Renal myofibroblast: Origin, Activation and Fate

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）进展为终末期肾衰竭的常见终点结果，在a-平滑肌肌动蛋白阳性肌成纤维细胞激活之前，主要效应细胞负责过度生产细胞外基质成分。此次重新提交竞争性更新申请是我们长期努力阐明肾成纤维细胞在肾纤维化中的起源、激活过程和命运的延续。本项目前期的研究表明，肌成纤维细胞可能来源于两个主要来源：通过表型激活的间质成纤维细胞和通过上皮-间质转化（EMT）的小管上皮细胞。在这个更新的应用程序中，我们建议研究导致EMT和成纤维细胞激活的分子机制和信号通路。需要验证的中心假设是：1)转录抑制剂Id1和Id3通过诱导小管上皮去分化和增强肾脏炎症，促进小管上皮向间质转化（EMT）；2) tPA作为促纤维化细胞因子，促进间质成纤维细胞的存活和增殖及其肌成纤维细胞的活化。这些假设将分别在整个动物，细胞和分子水平上通过三个具体目标来解决。Aim 1旨在研究转录抑制剂Id蛋白在介导小管EMT和肾脏炎症中的调控和功能。目的2是研究tPA在间质肌成纤维细胞活化中的作用，并剖析导致其作用的信号通路。目的3：探讨tPA在成纤维细胞和肌成纤维细胞存活和增殖中的作用。这些研究将为理解小管上皮细胞和间质成纤维细胞的肌成纤维细胞的激活机制提供基础和重要的见解。这些基本问题的解决不仅将为慢性肾纤维化的发病机制提供深入的见解，而且还将为设计合理的治疗这种毁灭性疾病的策略提供独特的机会。据估计，高达11%的美国成年人患有某种程度的慢性肾脏疾病（CKD），延迟CKD的进展仍然是一个未解决的问题。本应用程序中提出的研究有望为理解肾脏基质生成肌成纤维细胞在CKD发病机制中的起源、激活和命运提供重要见解。解决这些基本问题可能为设计治疗人类慢性肾病的合理策略提供独特的机会。

DESCRIPTION (provided by applicant): Tubulointerstitial fibrosis, a common endpoint outcome of a wide range of chronic kidney diseases (CKD) that progress to end-stage renal failure, 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 resubmission of a competitive renewal application is a continuation of our long-term efforts to elucidate the origins, activation process and fate of renal myofibroblasts in renal fibrogenesis. Studies in previous project period of this application suggest that myofibroblasts may originate from two major sources: from interstitial fibroblasts via a phenotypic activation and from tubular epithelial cells via epithelial-mesenchymal transition (EMT). In this renewal application, we propose to investigate the molecular mechanism and signal pathways leading to EMT and fibroblast activation. The central hypotheses to be tested are that: 1) transcriptional inhibitors Id1 and Id3 promote tubular epithelial to mesenchymal transition (EMT), via inducing tubular epithelial dedifferentiation and via potentiating renal inflammation; 2) tPA acts as a profibrotic cytokine that promotes the survival and proliferation of interstitial fibroblasts and their myofibroblastic activation. These hypotheses will be addressed by three specific aims at the whole animal, cellular and molecular levels, respectively. Aim 1 is designed to investigate the regulation and function of transcriptional inhibitor Id proteins in mediating tubular EMT and renal inflammation. Aim 2 is to investigate the role of tPA in interstitial myofibroblast activation and to dissect the signaling pathway leading to its action. Aim 3 is to investigate the role of tPA in fibroblast and myofibroblast survival and proliferation. These studies will provide fundamental and important insights into understanding the activation mechanisms of myofibroblasts from both tubular epithelial cells and interstitial fibroblasts. Resolution of these fundamental issues will not only provide mechanistic insights into the pathogenesis of chronic renal fibrosis, but also offers unique opportunities for designing rational strategies for the treatment of this devastating disease. PUBLIC HEALTH RELEVANCE It is estimated that up to 11% of the US adult population has some degree of chronic kidney disease (CKD), and delaying the progression of CKD is still unsolved problem. The studies proposed in this application promises to provide important insights into understanding the origins, activation and fate of renal matrix-producing myofibroblasts in the pathogenesis of CKD. Resolution of these fundamental issues may offer unique opportunities for designing rational strategies for the treatment of human CKD.