Role of a3a4a5(IV) collagen in podocyte behavior

a3a4a5(IV) 胶原蛋白在足细胞行为中的作用

• 批准号: 6827396
• 负责人: CORINA M BORZA
• 金额: $ 5.05万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-11 至 2006-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827396
• 关键词: Alport syndrome; basement membrane; biological signal transduction; cell adhesion; cell biology; cell migration; collagen; gene expression; glomerular filtration; kidney cell; postdoctoral investigator; protein protein interaction; protein purification; protein structure function; renal glomerulus; tissue /cell culture

DESCRIPTION (provided by applicant): Podocytes, endothelial cells, and the glomerular basement membrane (GBM) are the key components of the glomerular filtration barrier. The long term goal of this project is to understand how the composition of collagen IV in the GBM influences the behavior of podocytes (glomerular epithelial cells). Type IV collagen is expressed as an a1a1a2(IV) network in the immature GBM but is replaced by the a3a4a5(IV) network in the mature GBM. Failure to switch to the mature network due to mutations in any of the a3, a4 or a5 chains leads to Alport syndrome in humans and Alport-like phenotype in mouse and dog models of the disease. The mechanism whereby the a3a4a5(IV) collagen is required for the long term maintenance of the renal glomerular function is not known. We hypothesize that type IV collagen of the GBM, synthesized by podocytes, in turn provides signals to podocytes through integrins or other cellular receptors, which are required to maintain the appropriate podocyte function. To test this hypothesis, we will pursue two specific aims: (1) to express, isolate, and characterize the a3a4a5(IV) collagen in vitro; and (2) To define the influence of the a3a4a5(IV) collagen on the podocytes phenotype, including comparison of podocytes adhesion and migration on a3a4a5(IV) vs. a1a1a2(IV) collagen, identification of the podocyte integrins interacting with a3a4a5(IV) collagen, and identification of collagen IV domains that interact with podocytes. The successful completion of this project would help improve our understanding of the molecular defects in Alport syndrome, while broadening the applicant's research expertise and preparing her for the transition to an independent investigator status.

描述（由申请人提供）：足细胞、内皮细胞和肾小球基底膜（GBM）是肾小球滤过屏障的关键组成部分。该项目的长期目标是了解IV型胶原在GBM中的组成如何影响足细胞（肾小球上皮细胞）的行为。IV型胶原在未成熟的GBM中以a1a1a2（IV）网络表达，但在成熟的GBM中被a3a4a5（IV）网络所取代。由于a3、a4或a5链中的任何一个突变而无法切换到成熟网络，导致人类出现Alport综合征，小鼠和狗的疾病模型出现Alport样表型。a3a4a5（IV）胶原蛋白长期维持肾小球功能的机制尚不清楚。我们假设，由足细胞合成的GBM的IV型胶原，反过来通过整合素或其他细胞受体向足细胞提供信号，这是维持足细胞适当功能所必需的。为了验证这一假设，我们将追求两个具体目标：(1)在体外表达、分离和表征a3a4a5（IV）胶原蛋白；(2)确定a3a4a5（IV）胶原对足细胞表型的影响，包括比较a3a4a5（IV）与a1a1a2（IV）胶原对足细胞粘附和迁移的影响，鉴定与a3a4a5（IV）胶原相互作用的足细胞整合素，鉴定与足细胞相互作用的胶原IV结构域。该项目的成功完成将有助于提高我们对Alport综合征分子缺陷的理解，同时拓宽申请人的研究专业知识，为其过渡到独立研究者的身份做好准备。