Mesenchymal Cell Survival Signalling by TGF-B1

TGF-B1 的间充质细胞存活信号传导

• 批准号: 7267645
• 负责人: Jeffrey C Horowitz
• 金额: $ 13.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-05 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267645
• 关键词: Abnormal Epithelial Cell; Adhesions; Anoikis; Apoptosis; Apoptotic; Cell Differentiation process; Cell Survival; Cells; Cicatrix; Collagen; Data; Development; Disease; Epithelial Cells; Extracellular Matrix; Failure; Fibroblasts; Fibronectins; Fibrosis; Fostering; Goals; Grant; Growth; Growth Factor; Human; In Vitro; Laboratories; Lung; Lung diseases; Mediating; Mediator of activation protein; Mentorship; Mesenchymal; Modeling; Molecular; Mus; Myofibroblast; PTK2 gene; Pathogenesis; Pathologic; Phenotype; Physicians; Physiological; Prevention; Process; Protein-Serine-Threonine Kinases; Pulmonary Fibrosis; Receptor Protein-Tyrosine Kinases; Regulation; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Tissues; Training Programs; Tumor Suppressor Proteins; Wound Healing; autocrine; body system; career; cell injury; cell type; cytokine; design; extracellular; human TGFB1 protein; in vivo; insight; knowledge base; programs; repaired; response; response to injury; skills

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.

描述（由申请人提供）： 该赠款提出了一项为期五年的培训计划，旨在促进作为医师科学家独立调查生涯的发展。 除了完成以下概述的研究外，该计划的目标还旨在提供学术独立所必需的指导，技术技能，实验室管理技能和知识基础。肺纤维化是进行性的，令人衰弱的过程，没有有效的治疗。 纤维化疾病的发病机理涉及功能失调的修复反应，其特征是与肌纤维细胞活性增强有关的上皮细胞损伤。成纤维细胞/成肌纤维细胞细胞凋亡是正常伤口愈合的关键组成部分，成纤维细胞失败会导致病理疤痕形成和组织纤维化。 促进纤维化疾病中抗凋亡间充质细胞表型的机制尚不清楚。 转化生长因子-BETA 1（TGF-BETA1）是一种以细胞类型和上下文特异性方式作用的多功能细胞因子。 通过刺激间充质细胞分化，激活和存活，TGF-BETA1对于大多数器官系统中纤维化疾病的发病机理至关重要。我们假设TGF-BETA1通过促进人肺间充质细胞中的抗凋亡表型来促进纤维化疾病的发病机理。 我们建议研究TGF-BETA1通过使用体外研究组合来保护间充质细胞免受凋亡的机制，以定义相关信号相互作用和体内研究，以定义这些抗凋亡信号通路在纤维化肺部发育中的作用。 我们的具体目的是：1）调查TGF-BETA1促进促溶性/抗凋亡PI3K/AKT信号途径的特定分子机制，在人类肺成纤维细胞中，2）以调查TGF-BETA1诱导的PI3K/AKT和FAK ACTRONTION的作用。凋亡/Anoikis和3）在体内检查成纤维细胞特异性AKT激活在肺纤维化模型中的作用。 总的来说，这些研究将为TGF-BETA1使用的细胞信号传导途径提供重要的机械见解，以调节间充质细胞的存活。