Sonic Hedgehog信号通路在肾纤维化中的作用

Tubulointerstitial fibrosis, a common endpoint outcome of a wide range of chronic kidney diseases (CKD), is preceded by activation of the?α-smooth muscle actin-positive myofibroblasts, the principal effector cells that are responsible for the over-production of extracellular matrix. This application proposes to elucidate the activation and regulation of myofibroblasts in renal fibrogenesis. Recent studies from the applicant laboratory indicate that dysregulated activation of developmental sonic hedgehog (Shh) signaling plays a critical role in mediating fibroblast activation and renal fibrosis. In this application, studies are designed to test a central hypothesis that Shh, through mediating an 'epithelial-mesenchymal communication (EMC)', plays an essential role in promoting fibroblast activation, extracellular matrix production and renal fibrosis. The entire application consists of three specific aims. Aim 1 is to investigate the regulation of Shh in various models of CKD and to elucidate the underlying mechanisms. Aim 2 is to investigate the role of Shh in mediating fibroblast proliferation and phenotypic activation, as well as to investigate its role in mediating tubular cell injury. Aim 3 is to investigate the role of Shh in renal fibrogenesis in vivo by using mouse model with tubule-specific, conditional knockout of Shh, and by blocking Shh signaling with small molecule inhibitor. These studies promise to offer important insights into understanding how tubule-derived Shh 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.

肾间质纤维化是几乎所有类型慢性肾脏疾病(CKD)发展至终末期共同的病理损害，目前尚无有效治疗手段。因为肌成纤维细胞是肾脏纤维化过程中细胞外基质的主要来源，因此阐明它们的激活及其调节机制具有重要意义。申请人长期从事肾脏纤维化的基础性研究，系统研究了相关的关键细胞和分子信号通路。根据本项目组研究结果，我们提出：肾小管来源的Sonic hedgehog(Shh)能够诱导成纤维细胞激活，促进其增殖，并产生大量的细胞外基质。为验证这一工作假说，我们将研究Shh在各种CKD模型中的表达调节并探讨其机制、研究Shh在体外对成纤维细胞的增殖和激活的调节。并通过构建肾小管特异的、条件性Shh敲除小鼠模型，研究Shh缺失对CKD发生发展的影响。利用小分子抑制剂来评估靶向抑制Shh信号防治肾脏纤维化的可行性和有效性。这些研究对阐明肾脏纤维化的机制、制定有效的干预策略具有深远的意义和临床实用价值。

肾间质纤维化是几乎所有类型慢性肾脏疾病(CKD)发展至终末期共同的病理损害，目前尚无有效治疗手段。本项目系统研究了音猬信号(Shh)通路在CKD发生发展中的作用。其总体研究目标是1、分析Shh在CKD中的表达调控及其机制；2、分析Shh对成纤维细胞激活和肾小管上皮细胞损伤的影响3、分析条件性删除Shh对CKD进展的影响以及评价靶向抑制Shh的疗效。我们的主要研究结果是：1、发现“肾小管上皮-间充质细胞对话” (EMC) 新机制；2、发现肾素-血管紧张素系统(RAS)是Wnt/β-catenin下游新的靶基因；3、发现Wnt信号放大器、并提出肾小管上皮来源的Wnt在肾纤维化进程中的作用；4、阐明究Shh对肾小管上皮细胞的生物学效应；5、阐明肾小管shh条件性删除对肾脏纤维化的影响。这些研究结果以论文形式在本领域顶级杂志发表，目前共发表通讯作者论文9篇（其中4篇原创论文发表在肾脏病领域顶级期刊J Am Soc Nephrol)。论文分别获编辑部述评，Faculty of 1000推荐，获登JASN封面2次。论文总影响因子59.9, 平均单篇影响因子 7.49。这些研究对阐明肾脏纤维化的生物学机制、制定有效的干预策略具有深远的理论意义和潜在的临床实用价值。