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.
Most forms of chronic liver disease ultimately result in the formation of dense scarring within the liver, known as cirrhosis. In conjunction with this scarring abnormal blood vessel development occurs and is thought to promote further injury and scarring. This project is intended to study the underlying mechanisms that control abnormal blood vessel development and ultimately to generate therapeutic targets to slow or reverse the process of liver scarring.
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|Maiers, Jessica L; Kostallari, Enis; Mushref, Malek et al. (2017) The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice. Hepatology 65:983-998|
|Loarca, Lorena; De Assuncao, Thiago M; Jalan-Sakrikar, Nidhi et al. (2017) Development and characterization of cholangioids from normal and diseased human cholangiocytes as an in vitro model to study primary sclerosing cholangitis. Lab Invest 97:1385-1396|
|Merino-Azpitarte, Maite; Lozano, Elisa; Perugorria, María J et al. (2017) SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. J Hepatol 67:72-83|
|De Assuncao, Thiago M; Jalan-Sakrikar, Nidhi; Huebert, Robert C (2017) Regenerative Medicine and the Biliary Tree. Semin Liver Dis 37:17-27|
|Jalan-Sakrikar, Nidhi; De Assuncao, Thiago M; Lu, Jie et al. (2016) Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion. PLoS One 11:e0168266|
|Lu, Jie; Zhou, Yingqun; Hu, Tianyuan et al. (2016) Notch Signaling Coordinates Progenitor Cell-Mediated Biliary Regeneration Following Partial Hepatectomy. Sci Rep 6:22754|
|De Assuncao, Thiago M; Sun, Yan; Jalan-Sakrikar, Nidhi et al. (2015) Development and characterization of human-induced pluripotent stem cell-derived cholangiocytes. Lab Invest 95:684-96|
|Wang, Ruisi; Ding, Qian; Yaqoob, Usman et al. (2015) Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration. J Biol Chem 290:30684-96|
|de Assuncao, Thiago M; Lomberk, Gwen; Cao, Sheng et al. (2014) New role for Kruppel-like factor 14 as a transcriptional activator involved in the generation of signaling lipids. J Biol Chem 289:15798-809|
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