Integrin-linked Kinase and Renal Interstitial Fibrosis

整合素连接激酶与肾间质纤维化

• 批准号: 6912066
• 负责人: YOUHUA LIU
• 金额: $ 26.53万
• 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/6912066
• 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（由申请方提供）：肾小管间质纤维化被认为是各种慢性肾脏疾病（CKD）的最终常见结局，无论最初原因如何。间质纤维化的发病机制是一个非常单调的过程，其特征在于产生基质的肌成纤维细胞的重新激活。有证据表明，大部分间质成纤维细胞实际上是通过上皮间质转化（EMT）起源于肾小管上皮细胞。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），一种与α-整合素的胞质结构域相互作用的细胞内丝氨酸/苏氨酸蛋白激酶，在介导肾小管EMT和肾间质纤维化中起着重要作用。本申请的中心假设是：1）ILK是多组分细胞机制的中心元件，并且ILK的功能取决于其与关键配偶体的相互作用; 2）ILK在体内维持肾小管细胞表型和基质稳态中起重要作用;和3）ILK是用于设计慢性肾纤维化的有效疗法的主要分子靶标。这些假设将在以下四个具体目标中进行检验。目的1研究ILK与其配偶体之间的相互作用及其在介导肾小管上皮细胞转分化中的功能意义。目的2将描述PINCH，ILK的关键伙伴，在介导肾小管EMT和肾纤维化中的作用。目的3通过条件性基因敲除技术研究肾小管间充质细胞内IL-1激酶在体内的生理和病理作用。目的4评价ILK抑制剂对肾间质纤维化的治疗作用。这些研究不仅将为了解CKD背景下肾小管EMT的调节提供机制性见解，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。