observed at high agonist concentrations.
  • Beta-ARKl is an ubiquitous cytosolic enzyme that specifically phosphorylates the activated form of the beta-adrenergic and related G-protein-coupled receptors.
  • the beta-ARKl gene spans approximately 23 kb and is composed of 21 exons.
  • Beta-AR kinase (beta-ARKl) is known to be elevated in failing human heart tissue and its activity resulting in rapid desensitization via the abnormal coupling or uncoupling of beta- adrenergic receptor to G protein, receptor down-regulation, internalization and degradation, may account for some of the abnormalities of contractile function in the heart disease (see, Post, S. R., Hammond, H.K., Drei, P.A.,1999, Annu. Rev. Pharmacol. Vol. 39: 343-360) incorporated by reference.
  • Beta-adrenergic receptor kinase (beta-ARKl) phosphorylates the beta-2-adrenergic receptor and appears to mediate agonist-specific desensitization observed at high agonist concentrations.
  • Beta-ARKl is an ubiquitous cytosolic enzyme that specifically phosphorylates the activated form of the beta-adrenergic and related G-protein-coupled receptors.
  • the beta- ARKl gene spans approximately 23 kb and is composed of 21 exons.
  • Beta-AR kinase (beta- ARKl) is known to be elevated in failing human heart tissue and its activity resulting in rapid desensitization via the abnormal coupling or uncoupling of beta-adrenergic receptor to G protein, receptor down-regulation, internalization and degradation, may account for some of the abnormalities of contractile function in the heart disease (see, Post, S. R., Hammond, H.K., hisel, P.A.,1999, Annu. Rev. Pharmacol. Vol. 39: 343-360, inco ⁇ orated. herein by reference)
  • Beta-adrenergic receptor kinase-like protein and nucleic acid disclosed herein suggest that this Beta-adrenergic receptor kinase may have important structural and/or physiological functions characteristic of the Serine-threonine protein kinase family. Therefore, the nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool.
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.
  • nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the compositions of the present invention will have efficacy for treatment of patients suffering from: cardiac diseases, myocardial contractility in failing heart and other diseases, disorders and conditions of the like.
  • the disclosed NOV3 nucleic acid of the invention encoding a beta adrenergic receptor kinase -like protein includes the nucleic acid whose sequence is provided in Table 3 A or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 3A while still encoding a protein that maintains beta adrenergic receptor kinase-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any of the nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications. Such modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized.
  • modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.
  • the mutant or variant nucleic acids, and their complements up to about 2 percent of the bases may be so changed.
  • the disclosed NOV3 protein of the invention includes the beta adrenergic receptor kinase-like protein whose sequence is provided in Table 3B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 3B while still encoding a protein that maintains beta adrenergic receptor kinase-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 1 percent of the residues may be so changed.
  • NOV3 beta adrenergic receptor kinase-like protein and nucleic acid
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo.
  • the NOV3 nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various diseases and disorders described below.
  • the compositions of the present invention will have efficacy for treatment of patients suffering from cancer, inflammation, retinal disorders, neurological disorders, neuropsychiatric disorders, obesity, diabetes, bleeding disorders and/or other pathologies.
  • the NOV3 nucleic acid, or fragments thereof may further be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • NOV3 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV3 polypeptide has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV3 epitope is from about amino acids 20 to 70.
  • a contemplated NOV3 epitope is from about amino acids 95 to 115.
  • contemplated NOV3 epitopes are from about amino acids 120 to 190, 280 to 300, 305 to 375, 395 to 420, and 415 to 660.
  • a disclosed NOV4 nucleic acid of 8354 nucleotides is set forth as SEQ ID NO:13 (designated CuraGen Ace. No. CG50301-01) encoding a TEN-M4-like protein is shown in Table 4A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 35-37 and ending with a TAG codon at nucleotides 8342-8344. Putative untranslated regions are indicated by underline.
  • a disclosed NOV4 nucleic acid maps to chromosome 11, and is found in at least brain, spinal chord, testis, heart, lung, parathyroid, stomach, breast, colon, epidermis, ovary and kidney.
  • a NOV4 nucleic acid has 7504 of 8359 bases (89%) identical to a gb:GENBANK- ID:AB025413lacc: AB025413.1 mRNA from Mus musculus TEN-M4.
