Nephronectin-dependent signaling in kidney development

肾脏发育中的肾连接素依赖性信号传导

• 批准号: 6839960
• 负责人: Louis French Reichardt
• 金额: $ 20万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839960
• 关键词: JUN kinase; biological signal transduction; cell cell interaction; cell type; cytoplasmic receptors; extracellular matrix proteins; genetically modified animals; guanine nucleotide binding protein; histogenesis; immunocytochemistry; immunoprecipitation; integrins; laboratory mouse; mesenchyme; mitogen activated protein kinase; nephrogenesis; neurotrophic factors; phenotype; phosphatidylinositol 3 kinase; polymerase chain reaction; protein quantitation /detection; protein signal sequence; protein structure function; receptor binding; receptor expression; western blottings

DESCRIPTION (provided by applicant): The overall aim of this grant is to understand the role of a novel extracellular matrix protein named nephronectin in kidney development. In previous work, we have shown that the vast majority of mice lacking the integrin a8 subunit fail to develop the metanephric kidney with the initial phenotype of a deficit in ingrowth of the ureteric bud into the metanephric mesenchyrne, the site of expression of this integrin. We have identified nephronectin as an extracellular matrix protein expressed in the ureteric bud that is associated with the integrin a8bl and is distributed appropriately to activate its ligand-dependent signaling pathways. Because the phenotype during metanephric development of mice lacking a8bl is very similar to those of mice lacking any of the constituents of the GDNF-GFRal-c-ret signaling pathway, where the ligand GDNF is expressed in the mesenchyme and the receptor subunits GFRal and c-ret are expressed in the ureteric bud, we will examine possible interactions between these two signaling pathways and test the hypothesis that absence of a8bl results in reduced efficiency of signaling through this pathway. We will identify the receptors that mediate interactions of cells with nephronectin and determine which of the cell-types in the developing kidney interact directly with this ECM protein. In previous work, ligand engagement of integrins by extracellular matrix constituents has been shown to regulate many aspects of development including cellular proliferation, migration, differentiation and survival through interactions with the cytoskeleton and by activation of cytoplasmic signaling pathways including the ERK and Jun kinases, PI-3 kinase, and the cdc-42/radc-rho family of G proteins. We will attempt to determine which of these pathways are activated by nephronectin-engagement of a8bl and which are compromised by the absence of a8bl in the metanephric mesenchyme.

描述（由申请人提供）：该基金的总体目标是了解一种名为肾连蛋白的新型细胞外基质蛋白在肾脏发育中的作用。在以前的工作中，我们已经表明，绝大多数缺乏整合素α 8亚基的小鼠不能发展后肾肾，其初始表型为输尿管芽向内生长到后肾间充质（该整合素的表达部位）中的缺陷。我们已经确定肾连蛋白作为细胞外基质蛋白表达在输尿管芽，是与整合素a8 bl和适当分布激活其配体依赖性信号通路。 由于缺乏a8 bl的小鼠的后肾发育期间的表型与缺乏GDNF-GFR α 1-c-ret信号传导途径的任何组分的小鼠的表型非常相似，其中配体GDNF在间充质中表达，受体亚基GFR α 1和c-ret在输尿管芽中表达，我们将检验这两种信号传导途径之间可能的相互作用，并检验A8 BL的缺失导致通过该途径的信号传导效率降低的假设。我们将鉴定介导细胞与肾连蛋白相互作用的受体，并确定发育中的肾脏中哪种细胞类型直接与这种ECM蛋白相互作用。在以前的工作中，整合素的配体参与细胞外基质成分已被证明可以调节许多方面的发展，包括细胞增殖，迁移，分化和生存，通过与细胞骨架的相互作用，并通过激活细胞质信号传导途径，包括ERK和Jun激酶，PI-3激酶，和G蛋白的cdc-42/radc-rho家族。我们将试图确定这些途径中的哪一个是由肾连接蛋白与a8 bl的结合激活的，哪一个是由后肾间充质中a8 bl的缺失所损害的。