Characterization of TRPC6 mutations in inherited FSGS

遗传性 FSGS 中 TRPC6 突变的表征

• 批准号: 7304051
• 负责人: JOHANNES S SCHLONDORFF
• 金额: $ 5.4万
• 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/7304051
• 关键词: Affect; Area; Binding; Calcium; Calcium Channel; Cells; Disease; End stage renal failure; Family member; Filtration; Focal Segmental Glomerulosclerosis; In Vitro; Inherited; Investigation; Kidney; Lesion; Mediating; Mutation; Numbers; Patients; Phosphorylation; Population; Proteins; Role; Signal Transduction; System; Tyrosine Phosphorylation; Urine; base; mutant; nephrin; podocyte; prevent; slit diaphragm; trafficking

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(申请人提供)：局灶性节段性肾小球硬化(FSGS)是一种肾脏病变，见于多种疾病状态，在终末期肾脏疾病患者中占有重要地位。已经描述了几种遗传形式的FSGS。到目前为止，已发现的突变涉及足细胞中表达的蛋白质，对遗传FSGS的研究进一步加深了我们对足细胞如何帮助维持过滤屏障，防止蛋白质溢出到尿液中的理解。最近，钙通道TRPC6的突变被发现导致了一种常染色体显性的FSGS。已发现突变涉及TRPC6蛋白的几个不同区域，但它们如何影响TRPC6功能尚不清楚。我们提出了几条研究路线来表征基于细胞的和体外系统中的这些突变，包括对蛋白质稳定性、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家族成员的多聚体以及与足细胞裂隙隔膜的关键组件结合的能力。这些研究将进一步为TRPC6功能如何对足细胞正常功能起关键作用开辟新的研究途径。