Cholangiocyte growth and remodeling are critical for the maintenance of biliary mass and secretory function during the pathogenesis of chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Cholangiocytes, the epithelia lining the biliary system, participate in a diverse array of cellular processes. In cholestatic livr 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 specific factors that respond to the mechanical stress resulting from tissue injury may help limit inflammation and fibrosis that occur in hepatobiliary damages and diseases such as PBC, PSC and liver fibrosis. Emerging evidence indicates that exposure to cigarette smoke may stimulate the progression of chronic liver disease towards fibrosis such as PSC, PBC, chronic hepatitis C, and non-alcoholic fatty liver disease. Although mechanical stress such as occurs with biliary distention (commonly observed in PSC) and tobacco use (accelerates fibrosis in patients with PBC) activate cholangiocytes, the cellular and molecular mechanisms responsible for this phenotype remain unclear. The ?7-nicotinic acetylcholine receptor (?7-nAChR) mediates the proliferative and fibrogenic effects of nicotine and can also be activated by mechanical stress. We propose the overall hypothesis that ?7-nAChR activation is a key and common pathway responsible for mediating the profibrogenic cholangiocyte phenotype. This postulate will be tested in three Specific Aims, which will determine whether (i) ligand-dependent activation of ?7-nAChR during mechanical stress induces a profibrogenic phenotype via enhanced expression of miR-181 and -200;(ii) activation of mechanosensitive ?7-nAChR stimulates Ca2+-dependent ACh secretion and miR-181 and -200 expression;and (iii) inhibition of ?7-nAChR attenuates the activated biliary phenotype and fibrosis in vivo in cholestatic BDL mice. Completion of proposed studies will provide a framework for understanding how mechanical stimuli trigger local and systemic responses mediate hepatobiliary fibrosis. The findings will likely lead to new therapeutic approaches for cholestatic liver diseases and a reduction of morbidity and mortality in American Veterans with liver diseases.

Public Health Relevance

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. There is a high risk and incidence of chronic cholestatic liver diseases due to alcohol and hepatitis viruses in veterans, which is one of the most common reasons for hospitalization and mortality in American Veterans. 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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002192-01
Application #
8544056
Study Section
Gastroenterology (GAST)
Project Start
2013-10-01
Project End
2017-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Olin Teague Veterans Center
Department
Type
DUNS #
029847394
City
Temple
State
TX
Country
United States
Zip Code
76504
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Hall, Chad; Ehrlich, Laurent; Meng, Fanyin et al. (2017) Inhibition of microRNA-24 increases liver fibrosis by enhanced menin expression in Mdr2-/- mice. J Surg Res 217:160-169
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Raggi, Chiara; Gammella, Elena; Correnti, Margherita et al. (2017) Dysregulation of Iron Metabolism in Cholangiocarcinoma Stem-like Cells. Sci Rep 7:17667
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Ehrlich, Laurent; Hall, Chad; Meng, Fanyin et al. (2017) A Review of the Scaffold Protein Menin and its Role in Hepatobiliary Pathology. Gene Expr 17:251-263
Kyritsi, Konstantina; Meng, Fanyin; Zhou, Tianhao et al. (2017) Knockdown of Hepatic Gonadotropin-Releasing Hormone by Vivo-Morpholino Decreases Liver Fibrosis in Multidrug Resistance Gene 2 Knockout Mice by Down-Regulation of miR-200b. Am J Pathol 187:1551-1565
Ehrlich, Laurent; Hall, Chad; Venter, Julie et al. (2017) miR-24 Inhibition Increases Menin Expression and Decreases Cholangiocarcinoma Proliferation. Am J Pathol 187:570-580
Sato, Keisaku; Meng, Fanyin; Venter, Julie et al. (2017) The role of the secretin/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles. Sci Rep 7:11183
McDaniel, Kelly; Meng, Fanyin; Wu, Nan et al. (2017) Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in miceā€”. Hepatology 65:544-559

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