Integrin-linked Kinase and Renal Interstitial Fibrosis

描述（由申请人提供）：管间质纤维化被认为是多种慢性肾脏疾病（CKD）的最终常见结果，无论其初始原因如何。间质纤维化的发病机制是一个非常单调的过程，其特征是产生基质的肌成纤维细胞的重新激活。有证据表明，很大一部分间质成纤维细胞实际上是由小管上皮细胞通过上皮向间充质转化（EMT）产生的。然而，管状EMT的机制仍然难以捉摸。申请人实验室的研究表明，整合素连接激酶（ILK）是一种细胞内丝氨酸/苏氨酸蛋白激酶，与（-整合素）的细胞质结构域相互作用，在介导小管EMT和肾间质纤维化中起着重要作用。该应用的中心假设是：1)ILK是多组分细胞机制的中心元素，ILK的功能取决于其与关键伙伴的相互作用；2) ILK在维持体内小管细胞表型和基质稳态中起重要作用；3) ILK是设计有效治疗慢性肾纤维化的主要分子靶点。这些假设将在以下四个具体目标中进行测试。目的1是研究ILK与其伙伴的相互作用，并阐明它们在介导管状EMT中的功能意义。目的2将描述PINCH在介导小管EMT和肾纤维化中的作用，PINCH是ILK的一个关键伙伴。目的3旨在通过条件敲除方法研究ILK在体内肾小管中的生理和病理作用。目的4评价ILK抑制剂治疗肾间质纤维化的疗效。这些研究不仅为理解CKD背景下肾小管EMT的调控提供了机制见解，而且还为设计慢性肾纤维化治疗的合理策略提供了独特的机会。

DESCRIPTION (provided by applicant): Tubulointerstitial fibrosis is considered as a final common outcome of a wide range of chronic kidney diseases (CKD), regardless of the initial causes. The pathogenesis of interstitial fibrosis is a remarkably monotonous process characterized by de novo activation of the matrix-producing myofibroblasts. Evidence indicates that a large proportion of interstitial fibroblasts are actually originated from tubular epithelial cells via epithelial to mesenchymal transition (EMT). However, the mechanism underlying tubular EMT remains elusive. Studies from the applicant's laboratory demonstrate that integrin-linked kinase (ILK), an intracellular serine/threonine protein kinase that interacts with the cytoplasmic domains of (-integrins, plays an imperative role in mediating tubular EMT and renal interstitial fibrogenesis. The central hypotheses of this application are that: 1) ILK is a central element of a multi-component cellular machinery, and the function of ILK depends on its interactions with key partners; 2) ILK plays an imperative role in the maintenance of tubular cell phenotypes and matrix homeostasis in vivo; and 3) ILK is a prime molecular target for designing an effective therapy for chronic renal fibrosis. These hypotheses will be tested in the following four specific Aims. Aim 1 is to investigate the ILK interactions with its partners and to elucidate their functional significance in mediating tubular EMT. Aim 2 will delineate the role of PINCH, a key partner of ILK, in mediating tubular EMT and renal fibrosis. Aim 3 is designed to investigate the physiologic and pathologic role of ILK in renal tubules in vivo by conditional knockout approach. Aim 4 will evaluate the therapeutic efficacy of ILK inhibitor for renal interstitial fibrosis. These studies will not only provide mechanistic insights into understanding the regulation of tubular EMT in the setting of CKD, but also offer unique opportunities for designing rational strategies for the treatment of chronic renal fibrosis.