DESCRIPTION (provided by applicant): Cirrhosis and portal hypertension are the cause of significant morbidity, mortality, and healthcare expenditures. Since hepatic fibrosis and pathological angiogenesis are processes that are mutually dependent and since liver endothelial cell (LEC) invasion is a requisite step for angiogenesis, studies of the detailed molecular mechanisms governing LEC invasion are of great importance. LEC invasion is modulated by mechanisms involving localized cell volume regulation and osmotically driven membrane shape changes. Aquaporin-1 (AQP1) is an integral membrane water channel that is dramatically overexpressed in LEC during cirrhosis and facilitates invasion through the cirrhotic microenvironment. The precise mechanisms responsible for the overexpression of AQP1 in LEC during cirrhosis remain largely uninvestigated. Based on selected background rationale and novel preliminary data, we propose the central hypothesis that local osmotic fluctuation during cirrhosis drives AQP1 overexpression by altering levels of the osmotically sensitive, AQP1 regulatory miRNAs, miR-666 and miR-708, thereby promoting dynamic membrane blebbing, LEC invasion, and angiogenesis during cirrhosis. To accomplish our overall objective, we will employ complementary molecular, cell biologic, an in vivo approaches to establish the mechanism of AQP1 overexpression and the effect of AQP1 regulatory miRNAs on LEC invasion, angiogenesis, and cirrhosis. Aim I will focus on how local osmolality silences miR- 666 and miR-708 to subsequently increase AQP1 in LEC. Aim II investigates the effects of miR-666 and miR- 708 on the angiogenic phenotype of LEC. Aim III tests the effects of miR-666 and miR-708 overexpression on angiogenesis and fibrosis in vivo. The results will mechanistically extend the preliminary findings and provide novel information regarding the osmotically sensitive, miRNA-based mechanisms, controlling AQP1 overexpression and may ultimately produce the foundation for anti-angiogenic therapies targeting AQP1 and its molecular regulators in cirrhosis.
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