Renal Myfibroblast: Origins and Activation

描述(申请人提供)：肾小管间质纤维化是一系列慢性肾脏疾病(CKD)的共同终点结局，在此之前，α-平滑肌肌动蛋白阳性的肌纤维母细胞被激活，这是导致细胞外基质成分过度产生的主要效应细胞。这是对R01竞争性更新申请的A1修订，该申请建议继续我们的长期努力，以阐明肌成纤维细胞在肾脏纤维化形成中的起源、激活和调节。以前的研究 这项应用的项目期表明，关键发育信号的异常激活，如Sonic hedgehog(Shh)和Wnt/β-catenin，在介导成纤维细胞激活和肾脏纤维化中起着关键作用。在这一新的应用中，研究旨在检验一个中心假说，即Shh和Wnts介导肾小管上皮和间质成纤维细胞之间的双向串扰，这种“上皮-间充质沟通(EMC)”在促进成纤维细胞激活和基质产生方面起着至关重要的作用。整个申请由三个具体目标组成。目的1探讨小管源性Shh在促进成纤维细胞增殖和活化中的作用。目的2探讨成纤维细胞来源的WNTs在介导肾小管上皮细胞纤维化反应中的作用。目的3探讨小分子抑制剂或内源性拮抗剂阻断Shh或/和Wnt信号通路对肾纤维化的治疗作用。这些研究有望为理解病变肾脏的肾小管损伤如何推动成纤维细胞的增殖和激活，导致过度的基质产生和疤痕形成提供重要的见解。毫无疑问，这一应用所产生的数据将对理解损伤后肾纤维化的发病机制以及设计未来的治疗方案具有广泛的意义。

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.