Characterization of functional TGF-beta signaling networks that promote hepatic fibrogenesis through epithelial-mesenchymal transition in hepatocytes

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This proposal aims at elucidating hepatocytic epithelial mesenchymal transition (EMT) in vitro and its role in chronic liver diseases (CLD). TGF-b-dependent EMT in hepatocytes will be investigated with emphasis on cross-communicating signaling pathways acting complementary on the fibrogenic outcome. In murine CLD models based on different inciting injuries, temporal and spatial analyses will be conducted to determine the onset of hepatocyte EMT. Complementary studies will be performed with human tissues at different stages of CLD (ASH, NASH, HBV, HCV, Schistosomiasis) by immunohistochemical investigation of EMT. Given (i) the pivotal role of Snail in EMT and (ii) its significant transcriptional activation by TGF-b in hepatocytes and fibrotic liver diseases, Snail overexpressing and Snail knock out mice will be set up to study the functional impact on hepatocyte EMT and fibrogenic responses in CLD. The expected results will provide novel insights into the mechanisms underlying fibrogenesis and may pave the way for specific interventions, such as hepatocyte-specific drugs for hepatic diseases.