Renal Myfibroblast: Origins and Activation

描述（由申请人提供）：小管间质纤维化是多种慢性肾脏疾病（CKD）的常见终点结果，在a-平滑肌肌动蛋白阳性肌成纤维细胞激活之前，a-平滑肌成纤维细胞是负责细胞外基质成分过度产生的主要效应细胞。这是R01竞争性更新申请的A1修订，建议继续我们的长期努力，阐明肾纤维化中肌成纤维细胞的起源、激活和调控。之前的研究

DESCRIPTION (provided by applicant): Tubulointerstitial fibrosis, a common endpoint outcome of a wide range of chronic kidney diseases (CKD), is preceded by activation of the a-smooth muscle actin-positive myofibroblasts, the principal effector cells that are responsible for the over-production of extracellular matrix components. This is the A1 revision of a R01 competitive renewal application, which proposes to continue our long- term efforts to elucidate the origins, activation and regulation of myofibroblasts in renal fibrogenesis. Studies in previous project period of this application indicate that dysregulated activation of key developmental signaling such as sonic hedgehog (Shh) and Wnt/beta-catenin plays a critical role in mediating fibroblast activation and renal fibrosis. In this renewal application, studies are designed to testa central hypothesis that Shh and Wnts mediate a two-way cross-talk between tubular epithelium and interstitial fibroblasts, and such 'epithelial-mesenchymal communication (EMC)' plays an essential role in promoting fibroblast activation and matrix production. The entire application consists of three specific aims. Aim 1 is to investigate the role of tubule-derived Shh in promoting fibroblast proliferation and activation. Aim 2 is to investigate the role of fibroblast-derived Wnts in mediating the fibrogenic responses of tubular epithelium. Aim 3 is to investigate the therapeutic effects of blocking Shh or/and Wnt signaling with small molecule inhibitors or endogenous antagonist on renal fibrosis. These studies promise to offer important insights into understanding how tubular injury in diseased kidneys drives fibroblast proliferation and activation, leading to excessive matrix production and scar formation. Undoubtedly, the data generated from this application will have wide implications in comprehending the pathogenesis of renal fibrosis after injury, as well as in designing future therapeutic regimens for treatment.