  • a NOV4 polypeptide (SEQ ID NO: 14) encoded by SEQ ID NO: 13 is 2769 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 have a signal peptide and is likely to be localized mitochondrial inner membrane with a certainty of 0.8363.
  • NOV4 may also be localized to the plasma membrane with a certainty of 0.65 or to the nucleus with a certainty of 0.6000, or microbody with a certainty of 0.3936. Table 4B.
  • GNLHLLSPGNSARLTP RYDIRDRITRLGDVQYKMDEDGFLRQRGGDIFEYNSAGLLIKA 2280
  • the full amino acid sequence of the protein of the invention was found to have 2688 of 2771 amino acid residues (97%) identical to, and 2728 of 2771 amino acid residues (98%) similar to, the 2771 amino acid residue ptnr:SPTREMBL-ACC:Q9WTS7 protein from Mus musculus TEN-M4.
  • NOV4 also has homology to the amino acid sequences shown in the BLASTP data listed in Table 4C.
  • Tables 4E lists the domain description from DOMAIN analysis results against NOV4. This indicates that the NOV4 sequence has properties similar to those of other proteins known to contain this domain.
  • N0V4 (SEQ ID NO -.13)
  • N0V4 ⁇ gR g g ⁇ rgEgsP ⁇ l ⁇ E ⁇ i. «l ⁇ AJAHYLDRVVKEGffiGLHHG ⁇ R ⁇ T ⁇ LM ⁇ l-IS
  • the novel TE ⁇ -M-like protein encoded by the gene of invention has highest homology to the mouse TE ⁇ -M4 protein, which belongs to the ODZ/TENM family of proteins. This family was first identified in Drosophila as being a pair-rule gene affecting segmentation of the early embryo. It was the first pair-rule gene identified that was not a transcription factor, but a type II transmembrane protein. Vertebrate homologs of the TENM family have been identified in mouse and zebrafish. In the mouse, TEN-M4 expression was found to be on the cell surface, in the brain, trachea as well as developing limb and bone.
  • TEN-MI protein Analysis of the TEN- MI protein reveals that it can bind to itself, making it likely that TEN-M4 may be a dimeric moiety as well.
  • fragments of the TEN-M protems can bind the Drosophila PS2 integrins.
  • members of the TEN-M family have been identified to be downstream of the endoplasmic reticulum stress response pathway, which alters the response of cells to their environment. This suggests that the ODZ/TENM family may be involved in cell adhesion, spreading and motility.
  • PS2 ligands both contain RGD sequences, and RGD-containing fragments of these two proteins (DLAM-RGD and TENM-RGD) can support PS2 integrin-mediated cell spreading. In all cases, this spreading is inhibited specifically by short RGD-containing peptides.
  • TENM-RGD induces maximal spreading of cells expressing integrin containing the alphaPS2C splice variant. This is in contrast to DLAM-RGD, which is the first Drosophila polypeptide shown to interact preferentially with cells expressing the alphaPS2 m8 splice variant.
  • the betaPS integrin subunit also varies in the presumed ligand binding region as a result of alternative splicing.
  • the beta splice variant has little effect, but for DLAM-RGD, maximal cell spreading is supported only by the betaPS4A form of the protein.
  • the diversity in PS2 integrins due to splicing variations, in combination with diversity of matrix ligands, can greatly enhance the functional complexity of PS2-ligand interactions in the developing animal.
  • the data also suggest that the splice variants may alter regions of the subunits that are directly involved in ligand interactions, and this is discussed with respect to models of integrin structure.
  • EGF epidermal growth factor
  • the main structure is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet. Subdomains between the conserved cysteines vary in length.
  • the NHL (NCL-1, HT2A and LIN-41) repeat is found in a variety of enzymes of the copper type II, ascorbate-dependent monooxygenase family which catalyse the C- terminus alpha-amidation of biological peptides.
  • the repeat also occurs in a human zinc finger protein that specifically interacts with the activation domain of lentiviral Tat proteins.
  • the protein similarity information, expression pattern, and map location for the TEN- M4-like protein and nucleic acid disclosed herein suggest that this TEN-M4-like protein may have important structural and/or physiological functions characteristic of this family. Therefore, the nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool.
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.
  • the NOV4 nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various diseases and disorders described below and/or other pathologies.
