Methods for protecting dopaminergic neurons from stress and promoting proliferation and differentiation of oligodendrocyte progenitors by nrg-2

Abstract

The invention features methods of treatment and diagnosis using NRG-2 polypeptides, nucleic acid molecules, and antibodies. The invention also provides novel NRG-2 polypeptides and nucleic acid molecules.

1 . A method for increasing the mitogenesis, survival, growth, or differentiation of a cell, said method comprising administering a NRG-2 polypeptide to said cell in an amount effective for increasing the mitogenesis, survival, growth, or differentiation of said cell, wherein said cell expresses an erbB receptor that is selective for a NRG-2 polypeptide. 
     
     
         2 . The method of  claim 1 , wherein said erbB receptor is selected from the group consisting of an erbB4 homodimer, an erbB2/erbB4 heterodimer, and an erbB1/erbB3 heterodimer. 
     
     
         3 . The method of  claim 1 , wherein said cell is selected from the group consisting of a neuronal cell and a neuronal progenitor cell. 
     
     
         4 . The method of  claim 1 , wherein said cell is a neuronal-associated cell. 
     
     
         5 . The method of  claim 4 , wherein said neuronal-associated cell is selected from the group consisting of a Schwann cell, an astrocyte, an oligodendrocyte, an O-2A progenitor cell, a glial cell, a microglial cell, an olfactory bulb ensheathing cell, and a sensory organ cell. 
     
     
         6 . The method of  claim 1 , wherein said cell is a muscle cell. 
     
     
         7 . The method of  claim 6 , wherein said muscle cell is selected from the group consisting of a myoblast, a satellite cell, a myocyte, a skeletal muscle cell, a smooth muscle cell, and a cardiac muscle cell. 
     
     
         8 . A method of stimulating mitogenesis of a glial cell, said method comprising contacting said glial cell with a recombinant NRG-2 polypeptide. 
     
     
         9 . The method of  claim 8 , wherein said glial cell is selected from the group consisting of oligodendrocytes, microglia, myelinating glia, an olfactory bulb ensheathing cell, and glial cells in an adult. 
     
     
         10 . A method for inducing myelination of a neuronal cell by a glial cell, comprising contacting said glial cell with a NRG-2 polypeptide, said contacting sufficient to induce myelination of said neuronal cell by said glial cell. 
     
     
         11 . A method of increasing the cardiomyocyte survival, cardiomyocyte proliferation, cardiomyocyte growth, or cardiomyocyte differentiation in a mammal in need thereof, said method comprising administering a NRG-2 polypeptide to said mammal in an amount effective for increasing said cardiomyocyte survival, cardiomyocyte proliferation, cardiomyocyte growth, or cardiomyocyte differentiation. 
     
     
         12 . The method of  claim 11 , wherein said mammal is a human. 
     
     
         13 . The method of  claim 11 , wherein said mammal has a pathophysiological condition which affects cardiac muscle. 
     
     
         14 . The method of  claim 13 , wherein said condition is cardiomyopathy or ischemic damage. 
     
     
         15 . The method of  claim 14 , wherein said cardiomyopathy is a degenerative congenital disease. 
     
     
         16 . The method of  claim 13 , wherein said condition is cardiac trauma or heart failure. 
     
     
         17 . The method of  claim 11 , wherein said mammal has a pathophysiological condition which affects smooth muscle. 
     
     
         18 . The method of  claim 17 , wherein said condition is selected from the group consisting of atherosclerosis, vascular lesion, vascular hypertension, and degenerative congenital vascular disease. 
     
     
         19 . The method of  claim 11 , wherein said mammal is a patient with myasthenia gravis. 
     
     
         20 . A method of affecting cellular communication between a neuronal-associated cell and a neuronal cell in a mammal, comprising administering a NRG-2 polypeptide to said mammal wherein said neuregulin interacts with said neuronal-associated cell, resulting in the production of at least one neurotrophic agent by said neuronal-associated cell, and said neurotrophic agent or agents affect the mitogenesis, survival, growth, differentiation, or neurite outgrowth of said neuronal cell. 
     
     
         21 . The method of  claim 20 , wherein said mammal is a human. 
     
