Renal Myfibroblast: Origins and Activation

描述（由申请方提供）：肾小管间质纤维化是多种慢性肾脏疾病（CKD）的常见终点结局，在其发生之前，α-平滑肌肌动蛋白阳性肌成纤维细胞（负责细胞外基质成分过度产生的主要效应细胞）被激活。这是R 01竞争性更新申请的A1修订版，其建议继续我们的长期努力，以阐明肾纤维化中肌成纤维细胞的起源，激活和调节。以往的研究 本申请项目期间的研究表明，关键发育信号传导如音刺猬（Shh）和Wnt/β-连环蛋白的失调激活在介导成纤维细胞活化和肾纤维化中起关键作用。在该更新申请中，研究旨在测试中心假设，即Shh和Wnts介导肾小管上皮细胞和间质成纤维细胞之间的双向串扰，并且这种“上皮-间质通讯（EMC）”在促进成纤维细胞活化和基质产生中起着至关重要的作用。整个应用程序包括三个具体目标。目的1研究肾小管源性Shh对成纤维细胞增殖和活化的促进作用。目的二是研究成纤维细胞来源的Wnt在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。这些研究有望为了解病变肾脏中的肾小管损伤如何驱动成纤维细胞增殖和活化，导致过度基质产生和瘢痕形成提供重要见解。毫无疑问，从该应用程序中产生的数据将在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方面具有广泛的意义。

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.