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

终末期肾病（ESRD）是发病和死亡的主要原因。 1993 年期间，美国有超过 257,000 人接受了 ESRD 治疗。 仅 1993 年，就有超过 57,000 人开始接受 ESRD 治疗，并有超过 40,916 人死于 ESRD。糖尿病和高血压是 ESRD 的最常见原因，两者都会导致进行性肾纤维化，最终导致 ESRD。成骨蛋白-1 (OP-1) 是转化生长因子 - 分泌性生长因子 Beta 超家族的成员。 肾脏是OP-1合成的主要场所。 OP-1 表达遗传缺陷的小鼠肾脏发育明显异常，表明该蛋白可能在肾脏细胞分裂和形态发生的调节中发挥重要作用。 OP-1合成的全身给药。 OP-1 表达遗传缺陷的小鼠肾脏发育明显异常，表明该蛋白可能在肾脏细胞分裂和形态发生的调节中发挥重要作用。 在 5/6 肾切除大鼠肾小球纤维化模型中，全身给予 OP-1 已被证明可以延迟或阻止进展至终末期肾衰竭。 目前的提案重点是确定 OP-1 在纤维化中的病理生理作用机制。 目前的提案重点是确定 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肾纤维化糖尿病模型的基因治疗环境中。本提案中描述的实验将在 Vikas P. Sukhatme, M.D., PH.D. 的实验室进行。环境优越的哈佛医学院贝斯以色列女执事医疗中心。 Sukhatme 博士已成为分子肾病学领域的领导者。 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重大影响。 Sukhatme 博士的实验室目前有 11 名博士后研究员，他们有着不同的研究兴趣。 这种环境仅在他的实验室内就提供了广泛的支持。申请人已经完成了临床肾病学奖学金，并在过去两年中研究了 WTI 基因中的关键顺式元件和相应的转录激活因子，并开发了用于基因转移至肾脏的改良腺病毒载体。 申请人绝对致力于学术肾脏病学基础研究的职业生涯。申办者的实力、哈佛医学院的环境和申请人的研究经验相结合，为申请人提供了一个理想的论坛，不仅可以实现本提案中概述的目标，还可以成为一名独立研究者。

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.