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lntegrin binding proteins and the kidney

整合素结合蛋白和肾脏

基本信息

批准号：
10587019
负责人：
ROY ZENT
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587019
关键词：
Actins Affect Amino Acids Binding Binding Proteins Bundling Cell Adhesion Cell Polarity Cell Proliferation Cell physiology Chronic Chronic Kidney Failure Complex Cytoplasmic Protein Cytoplasmic Tail Cytoskeleton Data Defect Development Ductal Epithelial Cell ECM receptor Embryonic Development Epithelial Cells F-Actin Family Fibrosis Guanosine Triphosphate Phosphohydrolases Homeostasis Injury Injury to Kidney Integrin Binding Integrins Kidney Kidney Diseases Knowledge LIMK1 gene Mediating Membrane Microfilaments Mission Modality Modeling Mus Mutation Obstruction Pathway interactions Phenotype Process Proliferating Recovery Regulation Renal tubule structure Role Scaffolding Protein Signal Pathway Signal Transduction System Testing Tissues Tubular formation Veterans Wild Type Mouse cofilin depolymerization effective therapy improved injury recovery insight integrin-linked kinase interest kidney fibrosis kidney repair kinase inhibitor mechanical signal migration mouse model mutant nephrogenesis novel novel therapeutics prevent protein complex receptor repaired response response to injury rho rho GTP-Binding Proteins scaffold small molecule small molecule inhibitor transmission process

项目摘要

A hallmark of chronic kidney disease (CKD) is advancing tubulointerstitial (TI) fibrosis. While new mechanisms of fibrosis have been uncovered in recent decades, effective treatment to directly halt or reverse this process remains elusive. Our group has a long-standing interest in defining how extracellular matrix (ECM) receptors such as integrins and their binding partners regulate kidney development and response to injury. Among the integrin binding partners, we focus on the integrin linked kinase (ILK); pinch; α-parvin complex of scaffold proteins, also known as the IPP complex. We recently uncovered a novel modality to interfere with integrin dependent signaling pathways mediated by the IPP complex that may represent a new strategy to treat and prevent TI fibrosis and ultimately CKD. Integrins are transmembrane receptors composed of non-covalently bound α and β subunits. β1 is the most abundantly expressed subunit in the kidney and can bind 12 different α subunits. The β1 cytoplasmic tail functions by binding multiple cytoplasmic proteins which regulate integrin-mediated signaling and cytoskeleton modulation. The IPP complex is a major scaffolding hub that binds the integrin β1 cytoplasmic tail and its key function is to bundle actin filaments, thereby transmitting mechanical signals between integrins and the actin cytoskeleton. A normal actin cytoskeleton is required for most cell functions necessary for embryonic development and recovery of tissue from injury. ILK is the major scaffold protein that brings the IPP complex together; however, the α and β parvins are the major IPP complex proteins that regulate the actin cytoskeleton. We have preliminary evidence that α-parvin is required for normal kidney development and repair after injury. Deletion of α-parvin in mice at the initiation of the kidney collecting system (E10.5) causes severely dysmorphic kidneys with excessive basolateral F-actin. We also provide evidence that deleting α-parvin in the fully developed kidney collecting system (E 18.5) results in excessive tubular injury following a unilateral ureteric obstruction (UUO) model. Mice carrying a mutant ILK unable to bind to α-parvin (K-to-M mutation in a.a. 220: ILK-K220M mice) in the developing collecting system develop normally and wild-type mice treated with the small molecule Csbl-1 (that interferes with the ILK-α-parvin interaction) have decreased renal fibrosis following UUO. These data strongly suggest that α-parvin performs multiple cellular functions that are independent of its interactions with ILK and paradoxically disrupting ILK binding to α-parvin improves the response of the kidney to injury. Finally, we have evidence that α-parvin-null collecting duct (CD) cells have excessive F-actin formation, increased cell adhesion, spreading and migration as well as a profound increase in activated RhoA and Cdc42. Based on these data, we hypothesize that α-parvin-mediated regulation of actin dynamics via Rho-GTPase signaling promotes kidney tubule development, homeostasis, and recovery from injury. This hypothesis will be tested in the following 2 aims. Aim 1. Determine the role of α-parvin in kidney tubule development and injury. We will test the hypothesis that α-parvin-mediated actin filament bundling is required for normal kidney tubule development and protection from injury. Aim 2. Determine the mechanisms whereby α-parvin regulates actin-bundling dependent epithelial cell function. We will test the hypothesis that α-parvin-mediated inhibition of RhoA and Cdc42 activity promotes cofilin-mediated actin turnover dependent epithelial cell polarity and proliferation that is required for normal tubule formation and repair.

