Bile duct epithelial cells (i.e., cholangiocytes) are the target cells in cholangiopathies such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and cholangiocarcinoma (CCA), which are characterized by the damage and proliferation of cholangiocytes. Cholangiocyte growth and remodeling are critical for the maintenance of biliary mass and secretory function during the progression of chronic cholestatic liver diseases. In cholestatic liver diseases, cholangiocytes, through the products of their cellular activation, are implicated as the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. Targeting the factors that respond to the mechanical stress resulting from tissue injury may help limit inflammation and fibrosis that occur during hepatobiliary damage. Although mechanical stress such as occurs with biliary distention (commonly observed in PSC and extrahepatic cholestasis) activates cholangiocytes, the cellular and molecular mechanisms responsible for this activated neuroendocrine biliary phenotype remain unclear. There is a critical need to understand the triggers of cholangiocyte growth and their responses to damage during cholestasis, which will help identify key signaling pathways that represent viable targets for the development of effective therapeutic agents. Our long-term research goal is to develop an understanding of factors (such as mechanical stress) and signaling mechanisms regulating neuroendocrine biliary growth during cholestasis, which will provide a foundation for the discovery of prevention and new pharmaceutical interventions for cholangiopathies. Recent studies have indicated that apelin (APLN) plays a role in hepatic fibrosis and that the G-protein coupled apelin receptor (APJ) is also a mechanosensitive receptor. However, the role that APLN and APJ play in cholangiocyte pathophysiology is unknown. We propose the central hypothesis that the activation of the mechanosensitive miR-16APLNAPJ signaling is key for mediating the proliferative and activated profibrogenic biliary phenotype. To test our hypothesis, we propose three Specific Aims: (i) ligand-dependent activation of APJ stimulates cholangiocyte proliferation and activated neuroendocrine/profibrogenic biliary phenotype via Nox4/ROS/ERK-dependent downstream signaling; (ii) mechanical stress-dependent APLN synthesis induces cholangiocyte proliferation and activated neuroendocrine/profibrogenic biliary phenotype via downregulation of miR-16 and activation of the mechanosensitive APJ; and (iii) inhibition of the APLNAPJ axis and overexpression of miR-16 attenuates the activated neuroendocrine/profibrogenic biliary phenotype and fibrosis during cholestasis. Completion of proposed studies will provide a translational mechanism of how mechanical stimuli trigger local and systemic responses to mediate hepatobiliary fibrosis. !
The health relatedness of this grant proposal is that effective treatments are lacking for chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Chronic cholestatic liver diseases cause proliferation/damage of bile ducts in the liver. Management of chronic liver diseases represents one of the major challenges for the Veterans Administration. The successful completion of the studies can be expected to provide a greater understanding of cholestatic liver disease progression and to increase opportunities for the development of novel treatment paradigms for the management of chronic liver diseases.
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