Vascular Complications of Polycystic Kidney Disease

多囊肾的血管并发症

• 批准号: 7059343
• 负责人: QI QIAN
• 金额: $ 12.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059343
• 关键词: calcium channel; calcium flux; cardiovascular disorder; cardiovascular imaging /visualization; disease /disorder model; gene mutation; genetically modified animals; hypertension; immunoprecipitation; laboratory mouse; medical complication; molecular pathology; polycystic kidney; protein localization; protein structure function; proteins; tissue /cell culture; vascular smooth muscle; yeast two hybrid system

DESCRIPTION (provided by applicant): Dr. Qian's long-term objective is to contribute to a better understanding of kidney disease pathophysiology, especially the vascular complications of autosomal dominant polycystic kidney disease (ADPKD). Her aim, over five-years, is to become a well-trained independent physician scientist with advance theoretical and technical knowledge in genetics and molecular and cellular biology through the implementation of this proposal. The candidate's mentor, Dr. Torres, is an expert in clinical and vascular aspects of ADPKD and her co-mentor, Dr. Harris, brings a detailed knowledge of ADPKD genetics. The third mentor, Dr. Farrugia, is an expert in Ca2+ homeostasis and will provide valuable guidance for that part of the proposal. The particular focus of this proposal is to study the role of the ADPKD proteins, polycystin-1 and -2 in the vasculature and to determine if defects in these proteins are directly related to the vascular manifestations and hypertension associated with ADPKD. Preliminary studies have indicated that the polycystins are expressed in vascular smooth muscle cells (VSMC) and that they interact as a part of a polycystin complex that may play a role in maintaining intracellular Ca2+ The first two Specific Aims of the proposal are to examine the consequences of mutation to the murine Pkdl and Pkd2 genes, and over expression of the human protein in mouse, on the characteristics of VSMCs. These will be analyzed in vitro, as cultured VSMCs and in vivo, by study of the ultrastructure of the vasculature in the mouse mutants. Specific Aim 3 will identify components of a VSMC polycystin complex using imaging methods, co-immunoprecipitation and the yeast two- hybrid technique. The results of these studies will allow a VSMC polycystin complex to be defined and comparison made to corresponding complexes in epithelial cells. The final part of the proposal (Specific Aim 4) will examine the role of the polycystins in maintaining intracellular calcium homeostasis and analyze the consequences of Pkd1/2 mutation. Overall, the results from these studies should provide a clearer view of the function of the polycystins in VSMCs and the likely role that loss of these proteins may play in the vascular abnormalities and hypertension associated with ADPKD. This information will provide the basis for designing rational therapies for the treatment of these complications. This period of laboratory based study, plus the formalized career development program, is designed to train the candidate as a physician scientist with a unique expertise in vascular aspects of ADPKD.

描述（由申请人提供）： Qian博士的长期目标是有助于更好地了解肾脏病病理生理学，尤其是常染色体显性多囊肾脏病（ADPKD）的血管并发症。她的五年以上，她的目标是通过实施该提案，成为一名训练有素的独立医师科学家，具有遗传学以及分子和细胞生物学方面的理论和技术知识。候选人的导师托雷斯（Torres）博士是ADPKD的临床和血管方面的专家，她的同事Harris博士带来了对ADPKD遗传学的详细知识。第三位导师Farrugia博士是CA2+稳态的专家，将为该提案的一部分提供宝贵的指导。该提案的特定重点是研究ADPKD蛋白，polycystin -1和-2在血管系统中的作用，并确定这些蛋白质中的缺陷是否与与ADPKD相关的血管表现和高血压直接相关。初步研究表明，多囊素在血管平滑肌细胞（VSMC）中表达，并且它们作为多囊蛋白络合物的一部分相互作用，可能在维持细胞内Ca2+方面的第一个特定目的中起作用，以研究突变对鼠类PKDL和PKD2基因的突变的后果，对人类和人类表达的特征，以及人类的表现，以及人类的表现。通过研究小鼠突变体中脉管系统的超微结构，将它们在体外分析为培养的VSMC和体内。特定的目标3将使用成像方法，共免疫沉淀和酵母两种杂交技术鉴定VSMC多囊蛋白复合物的组成部分。这些研究的结果将允许定义VSMC多囊蛋白复合物，并比较与上皮细胞中的相应复合物。提案的最后一部分（特定目标4）将检查多囊蛋白在维持细胞内钙稳态中的作用，并分析PKD1/2突变的后果。总体而言，这些研究的结果应更清晰地了解多囊蛋白在VSMC中的功能，并且这些蛋白质丢失可能在与ADPKD相关的血管异常和高血压中起作用的可能作用。该信息将为设计有理疗法的治疗这些并发症提供基础。这一时期的基于实验室的研究以及正式的职业发展计划，旨在培训候选人为ADPKD血管方面具有独特专业知识的医师科学家。