Inhibitors of Epithelial TGFB signaling and EMT/Sheppard

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PROJECT SUMMARY (See instructions): TGFB1 signaling is prominent in the pathobiology of idiopathic pulmonary fibrosis (IPF) but is also critical in many physiological processes important to normal homeostasis. Anti-fibrotic drugs directed at attenuation of TGFB1 signaling could be expected to be less toxic and yet still effective if focused on aspects of signaling specific to fibrogenesis. An approach to achieve this goal in patients has to date remained elusive. Recent studies of epithelial mesenchymal transition (EMT) indicate EMT develops in vivo during experimental lung fibrosis and is important to the fibrotic process. EMT was found to critically depend on integrin a3B1-dependent generation of transcriptional complexes of a tyrosine phosphorylated (pY654) B-catenin and pSmad2. These transcriptional complexes are present in extracts of IPF lungs and localize to nuclei of accumulating myofibroblasts in this disorder, implying a relatively specific pathway of TGFB1 signaling approachable by novel therapeutics. The goal of this application is to develop new reagents that attenuate EMT and pulmonary fibrosis in vivo in mice that could be the basis for drug development in the clinical phase of the project. Recently identified integrin a3B1-derived peptides that block pY654-P-catenin generation and small molecules that promote turnover of BY-B-catenin will be the starting points for inhibitor optimization and testing in models of murine lung fibrosis. Both of these inhibitor classes block EMT ex vivo. In addition a high throughput cell based screen of small molecules that mimic the integrin-derived peptides and/or block EMT ex vivo will be used to develop additional lead compounds for optimization and in vivo testing. The project will work closely with the medicinal chemistry core for peptide and small molecule optimization, with the human tissue core to examine promising lead compounds with primary human alveolar epithelial cells, with the Longitudinal Cohort Core to charactize mechanistically informative biomarkers, and with Project 2 that will develop an aerosol system for drug delivery. We anticipate that the proposed studies should both test the principle that inhibition of EMT is an effective approach to attenuation of fibrogenesis and provide promising candidates for futher development as therapeutics for IPF.