  • the compositions of the present invention will have efficacy for treatment of patients suffering from: cardiac diseases, myocardial contractility in failing heart and other diseases, disorders and conditions of the like.
  • the disclosed NON4 nucleic acid of the invention encoding a TE ⁇ -M4-like protein includes the nucleic acid whose sequence is provided in Table 4A or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases maybe changed from the corresponding base shown in Table 4A while still encoding a protein that maintains TEN-M4-like protein-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any of the nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications. Such modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized.
  • modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject, hi the mutant or variant nucleic acids, and their complements, up to about 11 percent of the bases may be so changed.
  • the disclosed NON4 protein of the invention includes the TE ⁇ -M4-like protein whose sequence is provided in Table 3B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 4B while still encoding a protein that maintains beta adrenergic receptor kinase-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protein, up to about 3 percent of the residues may be so changed.
  • ⁇ ON4 may have important structural and/or physiological functions characteristic of the TE ⁇ -M4 protein family. Therefore, the NOV4 nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications.
  • nucleic acid or protein diagnostic and/or prognostic marker serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo.
  • the NOV4 nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications implicated in various diseases and disorders described below.
  • the compositions of the present invention will have efficacy for treatment of patients suffering from: Non Hippel-Lindau (NHL) syndrome, Alzheimer's disease, stroke, tuberous sclerosis, hypocalcaemia, Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy, Lesch- ⁇ yhan syndrome, multiple sclerosis, ataxia-telangiectasia, leukodystrophies, behavioral disorders, addiction, anxiety, pain, neurodegeneration, fertility disorders, hyperparathyroidism, hypoparathyroidism, cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-N) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (NSD), valve diseases, tube
  • ⁇ ON4 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti- ⁇ OVX Antibodies" section below.
  • the disclosed ⁇ OV4 polypeptide has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV4 epitope is from about amino acids 1 to 400.
  • a contemplated NOV4 epitope is from about amino acids 450 to 520.
  • contemplated NOV4 epitopes are from about amino acids 750 to 850, 1100 to 1200, 1250 to 1400, 1490 to 1750, 1760 to 2300, 2400 to 2600, and 2650 to 2725.
  • NOV5 includes two Out At First-like proteins disclosed below. The disclosed sequences have been named NOV5a and NOV5b.
  • a disclosed NOV5a nucleic acid of 822 nucleotides identified as SEQ ID NO: 15 (also referred to as CG55764-01) encoding an Out At First-like protein is shown in Table 5A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TGA codon at nucleotides 820-822.
  • a disclosed NOV5a polypeptide (SEQ ID NO.T 6) encoded by SEQ ID NO: 15 is 273 amino acid residues and is presented using the one-letter code in Table 5B.
  • Signal P, Psort and/or Hydropathy results predict that NOV5a has a signal peptide and is likely to be localized outside the cell with a certainty of 0.7523.
  • NOV5a may also be localized to the endoplasmic reticulum with a certainty of 0.1000 or microbody with a certainty of 0.1000.
  • the most likely cleavage site is between positions 27 and 28: residues GTG-AP.
  • the disclosed NOV5a amino acid sequence has 106 of 274 amino acid residues (38%) identical to, and 154 of 274 amino acid residues (56%) similar to, the 487 amino acid residue ⁇ tnr:SWISSNEW-ACC:Q9NLA6 protein from Drosophila melanogaster (fruit fly) (Out At First protein).
  • the Out At First Protein disclosed in this invention is expressed in at least the following tissues: Adipose, Adrenal Gland/Suprarenal gland, Amygdala, Aorta, Artery, Ascending Colon, Bone, Bone Marrow, Brain, Brown adipose, Cartilage, Cervix, Cochlea, Colon, Coronary Artery, Dermis, Duodenum, Epidermis, Hair Follicles, Heart, Hippocampus, Kidney, Kidney Cortex, Liver, Lung, Lymph node, Lymphoid tissue, Mammary gland/Breast, Myometrium, Esophagus, Ovary, Oviduct Uterine Tube/Fallopian tube, Pancreas, Parotid Salivary glands, Peripheral Blood, Pituitary Gland, Prostate, Respiratory Bronchiole, Retina, Salivary Glands, Skin, Small Intestine, Spinal Chord, Spleen, Stomach, Syn
  • a disclosed NOV5b nucleic acid of 1362 nucleotides identified as SEQ ID NO: 17 (also referred to as CG55764-02) encoding a novel serine/threonine kinase-like protein is shown in Table 5C.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 1-3 and ending with a TGA at nucleotides 820-822.
