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

OP-1 在啮齿动物肾纤维化模型中的基因递送

• 批准号: 6140561
• 负责人: GLENN A MCDONALD
• 金额: $ 5.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6140561
• 关键词: Adenoviridae; bone morphogenetic proteins; chronic renal failure; diabetic nephropathy; disease /disorder model; extracellular matrix proteins; fibrosis; gene expression; gene therapy; genetic transduction; immunomodulators; kidney; kidney cell; laboratory mouse; laboratory rat; molecular pathology; nonhuman therapy evaluation; pathologic process; technology /technique development; transfection /expression vector; transforming growth factors; western blottings

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.

终末期肾病（ESRD）是发病率和死亡率的主要原因。在1993年期间，美国有超过257,000人接受了ESRD治疗。仅1993年就有57,000多人开始接受治疗，40,916多人死于ESRD。糖尿病和高血压是ESRD最常见的病因，两者均可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- β超家族分泌生长因子中的一员。肾脏是OP-1合成的主要部位。OP-1基因表达缺失的小鼠肾脏发育明显异常，提示该蛋白可能在肾脏细胞分裂和形态发生的调控中起重要作用。全身给药OP-1合成。OP-1基因表达缺失的小鼠肾脏发育明显异常，提示该蛋白可能在肾脏细胞分裂和形态发生的调控中起重要作用。在5/6肾切除术大鼠肾小球纤维化模型中，全身给药OP-1已被证明可以延缓或阻止终末期肾衰竭的进展。目前的建议侧重于确定OP-1在纤维化中的病理生理机制。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消融和糖尿病肾纤维化模型的基因治疗设置。本提案中描述的实验将在哈佛医学院Beth Israel Deaconess医学中心的Vikas P. Sukhatme， M.D， PH.D.的实验室进行。Sukhatme博士已成为分子肾脏病学领域的领导者。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，尤其是对转录调控和基因转移的重视，极大地影响了我决定在他的实验室工作。Sukhatme博士的实验室目前有11名博士后，他们有着不同的研究兴趣。这种环境仅在他的实验室就提供了广泛的支持。申请人已经完成了他的临床肾脏病学奖学金，并在过去的两年里研究了WTI基因中的一个关键顺式元件和相应的转录激活子，并开发了用于基因转移到肾脏的改进的腺病毒载体。申请人绝对致力于学术肾脏病学的基础研究事业。赞助商的实力、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，而且可以成为一名独立的研究者。