     
         22 . The method of  claim 20 , wherein said neuronal-associated cell is selected from the group consisting of a Schwann cell, an astrocyte, an oligodendrocyte, an O-2A progenitor cell, a glial cell, an olfactory bulb ensheathing cell, a microglial cell, a sensory organ cell, and a muscle cell. 
     
     
         23 . The method of  claim 22 , wherein said muscle cell is selected from the group consisting of a skeletal muscle cell, a smooth muscle cell, and a cardiac muscle cell. 
     
     
         24 . The method of  claim 20 , wherein said affecting cellular communication is in the central nervous system of a mammal. 
     
     
         25 . The method of  claim 20 , wherein said affecting cellular communication is in the peripheral nervous system of a mammal. 
     
     
         26 . The method of  claim 20 , wherein said administering comprises administering a purified NRG-2 polypeptide-producing cell. 
     
     
         27 . A method for the treatment or prophylaxis of a pathophysiological condition of the nervous system in a mammal, said method comprising administering a therapeutically effective amount of a recombinant NRG-2 polypeptide to said mammal. 
     
     
         28 . The method of  claim 27 , wherein said pathophysiological condition is a condition of the peripheral nervous system. 
     
     
         29 . The method of  claim 27 , wherein said pathophysiological condition is a condition of the central nervous system. 
     
     
         30 . The method of  claim 27 , wherein said pathophysiological condition is selected from the group consisting of demyelination of nerve cells, damage of Schwann cells, loss of Schwann cells, and a neurodegenerative disorder. 
     
     
         31 . The method of  claim 27 , wherein said pathophysiological condition is a peripheral neuropathy. 
     
     
         32 . The method of  claim 31 , wherein said neuropathy is a sensory nerve fiber neuropathy. 
     
     
         33 . The method of  claim 31 , wherein said neuropathy is a motor fiber and a sensory nerve fiber neuropathy. 
     
     
         34 . The method of  claim 31 , wherein said neuropathy is a motor fiber neuropathy. 
     
     
         35 . The method of  claim 27 , wherein said treatment or prophylaxis requires neural regeneration or neural repair. 
     
     
         36 . The method of  claim 27 , wherein said pathophysiological condition is multiple sclerosis. 
     
     
         37 . The method of  claim 27 , wherein said pathophysiological condition is selected from the group consisting of amyotrophic lateral sclerosis, spinal muscular atrophy, nerve injury, Alzheimer's Disease, Parkinson's Disease, cerebellar ataxia, and spinal cord injury. 
     
     
         38 . The method of  claim 27 , wherein said NRG-2 polypeptide interacts with neuronal-associated cells, resulting in production of at least one neurotrophic agent by said neuronal-associated cells and said neurotrophic agent or agents affect the mitotic activity, survival, differentiation or neurite outgrowth of neuronal cells. 
     
     
         39 . The method of  claim 27 , wherein said administering is sufficient to induce myelination of a neuronal cell by a glial cell. 
     
     
         40 . The method of  claim 39 , wherein said glial cell is a Schwann cell or an oligodendrocyte. 
     
     
         41 . The method of  claim 27 , wherein said administering comprises administering a purified NRG-2 polypeptide-producing cell to said mammal. 
     
     
         42 . The method of  claim 26  or  41 , wherein said NRG-2 polypeptide-producing cell contains a recombinant DNA sequence, wherein said DNA sequence comprises a NRG-2 polypeptide-encoding sequence, and wherein said NRG-2 polypeptide-encoding DNA sequence is operably linked to a promoter. 
     
     
         43 . A method for the treatment of a tumor, said method comprising inhibiting proliferation of a tumor cell, said inhibiting comprising administering to a subject in need thereof an effective amount of an antibody that inhibits binding of a NRG-2 polypeptide to a receptor present on the surface of said tumor cell. 
     
     
         44 . The method of  claim 43 , wherein said tumor cell expresses an erbB receptor that is selective for a NRG-2 polypeptide. 
     
     
         45 . The method of  claim 43 , wherein said tumor is a glial tumor. 
     
     
         46 . A method for the treatment of neurofibromatosis, said method comprising inhibiting glial cell mitogenesis, said inhibiting comprising administering to a subject in need thereof an effective amount of an antibody which inhibits binding of a NRG-2 polypeptide to a receptor present on the surface of a glial tumor cell in an individual with neurofibromatosis. 
     