  • the NOV5b nucleic acid was identified on chromosome 11 and has 456 of 733 bases (62%) identical to a gb:GENBANK-ID:DROOAFPR]acc:L31349.1 mRNA from D. melanogaster (mRNA for out at first (oaf)).
  • a disclosed NOV5b polypeptide (SEQ ID NO:18) encoded by SEQ ID NO:17 is 273 amino acid residues and is presented using the one-letter code in Table 5D.
  • Signal P, Psort and or Hydropathy results predict that NOV5b has a signal peptide and is likely to be localized outside the cell with a certainty of 0.7523.
  • NOV5b may also be localized to the endoplasmic reticulum with a certainty of 0.1000 or microbody with a certainty of 0.1000.
  • the most likely cleavage site is between positions 27 and 28: residues GTG-AP.
  • the disclosed NOV5b amino acid sequence has 106 of 274 amino acid residues (38%) identical to, and 154 of 274 amino acid residues (56%) similar to, the 487 amino acid residue ⁇ tnr:SWISSNEW-ACC:Q9NLA6 protein from Drosophila melanogaster (fruit fly) (Out At First protein).
  • the NOV5b Out At First Protein disclosed in this invention is expressed in at least the following tissues: Adipose, Adrenal Gland/Suprarenal gland, Amygdala, Aorta, Artery, Ascending Colon, Bone, Bone Marrow, Brain, Brown adipose, Cartilage, Cervix, Cochlea, Colon, Coronary Artery, Dermis, Duodenum, Epidermis, Hair Follicles, Heart, Hippocampus, Kidney, Kidney Cortex, Liver, Lung, Lymph node, Lymphoid tissue, Mammary gland/Breast, Myometrium, Esophagus, Ovary, Oviduct/Uterine Tube/Fallopian tube, Pancreas, Parotid Salivary glands, Peripheral Blood, Pituitary Gland, Prostate, Respiratory Bronchiole, Retina, Salivary Glands, Skin, Small Intestine, Spinal Chord, Spleen
  • NOV5b also has homology to the amino acid sequences shown in the BLASTP data listed in Table 5E.
  • Tables 5G-I 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 this domain.
  • This sequence from human chromosome 11 encodes for a novel protein which shows some sequence similarity to the Drosophila melanogaster Out At First (OAF) protein.
  • Out At First is expressed in clusters of cells during germband extension, throughout the developing nervous system, and in the gonads of both sexes throughout the lifecycle. Mutation of the Drosophila gene is fatal and causes nervous system defects.
  • the disclosed NOV5 nucleic acid of the invention encoding an Out At First-like protein includes the nucleic acid whose sequence is provided in Table 5 A or a fragment thereof.
  • the invention also includes a mutant or variant nucleic acid any of whose bases may be changed from the corresponding base shown in Table 5A while still encoding a protein that maintains its Out At First-like activities and physiological functions, or a fragment of such a nucleic acid.
  • the invention further includes nucleic acids whose sequences are complementary to those just described, including nucleic acid fragments that are complementary to any of the nucleic acids just described.
  • the invention additionally includes nucleic acids or nucleic acid fragments, or complements thereto, whose structures include chemical modifications.
  • modifications include, by way of nonlimiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject. In the mutant or variant NOV5a and NOV5b nucleic acids, and their complements, up to about 38 percent of the bases may be so changed.
  • the disclosed NOV5a protein of the invention includes the Out At First-like protein whose sequence is provided in Table 5B.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 5B while still encoding a protein that maintains its Out At First-like activities and physiological functions, or a functional fragment thereof.
  • the mutant or variant protem up to about 62 percent of the residues may be so changed.
  • the disclosed NOV5b protein of the invention includes the Out At First-like protein whose sequence is provided in Table 5D.
  • the invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residue shown in Table 5D while still encoding a protein that maintains its Out At First-like activities and physiological functions, or a functional fragment thereof. In the mutant or variant protem, up to about 62 percent of the residues may be so changed.
