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）：该赠款的总体目的是了解一种新型的细胞外基质蛋白在肾脏发育中的作用。在先前的工作中，我们已经表明，缺乏整合素A8亚基的绝大多数小鼠无法发展出跨肾脏的肾脏，而在输尿管芽中不足的最初表型进入了元eNapephric mesenchyrne，这是该整合素的表达位点。我们已经将肾膦素鉴定为在输尿管芽中表达的细胞外基质蛋白，该蛋白与整合素A8BL相关并适​​当分布以激活其配体依赖性信号通路。 因为缺乏A8BL的小鼠的元肢发育过程中的表型与缺少GDNF-GFRAL-C-RER信号途径的任何成分的小鼠非常相似，其中配体GDNF在中质中表达了配体GDNF，在中质和受体ununits gfral和C-ret互动中，我们可能会在uret firmes中表现出这些信号，我们可能会表现出这些信号。 A8BL导致通过该途径的信号效率降低。我们将确定介导细胞与肾膦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该ECM蛋白相互作用。在先前的工作中，通过细胞外基质成分对整联蛋白的配体参与可以调节发育的许多方面，包括通过与细胞骨架的相互作用以及通过激活细胞质骨骼的相互作用，包括ERK和JUN激酶，PI-3 Kinase和cdc-42/rade-42/rade fors cdc-42/rade fors cdc-rho，包括细胞增殖，迁移，分化和生存。我们将尝试通过A8BL的肾上腺素毒素启动来确定这些途径中的哪些途径，哪些途径因元eNephric间充质中不存在A8BL而损害了这些途径。