End stage renal disease (ESRD) is a major cause of morbidity and mortality. During 1993 more then 257,000 people in the united sates were treated for ESRD. In 1993 alone more than 57,000 people were started for treatment for, and over 40,916 people died from, ESRD. Diabetes and hypertension are the most common causes of ESRD, each resulting in progressive renal fibrosis which can ultimately lead to ESRD. Osteogenic protein-1 (OP-1) is a member of the transforming growth factor - Beta super family of secreted growth factors. The kidney is the primary site of OP-1 synthesis. Mice genetically deficient in OP-1 expression have markedly abnormal renal development, suggesting that this protein may be important in regulation of cell division and morphogenesis in the kidney. Systemic administration of OP-1 synthesis. Mice genetically deficient in OP-1 expression have markedly abnormal renal development, suggesting that this protein may be important in regulation of cell division and morphogenesis in the kidney. Systemic administration of OP-1 has been shown to delay or halt progress to end stage renal failure in 5/6 nephrectomy rat model of glomerular fibrosis. The current proposal focuses on defining the pathophysiologic mechanism of action of OP-1 in fibrosis. The current proposal focuses on defining pathophysiologic mechanism of action of OP-1 in fibrosis and extending these preliminary findings in to a gene therapy setting for both the renal ablation and a diabetic model for renal fibrosis. The experiments described in this proposal will be performed in the laboratory of Vikas P. Sukhatme, M.D., PH.D. in the outstanding environment of Beth Israel Deaconess Medical Center at Harvard medical School. Dr. Sukhatme has established himself as a leader in the field of molecular nephrology. His laboratory has a strong emphasis on gene transfer, transcriptional regulation and fibrosis. It is this emphasis on basic science research, particularly on transcriptions regulation and gene transfer that was a strong influence on my decision to work in his laboratory. Dr. Sukhatme has 11 postdoctoral fellow sin his laboratory currently who have diverse research interests. This environment offers a broad range of support within his laboratory alone. The applicant has completed his clinical nephrology fellowship and has spent the last two years characterizing a critical cis element in the WTI gene and the corresponding transcriptional activator and developing improved adenoviral vectors for gene transfer to the kidney. The applicant is absolutely committed to a career in basic research in academic nephrology. The combination of the strength of the sponsor, the environment of Harvard medical School and the applicants research experience offers an ideal forum for the applicant to not only realize the objectives outlined in this proposal but also become an independent investigator.
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