  • the NOV5 nucleic acids and proteins of the invention are useful in potential therapeutic applications implicated in various diseases, disorders and conditions.
  • the NOV5 nucleic acid, or fragments thereof, may further be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed.
  • NOV5 nucleic acids and polypeptides are further useful in the generation of antibodies that bind immunospecifically to the novel substances of the invention for use in therapeutic or diagnostic methods. These antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the "Anti-NOVX Antibodies" section below.
  • the disclosed NOV5a polypeptide has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV5a epitope is from about amino acids 40 to 75.
  • a contemplated NOV5a epitope is from about amino acids 80 to 87.
  • contemplated NOV5a epitopes are from about amino acids 95 to 105, 110 to 145, 155 to 180, and 225 to 260.
  • the disclosed NOV5b polypeptide has multiple hydrophilic regions, each of which can be used as an immunogen.
  • a contemplated NOV5b epitope is from about amino acids 40 to 75.
  • a contemplated NOV5b epitope is from about amino acids 80 to 90.
  • contemplated NOV5b epitopes are from about amino acids 95 to 105, 110 to 145, 160 to 220, and 225 to 260.
  • ⁇ OV6 includes two EphA6/ehk-2-like proteins disclosed below. The disclosed sequences have been named NOV6a and NOV6b.
  • a disclosed NOV6a nucleic acid of 3641 nucleotides identified as SEQ ID NO: 19 (also referred to as CG55704-01) encoding an EphA6/ehk-2-like protein is shown in Table 6A.
  • An open reading frame was identified beginning with an ATG initiation codon at nucleotides 19- 2 land ending with a TGA codon at nucleotides 3124-3126. Putative untranslated regions are indicated by underline.
  • the disclosed NOV6a nucleic acid sequence has 3028 of 3367 bases (89%) identical to a gb:GENBANK-ID:MMU58332
  • the EphA6/ehk-2 disclosed in this invention maps to chromosome 3
  • a disclosed NOV6a polypeptide (SEQ ID NO:20) encoded by SEQ ID NO:19 is 1035 amino acid residues and is presented using the one-letter amino acid code in Table 6B.
  • Signal P, Psort and/or Hydropathy results predict that NOV6a appears to be a Type la membrane protein, contains a signal peptide, and is likely to be localized in the plasma membrane with a certainty of 0.4600.
  • NOV6a is also likely to be localized to the endoplasmic reticulum with a certainty of 0.1000, or outside the cell with a certainty of 0.1000.
  • the most probable cleavage site is between positions 22 and 23: residues LTA-WT. Table 6B.

Abstract

L'invention concerne des séquences d'acides nucléiques qui codent de nouveaux polypeptides. L'invention concerne également des polypeptides codés par ces séquences d'acides nucléiques, ainsi que des anticorps qui se lient de manière immunospécifique au polypeptide. L'invention concerne également des dérivés, variants, mutants ou fragments dudit polypeptide, polynucléotide ou anticorps. L'invention concerne en outre des méthodes de traitement, de diagnostic et de recherche pour diagnostiquer, traiter et prévenir des troubles dans lesquels intervient un acide nucléique quelconque ou une protéine quelconque de ces nouveaux acides nucléiques et protéines humains.
