TGF-Alpha POLYPEPTIDES, FUNCTIONAL FRAGMENTS AND METHODS OF USE THEREFOR

Abstract

Disclosed are TGF-α polypeptides, related polypeptides, fragments and mimetics thereof useful in stimulating stem cell or precursor cell proliferation, migration and differentiation. The methods of the invention are useful to treat tissue injury as well as expand stem cell populations in, or obtained from, gastrointestinal, musculoskeletal, urogenital, neurological and cardiovascular tissues. The methods include ex vivo and in vivo applications.

1 . A method for treating or preventing gastrointestinal tract mucositis, comprising:
 administering a transforming growth factor-α57 (TGF-α57) polypeptide that comprises the amino acid sequence set forth in SEQ ID NO:3, and thereby treating or preventing the gastrointestinal tract mucositis.   
     
     
         2 . The method of  claim 1  wherein the TGF-α57 polypeptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally. 
     
     
         3 . A method for treating or repairing a tissue of a subject, comprising:
 contacting a tissue with a transforming growth factor-α57 (TGF-α57) polypeptide that comprises the amino acid sequence set forth in SEQ ID NO:3, in an amount effective to induce stem cell or precursor cell proliferation, migration or differentiation in the tissue, wherein the tissue is selected from the group consisting of kidney tissue, liver tissue, spleen tissue, bone tissue, neural tissue, skin tissue, gastrointestinal tract tissue, urogenital tissue and musculoskeletal tissue, and thereby treating or repairing the tissue.   
     
     
         4 . The method of  claim 3  wherein the TGF-α57 polypeptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally. 
     
     
         5 . The method of  claim 3  wherein treating or repairing the tissue comprises treating or repairing gastrointestinal tract mucosal epithelium by increasing in number intestinal epithelial goblet cells to a level higher than is found in normal intestine. 
     
     
         6 . A method for treating or preventing an inflammatory reaction, comprising:
 administering a transforming growth factor-α57 (TGF-α57) polypeptide that comprises that comprises the amino acid sequence set forth in SEQ ID NO:3, and thereby treating or preventing the inflammatory reaction.   
     
     
         7 . The method of  claim 6  wherein the inflammatory reaction results from an autoimmune disease. 
     
     
         8 . The method of  claim 7  wherein the autoimmune disease is selected from diabetic retinopathy, macular degeneration, retinal vascular occlusion and multiple sclerosis. 
     
     
         9 . The method of  claim 6  wherein the TGF-α57 polypeptide prevents mast cell degranulation. 
     
     
         10 . The method of  claim 6  wherein the inflammatory reaction results from inflammatory bowel disease, Creutzfeldt-Jacob disease, AIDS encephalopathy, viral encephalitis or bacterial meningitis. 
     
     
         11 . The method of  claim 6  wherein the TGF-α57 polypeptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally. 
     
     
         12 . A method for enhancing or augmenting hematopoiesis, comprising:
 administering a transforming growth factor-α57 (TGF-α57) polypeptide that comprises the amino acid sequence set forth in SEQ ID NO:3, and thereby enhancing or augmenting hematopoiesis.   
     
     
         13 . The method of  claim 12  wherein the TGF-α57 polypeptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally. 
     
     
         14 . The method of  claim 12  further comprising administering a hematopoietic growth factor agent that is selected from the group consisting of erythropoietin, thrombopoietin, G-CSF, and GM-CSF. 
     
     
         15 . A method for treating a neurological deficit that is caused by at least one of (i) a degenerative disease, (ii) a traumatic or neurotoxic injury, (iii) ischemia, (iv) a developmental disorder, (v) a disorder affecting vision caused by loss or failure of retinal cells, (vi) a spinal cord injury, (vii) a demyelinating autoimmune disorder, and (viii) an infectious or inflammatory disease, said method comprising:
 administering a transforming growth factor-α57 (TGF-α57) polypeptide that comprises the amino acid sequence set forth in SEQ ID NO:3, and thereby treating the neurological deficit.   
     
     
         16 . The method of  claim 15  wherein the TGF-α57 polypeptide is administered (a) orally, (b) parenterally, or (c) orally and parenterally. 
     
     
         17 . The method of  claim 15  wherein:
 (i) the degenerative disease is selected from the group consisting of Alzheimer's Disease (AD), Parkinson's Disease (PD), and Huntington's Disease (HD),   (ii) the traumatic or neurotoxic injury is selected from the group consisting of a gunshot wound, a blunt force injury, a penetration injury, an injury caused by a surgical procedure, poisoning, shaken baby syndrome, an adverse reaction to a medication, a drug overdose, and post-traumatic encephalopathy,   (iii) the ischemia results from at least one of stroke, anoxia, hypoxia, partial drowning, myoclonus, severe smoke inhalation, a dystonia and acquired hydrocephalus,   (iv) the developmental disorder is selected from the group consisting of schizophrenia, mental retardation, cerebral palsy, congenital hydrocephalus, autism, Downs Syndrome, LHRH/hypothalamic disorder, and spina bifida,   (v) the disorder affecting vision caused by loss or failure of retinal cells is selected from the group consisting of diabetic retinopathy, retinal detachment, traumatic injury to the retina, retinal vascular occlusion, macular degeneration, and optic nerve atrophy,   (vi) the spinal cord injury is selected from the group consisting of post-polio syndrome, amyotrophic lateral sclerosis, traumatic spinal cord injury, surgical spinal cord injury, and a paralytic disease,   (vii) the demyelinating autoimmune disorder is multiple sclerosis, and   (viii) the infectious or inflammatory disease is selected from the group consisting of Creutzfeldt-Jacob disease, a slow virus infectious CNS disease, AIDS encephalopathy, post-encephalitic Parkinsonism, viral encephalitis and bacterial meningitis.