Integrin-linked Kinase and Renal Interstitial Fibrosis

整合素连接激酶与肾间质纤维化

• 批准号: 7068667
• 负责人: YOUHUA LIU
• 金额: $ 25.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068667
• 关键词: DNA binding protein; cell differentiation; cellular pathology; extracellular matrix; fibroblasts; fibrogenesis; fibrosis; genetically modified animals; integrins; interstitial; kidney disorder; kidney disorder chemotherapy; kinase inhibitor; laboratory mouse; nonhuman therapy evaluation; protein protein interaction; renal tubule; serine threonine protein kinase; small molecule; transforming growth factors

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.

描述(由申请人提供)：肾小管间质纤维化被认为是一系列慢性肾脏疾病(CKD)的最终共同结果，而不考虑最初的原因。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重新激活。有证据表明，很大比例的间质成纤维细胞实际上是通过上皮向间充质转化(EMT)起源于肾小管上皮细胞。然而，小管EMT的机制仍然不清楚。来自申请人实验室的研究表明，整合素连接的激酶(ILK)是一种细胞内的丝氨酸/苏氨酸蛋白激酶，它与(-整合素)的细胞质结构域相互作用，在介导肾小管上皮细胞转化和肾间质纤维化中发挥重要作用。这一应用的中心假设是：1)ILK是多组分细胞结构的中心元件，其功能取决于其与关键伙伴的相互作用；2)ILK在体内维持肾小管细胞表型和基质稳态方面起着至关重要的作用；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得到检验。目的1研究ILK与其伴侣之间的相互作用，并阐明它们在介导肾小管上皮细胞转化中的功能意义。目标2将描述ILK的关键合作伙伴PINCH在介导肾小管EMT和肾纤维化中的作用。目的用条件性基因敲除的方法研究ILK在活体肾小管中的生理和病理作用。目的评价ILK抑制剂对肾间质纤维化的治疗效果。这些研究不仅为理解肾小管上皮细胞间质转化在慢性肾脏病中的作用提供了机制上的见解，而且为设计合理的治疗慢性肾纤维化的策略提供了独特的机会。