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）：这项资助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。在之前的工作中，我们已经表明，绝大多数缺乏整合素a8亚基的小鼠无法发育出后肾，其初始表型是输尿管芽向内生长到后肾间质（该整合素的表达位点）的缺陷。我们已经将肾连接素鉴定为在输尿管芽中表达的细胞外基质蛋白，其与整合素a8bl相关并且适当分布以激活其配体依赖性信号传导途径。 由于缺乏 a8bl 的小鼠后肾发育过程中的表型与缺乏 GDNF-GFRal-c-ret 信号通路任何成分的小鼠非常相似，其中配体 GDNF 在间充质中表达，受体亚基 GFRal 和 c-ret 在输尿管芽中表达，因此我们将检查这两种信号通路之间可能存在的相互作用，并检验以下假设： a8bl 的减少导致通过该途径的信号传导效率降低。我们将鉴定介导细胞与肾连蛋白相互作用的受体，并确定发育中肾脏中的哪些细胞类型直接与该 ECM 蛋白相互作用。在之前的研究中，细胞外基质成分与整合素的配体结合已被证明可以通过与细胞骨架的相互作用以及通过激活细胞质信号通路（包括ERK和Jun激酶、PI-3激酶和G蛋白的cdc-42/radc-rho家族）来调节发育的许多方面，包括细胞增殖、迁移、分化和存活。我们将尝试确定这些途径中哪些途径是通过 a8bl 的肾连接素结合而激活的，哪些途径是由于后肾间质中 a8bl 的缺失而受到损害。