慢性肾病（CKD）的一个标志是肾小管间质（TI）纤维化。虽然新机制近几十年来，纤维化的研究已经发现，有效的治疗方法可以直接阻止或逆转这一过程，仍然难以捉摸我们的团队长期以来一直致力于确定细胞外基质（ECM）受体如整联蛋白及其结合配偶体调节肾脏发育和对损伤的反应。中整合素结合伴侣，我们专注于整合素连接激酶（ILK）;捏; α-parvin复合物的支架蛋白质，也称为IPP复合物。我们最近发现了一种新的方式来干扰整合素由IPP复合物介导的依赖性信号通路可能代表了一种治疗和预防TI纤维化和最终的CKD。整合素是由非共价结合的α和β亚基组成的跨膜受体。β1是最在肾脏中大量表达的亚基，可结合12种不同的α亚基。β1胞质尾区通过结合多种调节整合素介导的信号传导和细胞骨架的细胞质蛋白发挥作用调变IPP复合物是结合整合素β1胞质尾区的主要支架枢纽，其功能是使肌动蛋白丝成束，从而在整合素和肌动蛋白之间传递机械信号。细胞骨架正常的肌动蛋白细胞骨架是胚胎发育所必需的大多数细胞功能所必需的。组织从损伤中的发育和恢复。ILK是将IPP复合物然而，α和β parvins是调节肌动蛋白细胞骨架的主要IPP复合物蛋白。我们有初步证据表明，α-parvin是正常肾脏发育和损伤后修复所必需的。在小鼠肾脏收集系统（E10.5）启动时α-parvin的缺失导致严重的畸形基底外侧F肌动蛋白过多的肾脏我们还提供了证据，删除α-parvin在充分发展的肾集合系统（E 18.5）导致单侧输尿管梗阻后过度肾小管损伤 (UUO)模型携带不能与α-parvin结合的突变ILK的小鼠（a.a.第220章：一个人小鼠）正常发育，而用小分子处理的野生型小鼠 Csbl-1（干扰ILK-α-parvin相互作用）可减少UUO后的肾纤维化。这些数据有力地表明，α-parvin执行多种细胞功能，这些功能与其相互作用无关与ILK结合并矛盾地破坏ILK与α-parvin的结合改善了肾脏对损伤的反应。最后，我们有证据表明α-parvin无效的集合管（CD）细胞有过量的F-肌动蛋白形成，增加的细胞粘附、扩散和迁移以及活化的RhoA和Cdc 42的显著增加。基于这些数据，我们假设α-parvin通过Rho-GTdR介导的肌动蛋白动力学调节信号传导促进肾小管发育、体内平衡和从损伤中恢复。这一假设将在以下两个目标中进行测试。目标1.确定α-parvin在肾小管发育和损伤中的作用。我们将检验这个假设 α-parvin介导的肌动蛋白丝成束是正常肾小管发育所必需的，保护免受伤害。目标2.确定α-parvin调节肌动蛋白集束依赖性上皮细胞的机制功能我们将检验α-parvin介导的RhoA和Cdc 42活性抑制促进cofilin介导的肌动蛋白周转依赖性上皮细胞极性和增殖，正常的肾小管形成和修复所需的。