Regulation Of Biliary Growth And Fibrosis By Melatonin
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Project Summary/Cholangiocytes are the target cells in cholangiopathies; such as, primary biliary cirrhosis (PBC) and primarysclerosing cholangitis (PSC), which are characterized by the damage and proliferation of cholangiocytes. Incholestatic liver diseases, cholangiocytes, through the products of their cellular activation, are implicated asthe key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliaryinjury. While advances have been made to further our understanding of the neuroendocrine factors thatmodulate biliary proliferation and fibrosis during cholestasis, unfortunately, viable therapies for themanagement of cholangiopathies remain elusive. Our previous studies have revealed that cholangiocytesexpress the enzymes necessary to synthesize and secrete melatonin and that melatonin plays a role inregulating biliary hyperplasia during cholestasis. Our overall objective is to determine the molecularmechanisms by which biliary proliferation and fibrosis are regulated by the melatonin/MT1/MT2/GPR50signaling axis. Our central hypothesis, based upon the strong preliminary data, is that biliary proliferationand fibrosis are differentially regulated by the melatonin/melatonin receptor (MT1 or MT2)-signaling axis inthe presence/absence of MT1 or MT2. The central hypothesis was formulated on the basis that knockout ofMT1 and MT2 resulted in differential responses of the biliary epithelium to extrahepatic cholestasis. As such,we found: (i) a significant increase of biliary proliferation and fibrosis in MT2 knockout mice during BDL; and(ii) a substantial reduction in biliary proliferation and fibrosis in MT1 knockout mice following BDL. miRNAPCR array analysis of cholangiocytes from BDL MT2 knockout and Mdr2-/- mice exposed to prolongeddarkness (that increases melatonin secretion) revealed alterations in the expression levels of miRNAs (miR-125b, let-7a, miR-200b and miR-181a/b) that will be evaluated as potential targets to regulate biliaryproliferation and fibrosis through the melatonin/MT1/MT2/GPR50 signaling axis. To test our centralhypothesis, we propose two Specific Aims: (1) disruption of the melatonin/MT1/MT2/GPR50 signaling axisalters biliary proliferation and liver fibrosis during cholestasis and (2) biliary proliferation and liver fibrosis isregulated by the melatonin/MT1/MT2/GPR50 signaling axis via miRNA-regulated proliferative and pro-fibrogenic mechanisms. The successful completion of the studies may provide tools for the development ofnovel treatment paradigms targeting the melatonin/MT1/MT2/GPR50 signaling axis during chronic liverdiseases.