Vascular Complications of Polycystic Kidney Disease

多囊肾的血管并发症

• 批准号: 7231016
• 负责人: QI QIAN
• 金额: $ 11.98万
• 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/7231016
• 关键词: Animals; Arteries; Autosomal Dominant Polycystic Kidney; Binding; Blood Vessels; Calcium; Cell Line; Characteristics; Clinical; Co-Immunoprecipitations; Complex; Defect; Development; Endothelium; Epithelial Cells; Family; Figs - dietary; Functional disorder; Genes; Genetic; Goals; Homeostasis; Human; Hypertension; Image; In Vitro; Intracranial Aneurysm; Ion Channel; Kidney; Kidney Diseases; Knock-out; Knowledge; Laboratories; Life; Link; Location; Maintenance; Mentors; Methods; Molecular and Cellular Biology; Multiprotein Complexes; Mus; Mutant Strains Mice; Mutate; Mutation; Nitric Oxide; Numbers; PKD2 protein; Pathogenesis; Patients; Pattern; Phenotype; Physicians; Play; Polycystic Kidney Diseases; Positioning Attribute; Program Development; Proteins; Qi; Regulation; Relaxation; Research; Research Proposals; Resistance; Role; Scientist; Signal Transduction; Smooth Muscle Myocytes; Staging; Stress; System; Tea; Techniques; Thinking; Thoracic Aortic Aneurysm; Training; Transgenic Mice; Vascular Smooth Muscle; Yeasts; base; career; design; hemodynamics; in vivo; normotensive; pol genes; polycystic kidney disease 1 protein; response; subcutaneous; tool; 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）： 博士Qian的长期目标是更好地了解肾脏疾病的病理生理学，特别是常染色体显性多囊肾病（ADPKD）的血管并发症。她的目标，在五年内，是成为一个训练有素的独立的医生科学家与先进的理论和技术知识，遗传学和分子和细胞生物学通过实施这一建议。候选人的导师托雷斯博士是ADPKD临床和血管方面的专家，她的共同导师哈里斯博士带来了ADPKD遗传学的详细知识。第三位导师Farrugia博士是Ca 2+稳态方面的专家，将为提案的这一部分提供有价值的指导。该建议的特别重点是研究ADPKD蛋白，多囊蛋白-1和-2在血管系统中的作用，并确定这些蛋白的缺陷是否与ADPKD相关的血管表现和高血压直接相关。初步研究表明，多囊蛋白在血管平滑肌细胞（VSMC）中表达，并且它们作为多囊蛋白复合物的一部分相互作用，该复合物可能在维持细胞内Ca 2+中起作用。该提议的前两个具体目的是检查鼠Pkd 1和Pkd 2基因突变以及人蛋白在小鼠中过度表达对VSMC特性的影响。这些将在体外进行分析，作为培养的VSMC和在体内，通过研究小鼠突变体中的脉管系统的超微结构。特异性目标3将使用成像方法、免疫共沉淀和酵母双杂交技术鉴定VSMC多囊蛋白复合物的组分。这些研究的结果将允许定义VSMC多囊蛋白复合物，并与上皮细胞中相应的复合物进行比较。该提案的最后部分（具体目标4）将检查多囊蛋白在维持细胞内钙稳态中的作用，并分析Pkd 1/2突变的后果。总的来说，这些研究的结果应该提供一个更清晰的观点，多囊蛋白在VSMC中的功能，以及这些蛋白的丢失可能在ADPKD相关的血管异常和高血压中发挥的作用。这些信息将为设计治疗这些并发症的合理疗法提供基础。这段基于实验室的研究，加上正式的职业发展计划，旨在培养候选人成为一名在ADPKD血管方面具有独特专业知识的医生科学家。

项目成果

Pkd2+/- vascular smooth muscles develop exaggerated vasocontraction in response to phenylephrine stimulation.

Pkd2 /- 血管平滑肌响应去氧肾上腺素刺激而产生过度的血管收缩。

• DOI: 10.1681/asn.2006050501
• 发表时间: 2007
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Qian,Qi;Hunter,LarryW;Du,Hui;Ren,Qun;Han,Young;Sieck,GaryC
• 通讯作者: Sieck,GaryC

Phenylephrine induces elevated RhoA activation and smooth muscle alpha-actin expression in Pkd2+/- vascular smooth muscle cells.

去氧肾上腺素诱导 Pkd2/- 血管平滑肌细胞中 RhoA 活化和平滑肌 α-肌动蛋白表达升高。

• DOI: 10.1038/hr.2009.173
• 发表时间: 2010
• 期刊: Hypertension research : official journal of the Japanese Society of Hypertension
• 作者: Du,Hui;Wang,Xiangling;Wu,Jun;Qian,Qi
• 通讯作者: Qian,Qi