The ILK/PINCH/Parvin complex in renal tubulogenesis

ILK/PINCH/Parvin 复合物在肾小管发生中的作用

• 批准号: 8543139
• 负责人: ROY ZENT
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543139
• 关键词: Acute; Adult; Affect; Amino Acids; Binding; Biochemical; Biological; Biological Process; Cell Culture Techniques; Cell physiology; Cells; Cellular biology; Chronic Kidney Failure; Complex; Comprehension; Cystic Kidney Diseases; Cytoplasmic Protein; Cytoplasmic Tail; Cytoskeleton; Development; Duct (organ) structure; Dysplasia; ECM receptor; Embryonic Development; Epithelial Cells; Etiology; Extracellular Matrix; Functional disorder; Funding; Goals; In Vitro; Individual; Injury; Integrin Binding; Integrins; Kidney; Kidney Diseases; Kidney Papilla; Knockout Mice; Knowledge; LIMS1 gene; Lead; Maintenance; Mass Spectrum Analysis; Mediating; Mesenchyme; Metanephric Diverticulum; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Nephrons; Phenocopy; Phosphotransferases; Play; Point Mutation; Polycystic Kidney Diseases; Population; Process; Recovery; Recruitment Activity; Relative (related person); Renal tubule structure; Role; Signal Transduction; Stable Isotope Labeling; Structure; Structure of mesonephric duct; System; Tail; Testing; Veterans; base; bladder trigone; collecting tubule structure; insight; integrin-linked kinase; mortality; mutant; nephrogenesis; novel; novel therapeutics; public health relevance; scaffold

DESCRIPTION (provided by applicant): Our overall goal is to define the molecular mechanisms whereby cell-extracellular matrix (ECM) interactions regulate renal tubulogenesis. Renal tubules are highly ordered terminally differentiated structures consisting of polarized epithelial cells derived from either the ureteric bud (UB) or the metanephric mesenchyme (MM). Because biological changes occurring during renal tubulogenesis are best characterized in the context of renal development, we use the UB as a model to study basic mechanisms of tubule formation. However these processes are also critically important in understanding the pathophysiology of congenital renal diseases such as polycystic kidney disease and renal dysplasia which affect the adult Veteran population. Furthermore, many features of renal tubule development are recapitulated in renal recovery following acute kidney tubule injury, which is a major cause of morbidity and mortality in Veterans. The UB originates from the Wolffian duct and gives rise to the collecting system of the mature kidney from the collecting ducts (CD) to the trigone of the bladder. The renal papilla and CDs develop by undergoing iterative branching morphogenesis, a complex process that is, at least in part, dependent on cell-ECM interactions. We previously demonstrated that integrins are critical for tubulogenesis. Integrins are transmembrane receptors for ECM composed of non-covalently bound and subunits. 1 is the most abundantly expressed integrin subunit in the kidney and can bind 12 different a subunits. The 1 cytoplasmic tail plays a critical role in integrn function by binding multiple cytoplasmic proteins which regulate integrin- mediated signaling and cytoskeleton modulation. The integrin linked kinase (ILK)/Pinch/Parvin (IPP) complex is one of the key scaffolding hubs that bind the integrin 1 cytoplasmic tail. We previously showed that ILK and Pinch are critical for tubule formation; however, the role of Parvin is still unknown. In this Merit renewal we will define how the IPP complex interacts with the 1 integrin tail and how specific interactions among the various IPP components regulate renal tubulogenesis by testing the hypotheses that a) distinct IPP components have specific roles in mediating renal tubulogenesis and b) IPP/1 integrin interactions are dynamically regulated by certain 1 tail residues. To test these hypotheses we will perform the following 3 aims. 1) Determine the mechanisms whereby ILK regulates development and maintenance of the kidney collecting system. 2) Determine the role of Parvin in the development and maintenance of the kidney collecting system. 3) Determine the mechanism whereby the 1 integrin cytoplasmic tail recruits the IPP complex. This study will generate novel insights into the molecular basis whereby 1 integrins and the ILK/Pinch/Parvin complex regulate renal tubulogenesis. Understanding this basic cell biological process will help with our comprehension of the pathophysiology of congenital renal diseases resulting in abnormal tubule formation as well as how tubules recover from acute injury. Ultimately a better understanding of these processes might lead to novel therapeutics for the treatment of renal disease caused by dysregulated tubule formation.

描述（由申请人提供）： 我们的总体目标是确定细胞-细胞外基质（ECM）相互作用调节肾小管发生的分子机制。肾小管是高度有序的终末分化结构，由来自输尿管的极化上皮细胞组成 芽（UB）或后肾间充质（MM）。由于肾小管发生过程中发生的生物学变化在肾脏发育的背景下得到最好的表征，因此我们使用 UB 作为模型来研究肾小管形成的基本机制。然而，这些过程对于了解影响成年退伍军人群体的先天性肾病（例如多囊肾病和肾发育不良）的病理生理学也至关重要。此外，肾小管发育的许多特征在急性肾小管损伤后的肾脏恢复中得到重现，这是退伍军人发病和死亡的主要原因。 UB起源于沃尔夫管，并产生从集合管（CD）到膀胱三角的成熟肾脏的集合系统。肾乳头和 CD 通过反复分支形态发生而发育，这是一个至少部分依赖于细胞-ECM 相互作用的复杂过程。我们之前证明整合素对于肾小管发生至关重要。整合素是 ECM 的跨膜受体，由非共价结合的 1 和 2 亚基组成。 1 是肾脏中表达最丰富的整合素亚基，可以结合 12 个不同的 a 亚基。 1 细胞质尾通过结合多种细胞质蛋白在整合素功能中发挥关键作用，这些蛋白质调节整合素介导的信号传导和细胞骨架调节。整合素连接激酶 (ILK)/Pinch/Parvin (IPP) 复合体是结合整合素 1 细胞质尾部的关键支架枢纽之一。我们之前表明 ILK 和 Pinch 对于肾小管形成至关重要；然而，帕尔文的角色仍然未知。在本次优点更新中，我们将通过测试以下假设来定义 IPP 复合物如何与 1 整合素尾部相互作用，以及各种 IPP 成分之间的特定相互作用如何调节肾小管发生：a) 不同的 IPP 成分在介导肾小管发生中具有特定作用，b) IPP /1 整合素相互作用受到某些 1 尾部残基的动态调节。为了检验这些假设，我们将实现以下 3 个目标。 1) 确定ILK调节肾集合系统发育和维护的机制。 2) 确定Parvin在肾集合系统发育和维护中的作用。 3) 确定 1 整合素胞质尾招募 IPP 复合物的机制。 这项研究将对 1 整合素和 ILK/Pinch/Parvin 复合物调节肾小管发生的分子基础产生新的见解。了解这一基本的细胞生物学过程将有助于我们理解导致肾小管形成异常的先天性肾病的病理生理学以及肾小管如何从急性损伤中恢复。最终，更好地了解这些过程可能会带来新的疗法，用于治疗由肾小管形成失调引起的肾脏疾病。