Renal Myofibroblast: Origins, Activation and Fate

终末期肾病（End-stage renal disease， ESRD）是世界上最具破坏性的疾病之一，发病率和死亡率都很高，在世界范围内患者数量呈上升趋势。尽管原发性病因多种多样，但慢性肾脏疾病发展为ESRD的发病机制是一个非常单调的过程，其特征是细胞外基质（ECM）的持续积累导致广泛的组织纤维化。由于肾纤维化发生在(z-平滑肌肌动蛋白阳性、产生基质的肌成纤维细胞激活之前，因此找到一种抑制病变肾脏中肾肌成纤维细胞激活的策略可能是有效治疗进行性肾纤维化的关键。尽管如此，人们对肌成纤维细胞的起源、激活过程和命运知之甚少。在这项应用中，我们假设肌成纤维细胞起源于不同的起源，在肾间质纤维化的发病机制中具有不同的动力学，肌成纤维细胞的最终命运包括逆转为静止的成纤维细胞、凋亡和再分化为小管上皮细胞。我们建议通过体内和体外研究肾脏中活化的肌成纤维细胞的细胞起源、基因和信号及其激活的关键以及命运来验证这些假设。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治疗效果。这些将在四个特定目标中完成，即在全动物，细胞和分子水平上解决肌成纤维细胞的起源，激活，命运和治疗干预。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。

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.