     
         47 . A method for inhibiting proliferation of a cell, said method comprising contacting said cell with an effective amount of an antibody that inhibits binding of a NRG-2 polypeptide to a receptor present on the surface of said cell. 
     
     
         48 . A method for stimulating proliferation of a cell, said method comprising administering a NRG-2 polypeptide to said cell. 
     
     
         49 . The method of  claims 47  and  48 , wherein said cell is selected from the group consisting of a neuronal cell, a neuronal-associated cell, and a muscle cell. 
     
     
         50 . The method of  claims 1 ,  8 ,  10 ,  11 ,  20 ,  27 ,  43 ,  46 ,  47 , and  48 , wherein said NRG-2 polypeptide comprises the amino acid sequence set forth in SEQ ID NOs: 2 or 4. 
     
     
         51 . The method of  claims 1 ,  8 ,  10 ,  11 ,  20 ,  27 ,  43 ,  46 ,  47 , and  48 , wherein said NRG-2 polypeptide consists of the amino acid sequence set forth in SEQ ID NOs: 2 or 4. 
     
     
         52 . The method of  claims 1 ,  8 ,  10 ,  11 ,  20 ,  27 ,  43 ,  46 ,  47 , and  48 , wherein said NRG-2 polypeptide is encoded by the nucleic acid sequence set forth in SEQ ID NOs: 1 or 3. 
     
     
         53 . A substantially pure NRG-2 polypeptide comprising the amino acid sequence set forth in SEQ ID NOs: 2 or 4. 
     
     
         54 . A substantially pure NRG-2 polypeptide consisting of the amino acid sequence set forth in SEQ ID NOs: 2 or 4. 
     
     
         55 . A substantially pure nucleic acid molecule comprising a sequence encoding a polypeptide comprising the amino acid sequence set forth in SEQ ID NOs: 2 or 4. 
     
     
         56 . A substantially pure nucleic acid molecule comprising a nucleic acid sequence that is substantially identical to the nucleic acid sequence set forth in SEQ ID NOs: 1 or 3. 
     
     
         57 . A substantially pure nucleic acid molecule consisting of the nucleic acid sequence set forth in SEQ ID NOs: 1 or 3. 
     
     
         58 . A nucleic acid molecule comprising a sequence that is antisense to the coding strand sequence of the nucleic acid sequence set forth in SEQ ID NOs: 1 or 3, or a fragment thereof. 
     
     
         59 . A vector comprising the nucleic acid molecule of  claim 55 , operably linked to a promoter. 
     
     
         60 . The vector of  claim 59 , wherein said vector is a gene therapy vector. 
     
     
         61 . A cell comprising the vector of  claim 60 . 
     
     
         62 . A non-human transgenic animal comprising the nucleic acid molecule of  claim 55 . 
     
     
         63 . A non-human animal having a knockout mutation in one or both alleles encoding the NRG-2 polypeptide comprising the amino acid sequence set forth in SEQ ID NOs: 2 or 4. 
     
     
         64 . A cell from the non-human animal of  claim 63 . 
     
     
         65 . An antibody that specifically binds to a NRG-2 polypeptide comprising the amino acid sequence set forth in SEQ ID NOs: 2 or 4. 
     
     
         66 . A method of detecting the presence of a NRG-2 polypeptide in a sample, said method comprising contacting said sample with the antibody of  claim 65  and assaying for binding of said antibody to said polypeptide. 
     
     
         67 . A method of diagnosing an increased likelihood of developing a NRG-2-related disease or condition in a test subject, said method comprising analyzing nucleic acid molecules of said test subject to determine whether said test subject contains a mutation in NRG-2 gene that encodes a NRG-2 polypeptide comprising the amino acid sequence set forth in SEQ ID Nos: 2 or 4, wherein the presence of said mutation is an indication that said test subject has an increased likelihood of developing a NRG-2-related disease. 
     
     
         68 . The method of  claim 67 , wherein said test subject is human. 
     
     
         69 . A kit for the analysis of a NRG-2 polypeptide of a test subject, said kit comprising the antibody of  claim 65 .