PCT/US2001/050331 2000-12-19 2001-12-19 Polypeptides et acides nucleiques codant ces derniers WO2002057453A2 (fr)

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JP2002558505A JP2005508601A (ja) 2000-12-19 2001-12-19 ポリペプチドおよびそれをコードする核酸
CA002433313A CA2433313A1 (fr) 2000-12-19 2001-12-19 Polypeptides et acides nucleiques codant ces derniers
EP01993342A EP1352065A2 (fr) 2000-12-19 2001-12-19 Polypeptides et acides nucleiques codant ces derniers

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US26570400P 2000-12-19 2000-12-19
US60/256,704 2000-12-19
US25731400P 2000-12-20 2000-12-20
US60/257,314 2000-12-20
US28815301P 2001-05-02 2001-05-02
US60/288,153 2001-05-02
US29407501P 2001-05-29 2001-05-29
US60/294,075 2001-05-29
US30750601P 2001-07-24 2001-07-24
US60/307,506 2001-07-24
US31159001P 2001-08-10 2001-08-10
US31161301P 2001-08-10 2001-08-10
US60/311,590 2001-08-10
US60/311,613 2001-08-10
US31561701P 2001-08-29 2001-08-29
US60/315,617 2001-08-29
US32235801P 2001-09-14 2001-09-14
US60/322,358 2001-09-14

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WO2003038094A1 (fr) * 2001-10-30 2003-05-08 Bayer Healthcare Ag Regulation du transporteur de glucose humain
WO2003054190A1 (fr) * 2001-12-21 2003-07-03 Takeda Chemical Industries, Ltd. Nouvelles proteines et adn correspondants
WO2002055704A3 (fr) * 2001-01-09 2003-10-30 Curagen Corporation Proteines, polynucleotides codant pour elles et procedes d'utilisation correspondants
WO2004106935A2 (fr) * 2003-05-27 2004-12-09 Bayer Healthcare Ag Agents diagnostiques et therapeutiques destines a des maladies associees au recepteur 103 couples aux proteines g (gpr103)
WO2005079840A2 (fr) * 2004-02-20 2005-09-01 Develogen Aktiengesellschaft Utilisation de produits de proteines secretees pour la prevention et le traitement de maladies du pancreas et/ou de l'obesite, et/ou du syndrome metabolique
WO2006055704A2 (fr) * 2004-11-17 2006-05-26 Curagen Corporation Anticorps diriges contre des proteines ten-m et utilisations associees
WO2006062135A1 (fr) * 2004-12-07 2006-06-15 Riken Diagnostic pour maladie mentale
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US8008332B2 (en) 2006-05-31 2011-08-30 Takeda San Diego, Inc. Substituted indazoles as glucokinase activators
US8034822B2 (en) 2006-03-08 2011-10-11 Takeda San Diego, Inc. Glucokinase activators
US8124617B2 (en) 2005-09-01 2012-02-28 Takeda San Diego, Inc. Imidazopyridine compounds
US8163779B2 (en) 2006-12-20 2012-04-24 Takeda San Diego, Inc. Glucokinase activators
US8173645B2 (en) 2007-03-21 2012-05-08 Takeda San Diego, Inc. Glucokinase activators
US8460927B2 (en) 1999-11-30 2013-06-11 Mayo Foundation For Medical Education And Research B7-H1 antibodies and method of use
US8747833B2 (en) 2004-10-06 2014-06-10 Mayo Foundation For Medical Education And Research B7-H1 and methods of diagnosis, prognosis, and treatment of cancer
US10167336B2 (en) 2013-03-14 2019-01-01 Mayo Foundation For Medical Education And Research Methods and materials for treating cancer
US10259875B2 (en) 2013-10-01 2019-04-16 Mayo Foundation For Medical Education And Research Methods for treating cancer in patients with elevated levels of BIM
US10302653B2 (en) 2014-05-22 2019-05-28 Mayo Foundation For Medical Education And Research Distinguishing antagonistic and agonistic anti B7-H1 antibodies
US10517875B2 (en) 2014-07-23 2019-12-31 Mayo Foundation for Medical Engineering and Research Targeting DNA-PKcs and B7-H1 to treat cancer
US10875923B2 (en) 2015-10-30 2020-12-29 Mayo Foundation For Medical Education And Research Antibodies to B7-H1

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US8460927B2 (en) 1999-11-30 2013-06-11 Mayo Foundation For Medical Education And Research B7-H1 antibodies and method of use
US7560540B2 (en) 2000-04-28 2009-07-14 The Johns Hopkins University Nucleic acid encoding dendritic cell co-stimulatory molecules
US8053414B2 (en) 2000-04-28 2011-11-08 The Johns Hopkins University Methods of using B7-DC molecules to induce or enhance an immune response
US8053558B2 (en) 2000-04-28 2011-11-08 The Johns Hopkins University Dendritic cell co-stimulatory molecules
