TGF-beta1 is a critical mediator of tissue fibrosis. However, the mechanism(s) by which TGF-beta1 induces fibrosis is incompletely understood. To characterize the effector functions of TGF-beta1, we developed a novel, CC10 promoter-driven, triple transgenic system that allowed us to bypass fetal lethality and target biologically bioactive TGF-beta1 to mature respiratory tissues. These animals manifest an impressive phenotype with a transient wave of epithelial apoptosis that is followed by inflammation, airway fibrosis, parenchymal fibrosis, myocyte and myofibroblast hyperplasia and parenchymal remodeling. Studies with these mice demonstrated that 2 different interventions, a null mutation of early growth response gene-1 (EGR-1) and treatment with the caspase inhibitor Z-VAD-fmk, blocked TGF-(1-induced apoptosis. In both cases, fibrosis was also ameliorated. In addition, the fibrotic response in these animals was reversible after the cessation of transgene expression. These studies led us to the following hypothesis: Hypothesis TGF-beta1 is a multifaceted regulator that induces epithelial apoptosis, fibrosis, myocyte and myofibroblast hyperplasia, inflammation and tissue destruction in the lung. EGR-1 plays a key role in the pathogenesis of the in vivo TGF-beta1 phenotype in the lung. TGF-beta1-induced epithelial cell apoptosis is mediated by an EGR-1-dependent pathway that involves the death receptor and p53/mitochondrial apoptosis pathways and is inhibited by Bcl-2A, p21 (waf 1), Bcl-3 and/or growth factors such as IGF-1 and FGF-2. Epithelial cell apoptosis is a critical precursor of and a critical determinant of the severity and reversibility of selected aspects of the TGF-beta1 phenotype. To test this hypothesis we propose the following;
Aims #1, Generate and characterize inducible, lung-targeted TGF-beta1 overexpressing transgenic (TGFbeta1 OE) mice and identify candidate genes involved in the pathogenesis of the TGF-(1 phenotype. #2. Characterize the contributions of EGR-1 to the pathogenesis of the TGF-beta1 phenotype in the lung. #3. Characterize the mechanism(s) of induction and resolution of TGF-beta1-induced epithelial cell apoptosis. #4. Characterize the relationship(s) between epithelial apoptosis and the inflammatory and remodeling features and permanence of the TGF-beta1 phenotype.
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