GENE DELIVERY OF OP-1 IN RODENT MODEL OF RENAL FIBROSIS

终末期肾病(ESRD)是导致发病率和死亡率的主要原因。1993年，美国有257,000多人接受了终末期肾病的治疗。仅在1993年，就有57000多人开始接受ESRD治疗，40916多人死于ESRD。糖尿病和高血压是终末期肾病最常见的原因，每一种都会导致进行性肾脏纤维化，最终可能导致终末期肾病。成骨蛋白-1(OP-1)是分泌型生长因子中的转化生长因子-β超家族成员。肾脏是OP-1合成的主要部位。OP-1基因表达缺陷的小鼠肾脏发育明显异常，提示该蛋白可能在调节肾脏细胞分裂和形态发生中起重要作用。全身性应用OP-1合成。OP-1基因表达缺陷的小鼠肾脏发育明显异常，提示该蛋白可能在调节肾脏细胞分裂和形态发生中起重要作用。在5/6肾切除大鼠肾小球纤维化模型中，系统应用OP-1可以延缓或阻止进展为终末期肾功能衰竭。目前的建议侧重于确定OP-1在纤维化中的病理生理作用机制。目前的建议侧重于确定OP-1在纤维化中的病理生理作用机制，并将这些初步发现扩展到肾脏消融和糖尿病肾脏纤维化模型的基因治疗环境中。本提案中描述的实验将在哈佛医学院贝丝以色列女执事医学中心杰出环境下的Vikas P.Sukhatme医学博士的实验室进行。苏哈特姆博士已经确立了自己在分子肾脏学领域的领导者地位。他的实验室非常重视基因转移、转录调控和纤维化。正是这种对基础科学研究的重视，特别是对转录调控和基因转移的重视，对我决定在他的实验室工作产生了强烈的影响。苏哈特姆博士的实验室目前有11名博士后研究员，他们有不同的研究兴趣。这种环境仅在他的实验室内就提供了广泛的支持。申请者已经完成了他的临床肾脏学研究，并在过去的两年里一直在鉴定WTI基因中的一个关键顺式元件和相应的转录激活子，并开发改进的腺病毒载体，用于将基因转移到肾脏。申请者完全致力于学术肾脏病基础研究的事业。发起人的实力、哈佛医学院的环境和申请者的研究经验相结合，为申请者提供了一个理想的论坛，不仅可以实现这项提议中列出的目标，还可以成为一名独立的研究人员。

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.