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.
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