Renal Myofibroblast: Origins, Activation and Fate

描述（申请人提供）：终末期肾病（ESRD）是最具破坏性的疾病之一，发病率和死亡率都很高，全球范围内患者数量呈上升趋势。尽管主要病因多种多样，但进展为ESRD的慢性肾脏疾病的发病机制是一个非常单调的过程，其特征在于细胞外基质（ECM）的不断积累，导致广泛的组织纤维化。由于肾纤维化之前是α-平滑肌肌动蛋白阳性的、产生基质的肌成纤维细胞的活化，因此有效治疗进行性肾纤维化的可能关键是找到抑制患病肾脏中肾肌成纤维细胞活化的策略。尽管如此，对肌成纤维细胞的起源、激活过程和命运知之甚少。在本申请中，我们假设肌成纤维细胞来源于不同的来源，在肾间质纤维化的发病机制中具有不同的动力学，并且肌成纤维细胞的最终命运包括逆转为静止成纤维细胞、凋亡和再分化为肾小管上皮细胞。我们建议通过研究细胞起源，基因和信号转导的关键，他们的激活和命运的激活肌成纤维细胞在肾脏中的体内和体外测试这些假设。我们还将评估旨在抑制慢性肾纤维化肌成纤维细胞活化的新治疗方案的疗效。这些将在四个具体目标中实现，这些目标在整个动物、细胞和分子水平上解决肌成纤维细胞的起源、活化、命运和治疗干预。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。

DESCRIPTION (provided by applicant): End-stage renal disease (ESRD) is one of the most devastating diseases with great morbidity and mortality, and the number of patients is on the rise worldwide. Despite diverse primary etiologies, the pathogenesis of chronic renal diseases progressing to ESRD is a remarkably monotonous process characterized by relentless accumulation of extracellular matrix (ECM) leading to widespread tissue fibrosis. Because renal fibrosis is preceded by activation of (z-smooth muscle actin-positive, matrix-producing myofibroblasts, a possible key to an effective therapy for progressive renal fibrosis is to find a strategy that inhibits the activation of renal myofibroblasts in the diseased kidney. Despite this, little is known as to the origins, activation process, and fate of myofibroblasts. In this application, we hypothesize that myofibroblasts originate from diverse origins with distinct dynamics in the pathogenesis of renal interstitial fibrosis and that the ultimate fate of myofibroblasts includes reversal to quiescent fibroblasts, apoptosis, and re-differentiation to tubular epithelial cells. We propose to test these hypotheses by investigating the cellular origins, the genes and signaling critical for their activation and the destiny of activated myofibroblasts in the kidney both in vivo and in vitro. We will also evaluate the therapeutic efficacy of new treatment regimes aimed at inhibition of myofibroblast activation for chronic renal fibrosis. These will be accomplished in the four specific aims, which address the origins, activation, fate and therapeutic intervention of myofibroblast cells at whole animal, cellular iand molecular levels. 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.