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Mesenchymal Cell Survival Signalling by TGF-B1

TGF-B1 的间充质细胞存活信号传导

基本信息

批准号：
7663866
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
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-05 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7663866
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 effective therapy extracellular human TGFB1 protein in vivo insight knowledge base programs repaired response response to injury skills

项目摘要

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）：该补助金提出了一个为期五年的培训计划，旨在促进作为一名医生科学家的独立调查事业的发展。该计划的目标，除了完成下面总结的研究，是提供指导，技术技能，实验室管理技能，和学术独立所需的知识基础。肺纤维化是一种进行性的、使人衰弱的过程，目前尚无有效的治疗方法。纤维化疾病的发病机制涉及功能障碍性修复反应，其特征在于与肌成纤维细胞活性升高相关的上皮细胞损伤。成纤维细胞/肌成纤维细胞凋亡是正常伤口愈合的关键组成部分，成纤维细胞不能经历凋亡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仍不清楚。转化生长因子-β 1（TGF-β 1）是一种多功能细胞因子，以细胞类型和环境特异性方式发挥作用。通过刺激间充质细胞分化、活化和存活，TGF-β 1是大多数器官系统纤维化疾病发病机制的核心。我们假设TGF-β 1通过促进人肺间充质细胞的抗凋亡表型而参与纤维化疾病的发病机制。我们建议研究TGF-β 1保护间充质细胞免于凋亡的机制，结合体外研究来定义相关的信号相互作用，并结合体内研究来定义这些抗凋亡信号通路在纤维化肺疾病发展中的作用。我们的具体目标是：1）研究TGF-β 1促进人肺成纤维细胞中促存活/抗凋亡PI 3 K/Akt信号通路的自分泌激活的特定分子机制，2）研究TGF-β 1诱导的PI 3 K/Akt和FAK激活在调节和预防成纤维细胞凋亡/失巢凋亡中的作用，和3）在体内检查，成纤维细胞特异性Akt活化在肺纤维化小鼠模型中的作用。总的来说，这些研究将为TGF-β 1调节间充质细胞存活所利用的细胞信号通路提供重要的机制见解。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosis.

DOI：
10.1016/j.biocel.2011.10.011
发表时间：
2012-01
期刊：
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
影响因子：
4
作者：
Horowitz, Jeffrey C.;Ajayi, Iyabode O.;Kulasekaran, Priya;Rogers, David S.;White, Joshua B.;Townsend, Sarah K.;White, Eric S.;Nho, Richard S.;Higgins, Peter D. R.;Huang, Steven K.;Sisson, Thomas H.
通讯作者：
Sisson, Thomas H.

PAI-1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury.

DOI：
10.1002/path.3992
发表时间：
2012-10
期刊：
JOURNAL OF PATHOLOGY
影响因子：
7.3
作者：
Osterholzer, John J.;Christensen, Paul J.;Lama, Vibha;Horowitz, Jeffrey C.;Hattori, Noboru;Subbotina, Natalya;Cunningham, Andrew;Lin, Yujing;Murdock, Benjamin J.;Morey, Roger E.;Olszewski, Michal A.;Lawrence, Daniel A.;Simon, Richard H.;Sisson, Thomas H.
通讯作者：
Sisson, Thomas H.

Stress in the ER (endoplasmic reticulum): a matter of life and death for epithelial cells.

ER（内质网）中的压力：事关上皮细胞的生死。