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.
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