Mesenchymal Cell Survival Signalling by TGF-B1

描述(由申请人提供)： 这笔赠款提出了一项为期五年的培训计划，旨在促进作为内科科学家的独立调查职业的发展。这项计划的目标，除了完成以下概述的研究外，还旨在提供学术独立所需的导师、技术技能、实验室管理技能和知识库。肺纤维化是一个进行性的、衰弱的过程，目前还没有有效的治疗方法。纤维性疾病的发病机制涉及一种功能失调的修复反应，其特征是上皮细胞损伤与肌成纤维细胞活性升高相关。成纤维细胞/肌成纤维细胞的凋亡是伤口正常愈合的重要组成部分，成纤维细胞不能发生凋亡会导致病理性瘢痕形成和组织纤维化。在纤维化疾病中促进抗凋亡间充质细胞表型的机制尚不清楚。转化生长因子-β1(转化生长因子-β1)是一种多功能细胞因子，其作用方式与细胞类型和环境有关。通过刺激间充质细胞的分化、激活和存活，转化生长因子-β1在大多数器官系统的纤维化疾病的发病机制中起核心作用。我们假设转化生长因子-β1通过促进人肺间充质细胞的抗凋亡表型参与纤维化疾病的发病机制。我们建议使用体外研究和体内研究相结合的方法来研究转化生长因子-β1保护间充质细胞免于凋亡的机制，以确定相关的信号相互作用和体内研究在纤维化肺疾病的发展中所起的作用。我们的具体目标是：1)研究转化生长因子-β1促进人肺成纤维细胞PI3K/Akt信号通路自分泌激活的具体分子机制；2)研究转化生长因子-β1诱导的PI3K/Akt和FAK激活在调控和预防成纤维细胞凋亡/失巢凋亡中的作用；3)在体内检测成纤维细胞特异性Akt激活在小鼠肺纤维化模型中的作用。总之，这些研究将为转化生长因子-β1调节间充质细胞存活所使用的细胞信号通路提供重要的机械性见解。

DESCRIPTION (provided by applicant): This grant proposes a five year training program designed to foster the development of an independent investigative career as a physician-scientist. The goals of this plan, in addition to completing the research summarized below, are to provide the mentorship, technical skills, laboratory management skills, and knowledge base necessary for academic independence. Pulmonary fibrosis is progressive, debilitating process for which no effective therapy exists. The pathogenesis of fibrotic disease involves a dysfunctional repair response characterized by epithelial cell injury associated with heightened myofibroblast activity. Fibroblast/myofibroblast apoptosis is a crucial component of normal wound healing and failure of fibroblasts to undergo apoptosis results in pathologic scar formation and tissue fibrosis. The mechanisms promoting an anti-apoptotic mesenchymal cell phenotype in fibrotic disease remain unclear. Transforming growth factor-beta 1 (TGF-beta1) is a multifunctional cytokine that acts in a cell-type and context-specific manner. Through stimulation of mesenchymal cell differentiation, activation, and survival, TGF-beta1 is central to the pathogenesis of fibrotic disease in most organ systems. We hypothesize that TGF-beta1 contributes to the pathogenesis of fibrotic disease by promoting an anti-apoptotic phenotype in human lung mesenchymal cells. We propose to examine the mechanisms through which TGF-beta1 protects mesenchymal cells from apoptosis using a combination of in vitro studies to define pertinent signaling interactions and in vivo studies to define the role of these anti-apoptotic signaling pathways in the development of fibrotic lung disease. Our specific aims are: 1) to investigate the specific molecular mechanisms by which TGF-beta1 promotes autocrine activation of the pro-survival/anti-apoptotic PI3K/Akt signaling pathway in human lung fibroblasts, 2) to investigate the role of TGF-beta1 induced PI3K/Akt and FAK activation in the modulation and prevention of fibroblast apoptosis/anoikis, and 3) to examine, in vivo, the role of fibroblast-specific Akt activation in a murine model of pulmonary fibrosis. Collectively, these studies will provide important mechanistic insights into the cellular signaling pathways utilized by TGF-beta1 to regulate mesenchymal cell survival.