Renal myofibroblast: Origin, Activation and Fate

描述（由申请人提供）：肾小管间质纤维化是进展为终末期肾衰竭的多种慢性肾脏疾病（CKD）的常见终点结局，在其之前是α-平滑肌肌动蛋白阳性肌成纤维细胞（负责细胞外基质组分过度产生的主要效应细胞）的活化。重新提交的竞争性更新申请是我们长期努力的延续，以阐明肾纤维化中肾肌成纤维细胞的起源，激活过程和命运。本申请前期项目期间的研究表明，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-间充质转化（EMT）的肾小管上皮细胞。在这个更新的应用程序中，我们建议调查的分子机制和信号通路，导致EMT和成纤维细胞活化。待检验的中心假设是：1）转录抑制剂Id 1和Id 3通过诱导肾小管上皮细胞去分化和通过增强肾脏炎症促进肾小管上皮细胞向间质细胞转化（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纤维母细胞活化。这些假设将通过三个具体的目标，在整个动物，细胞和分子水平，分别解决。目的1研究转录抑制因子Id蛋白在肾小管上皮细胞转分化和肾脏炎症中的调控作用。目的二是研究tPA在间质肌成纤维细胞活化中的作用，并分析其信号通路。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。这些研究将为了解肾小管上皮细胞和间质成纤维细胞的肌成纤维细胞的活化机制提供基础和重要的见解。这些基本问题的解决将不仅提供机制的见解慢性肾纤维化的发病机制，但也提供了独特的机会，设计合理的策略来治疗这种毁灭性的疾病。据估计，高达11%的美国成年人口患有一定程度的慢性肾脏疾病（CKD），延缓CKD的进展仍然是未解决的问题。本申请中提出的研究有望为了解CKD发病机制中产生肾基质的肌成纤维细胞的起源、激活和命运提供重要见解。这些基本问题的解决可能为设计合理的人类CKD治疗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.