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）： 我们的总体目标是定义分子机制，通过该机制，细胞 - 授予细胞基质（ECM）相互作用调节肾小管发生。肾小管小管是高度有序的终端分化结构，由衍生自ureteric的极化上皮细胞组成 芽（UB）或元脑间质（mm）。由于在肾小管发生过程中发生的生物学变化在肾发育的背景下最好地表征了，因此我们将UB作为研究小管形成的基本机制的模型。但是，这些过程对于理解先天性肾脏疾病的病理生理学（如多囊肾脏疾病和影响成年退伍军人人群）的病理生理也至关重要。此外，急性肾小管损伤后肾脏恢复中概括了肾小管发育的许多特征，这是退伍军人发病率和死亡率的主要原因。 UB起源于Wolffian管道，并从收集管道（CD）到膀胱的三角形产生成熟肾脏的收集系统。肾乳头和CD通过进行迭代分支形态发生而发展，这是一个复杂的过程，至少部分取决于细胞ECM相互作用。我们先前证明整联蛋白对于微管生成至关重要。整合素是由非共价结合和亚基组成的ECM的跨膜受体。 1是肾脏中最丰富的整联蛋白亚基，可以结合12个不同的亚基。 1个细胞质尾巴通过结合多种细胞质蛋白来调节整合素介导的信号传导和细胞骨架调制，在整合功能中起关键作用。整联蛋白连接的激酶（ILK）/Pinch/Parvin（IPP）复合物是结合整联蛋白1细胞质尾巴的关键脚手架。我们先前表明，幼虫和捏对于小管的形成至关重要。但是，帕尔文的作用仍然未知。在此功绩更新中，我们将定义IPP复合物如何与1个整合素尾巴相互作用，以及各种IPP组件之间的特定相互作用如何通过测试假设的假设来调节肾小管生成，即A）不同的IPP组件在介导肾小管肾小管生成和B）IPP/1整合蛋白相互作用中具有特定的作用在介导的肾小管中的特定作用受到IPP/1整合蛋白相互作用受到某些动态调节的尾巴。为了检验这些假设，我们将执行以下3个目标。 1）确定ILK调节肾脏收集系统的发展和维护的机制。 2）确定帕尔文在肾脏收集系统的开发和维护中的作用。 3）确定1个整合素细胞质尾巴募集IPP复合物的机制。 这项研究将产生对分子基础的新见解，在该基础上，1整联蛋白和ILK/PINCH/PARVIN复合物调节肾小管发生。了解这一基本细胞生物学过程将有助于我们理解先天性肾脏疾病的病理生理学，从而导致异常小管形成以及小管从急性损伤中恢复。最终，对这些过程的更好理解可能会导致新的治疗肾小管形成引起的肾脏疾病的治疗方法。