Characterization of TRPC6 mutations in inherited FSGS

遗传性 FSGS 中 TRPC6 突变的表征

• 批准号: 7056985
• 负责人: JOHANNES S SCHLONDORFF
• 金额: $ 5.2万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-30 至 2008-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056985
• 关键词: autosomal dominant trait; calcium channel; chemical stability; gene mutation; genetic disorder; glomerulosclerosis; membrane proteins; phosphorylation; podocyte; postdoctoral investigator; protein binding; protein localization; protein protein interaction; protein structure function; protein transport; tissue /cell culture

DESCRIPTION (provided by applicant): Focal segmental glomerular sclerosis (FSGS) is a kidney lesion seen in a number of disease states, and contributes significantly to the population of patients with end-stage renal disease. Several inherited forms of FSGS have been described. Mutations identified to date involve proteins expressed in the podocyte, and studies of inherited FSGS have furthered our understanding of how podocytes help maintain the filtration barrier that prevents protein from spilling into the urine. Recently, mutations in TRPC6, a calcium channel, have been identified as causing an autosomal dominant form of FSGS. Mutations have been found to involve several different areas of the TRPC6 protein, yet how they might affect TRPC6 function is unclear. We propose several lines of investigation to characterize these mutations in cell based and in vitro systems, including possible effects on protein stability, localization, phosphorylation, and channel activity. In addition, we plan to assess the ability of these mutant channels to multimerize with other TRPC family members as well as bind to key components of the podocyte slit diaphragm. These studies will further open new lines of investigation into how TRPC6 function is crucial for proper podocyte function.

描述（由申请方提供）：局灶节段性肾小球硬化（FSGS）是一种见于多种疾病状态的肾脏病变，在终末期肾病患者人群中有显著作用。已经描述了几种遗传形式的FSGS。迄今为止发现的突变涉及足细胞中表达的蛋白质，对遗传性FSGS的研究进一步加深了我们对足细胞如何帮助维持防止蛋白质溢出到尿液中的过滤屏障的理解。最近，TRPC6（一种钙通道）的突变已被确定为导致常染色体显性形式的FSGS。已发现突变涉及TRPC 6蛋白的几个不同区域，但它们如何影响TRPC 6功能尚不清楚。我们提出了几条线的调查，以表征这些突变在细胞为基础的和在体外系统，包括对蛋白质的稳定性，定位，磷酸化和通道活性的可能影响。此外，我们计划评估这些突变通道与其他TRPC家族成员多聚化以及与足细胞狭缝隔膜的关键成分结合的能力。这些研究将进一步开辟新的研究路线，以了解TRPC 6的功能如何对足细胞的正常功能至关重要。