The ILK/PINCH/Parvin complex in renal tubulogenesis

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形成的分子机制。肾小管是高度有序的终末分化结构，由来自输尿管上皮细胞和肾小管上皮细胞的极化上皮细胞组成。 芽（UB）或后肾间充质（MM）。由于肾小管形成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，我们使用UB作为模型来研究肾小管形成的基本机制。然而，这些过程对于理解影响成年退伍军人群体的先天性肾脏疾病（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恢复中重现，这是退伍军人发病率和死亡率的主要原因。 UB起源于Wolffian管，并从集合管（CD）到膀胱三角区形成成熟肾脏的集合系统。肾乳头和CD通过经历反复的分支形态发生而发展，这是一个复杂的过程，至少部分依赖于细胞-ECM相互作用。我们以前证明，整合素是至关重要的小管。整合素是ECM的跨膜受体，由非共价结合的和亚基组成。1是肾脏中表达最丰富的整联蛋白亚基，可以结合12种不同的α亚基。1胞质尾区通过结合多种胞质蛋白调节整合素介导的信号传导和细胞骨架调节在整合素功能中起关键作用。整合素连接激酶（ILK）/Pinch/Parvin（IPP）复合物是结合整合素1胞质尾区的关键支架枢纽之一。我们先前表明ILK和Pinch对小管形成至关重要;然而，Parvin的作用仍然未知。在本次Merit更新中，我们将通过检验以下假设来定义IPP复合物如何与1整联蛋白尾部相互作用以及各种IPP组分之间的特异性相互作用如何调节肾小管形成：a）不同的IPP组分在介导肾小管形成中具有特定作用，以及B）IPP/1整联蛋白相互作用受某些1尾部残基的动态调节。为了验证这些假设，我们将执行以下3个目标。1)确定ILK调节肾脏收集系统发育和维持的机制。2)确定Parvin在肾脏收集系统的发育和维持中的作用。3)确定1整合素胞质尾区募集IPP复合物的机制。 这项研究将产生新的见解的分子基础，其中1整合素和ILK/捏/Parvin复合物调节肾小管。了解这一基本的细胞生物学过程将有助于我们理解导致异常肾小管形成的先天性肾脏疾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导致新的治疗方法，用于治疗由肾小管形成失调引起的肾脏疾病。

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.