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，具有极高的发病率和死亡率，全球患者数量呈上升趋势。尽管病因多种多样，但慢性肾脏疾病进展到终末期肾病的发病机制是一个非常单调的过程，其特点是细胞外基质(ECM)的持续堆积导致广泛的组织纤维化。由于肾脏纤维化发生在(z-平滑肌肌动蛋白阳性的、产生基质的肌纤维母细胞)激活之前，因此有效治疗进行性肾纤维化的一个可能的关键是找到一种策略来抑制病变肾脏中的肾脏肌成纤维细胞的激活。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。在这一应用中，我们假设肌成纤维细胞起源于不同的来源，在肾间质纤维化的发病机制中具有不同的动力学特征，并且肌成纤维细胞的最终命运包括逆转为静止的成纤维细胞、凋亡和重新分化为肾小管上皮细胞。我们建议通过研究体内和体外肾脏中激活的肌成纤维细胞的细胞起源、激活的关键基因和信号以及激活的肌成纤维细胞的命运来检验这些假说。我们还将评估旨在抑制肌成纤维细胞激活的新治疗方案对慢性肾纤维化的治疗效果。这些将在四个具体目标中实现，这四个目标涉及肌成纤维细胞的起源、激活、命运和治疗干预，在整个动物、细胞和分子水平上。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机械性的见解，也将为设计合理的治疗这一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.