US7122345B2 (en) 2001-01-09 2006-10-17 Curagen Corporation Nucleic acid encoding a NOVX13 polypeptide
WO2002055704A3 (fr) * 2001-01-09 2003-10-30 Curagen Corporation Proteines, polynucleotides codant pour elles et procedes d'utilisation correspondants
WO2003038094A1 (fr) * 2001-10-30 2003-05-08 Bayer Healthcare Ag Regulation du transporteur de glucose humain
WO2003054190A1 (fr) * 2001-12-21 2003-07-03 Takeda Chemical Industries, Ltd. Nouvelles proteines et adn correspondants
WO2004106935A2 (fr) * 2003-05-27 2004-12-09 Bayer Healthcare Ag Agents diagnostiques et therapeutiques destines a des maladies associees au recepteur 103 couples aux proteines g (gpr103)
WO2004106935A3 (fr) * 2003-05-27 2008-01-17 Bayer Healthcare Ag Agents diagnostiques et therapeutiques destines a des maladies associees au recepteur 103 couples aux proteines g (gpr103)
WO2005079840A2 (fr) * 2004-02-20 2005-09-01 Develogen Aktiengesellschaft Utilisation de produits de proteines secretees pour la prevention et le traitement de maladies du pancreas et/ou de l'obesite, et/ou du syndrome metabolique
WO2005079840A3 (fr) * 2004-02-20 2006-10-26 Develogen Ag Utilisation de produits de proteines secretees pour la prevention et le traitement de maladies du pancreas et/ou de l'obesite, et/ou du syndrome metabolique
US9803015B2 (en) 2004-10-06 2017-10-31 Mayo Foundation For Medical Education And Research Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target
US8747833B2 (en) 2004-10-06 2014-06-10 Mayo Foundation For Medical Education And Research B7-H1 and methods of diagnosis, prognosis, and treatment of cancer
US11242387B2 (en) 2004-10-06 2022-02-08 Mayo Foundation For Medical Education And Research Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target
US11939378B2 (en) 2004-10-06 2024-03-26 Mayo Foundation For Medical Education And Research Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target
WO2006055704A2 (fr) * 2004-11-17 2006-05-26 Curagen Corporation Anticorps diriges contre des proteines ten-m et utilisations associees
WO2006055704A3 (fr) * 2004-11-17 2006-10-12 Curagen Corp Anticorps diriges contre des proteines ten-m et utilisations associees
WO2006062135A1 (fr) * 2004-12-07 2006-06-15 Riken Diagnostic pour maladie mentale
US8124617B2 (en) 2005-09-01 2012-02-28 Takeda San Diego, Inc. Imidazopyridine compounds
US8034822B2 (en) 2006-03-08 2011-10-11 Takeda San Diego, Inc. Glucokinase activators
US8394843B2 (en) 2006-05-31 2013-03-12 Takeda California, Inc. Substituted isoindoles as glucokinase activators
US8008332B2 (en) 2006-05-31 2011-08-30 Takeda San Diego, Inc. Substituted indazoles as glucokinase activators
US8163779B2 (en) 2006-12-20 2012-04-24 Takeda San Diego, Inc. Glucokinase activators
US8173645B2 (en) 2007-03-21 2012-05-08 Takeda San Diego, Inc. Glucokinase activators
WO2010052288A1 (fr) * 2008-11-07 2010-05-14 Novartis Forschungsstiftung, Zweigniederlassung, Friedrich Miescher Institute For Biomedical Research Teneurine et cancer
US8642280B2 (en) 2008-11-07 2014-02-04 Novartis Forschungsstiftung Zweigniederlassung Friedrich Miescher Institute For Biomedical Research Teneurin and cancer
US10167336B2 (en) 2013-03-14 2019-01-01 Mayo Foundation For Medical Education And Research Methods and materials for treating cancer
US10259875B2 (en) 2013-10-01 2019-04-16 Mayo Foundation For Medical Education And Research Methods for treating cancer in patients with elevated levels of BIM
US11136393B2 (en) 2013-10-01 2021-10-05 Mayo Foundation For Medical Education And Research Methods for treating cancer in patients with elevated levels of Bim
US10302653B2 (en) 2014-05-22 2019-05-28 Mayo Foundation For Medical Education And Research Distinguishing antagonistic and agonistic anti B7-H1 antibodies
US10517875B2 (en) 2014-07-23 2019-12-31 Mayo Foundation for Medical Engineering and Research Targeting DNA-PKcs and B7-H1 to treat cancer
US11504376B2 (en) 2014-07-23 2022-11-22 Mayo Foundation For Medical Education And Research Targeting DNA-PKCS and B7-H1 to treat cancer
US10875923B2 (en) 2015-10-30 2020-12-29 Mayo Foundation For Medical Education And Research Antibodies to B7-H1

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