Cholangiocytes are the target cells in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), which are characterized by the damage/ proliferation of cholangiocytes of different sizes and function. Cholangiocyte proliferation and regrowth are critical for the maintenance of biliary mass and the functional recovery during the pathogenesis of these cholangiopathies. The elucidation of the intracellular mechanisms regulating the proliferative/regenerative responses of large and small bile ducts to cholestasis will play a pivotal role in the development of therapeutic strategies for the treatment of cholestatic liver diseases. Secretin (SEC), a gastrointestinal hormone, is critical for hepatobiliary growth and regeneration. As the secretin receptor (SR) is only expressed by cholangiocytes in the liver, levels of cyclic-AMP in the bile ducts increase and bicarbonate rich bile is secreted after administration of secretin. During hepatobiliary growth/damage, cholangiocytes acquire neuroendocrine phenotypes and thereby secrete and respond to neuroendocrine hormones such as VEGF/NGF and secretin that regulate biliary mass and response to damage. Targeting specific factors that are activated/deactivated during liver injury may help limit biliary damage and the progression of PBC, PSC and liver fibrosis. We have shown that SEC/SR (expressed only by cholangiocytes) axis regulate biliary mass during bile duct ligation (BDL). Secretin levels are elevated during the early stages of BDL. Lack of SR expression leads to: (i) ablation of biliary growth during BDL;and (ii) exacerbation of biliary damage in response to toxins indicating that SEC is a pro-proliferative/protective factor. The mechanisms regulated by the SEC/SR axis during models of acute (short-term BDL and CCl4 administration) and chronic biliary damage (animal models of PSC and PBC) are unknown. Preliminary data indicate that: (i) the SEC/SR axis has pro-proliferative and protective functions during biliary injury (e.g., CCl4 administration and in dnTGFbetaRII KO mice);(ii) activation of the SEC/SR axis (which increases biliary growth) results in the downregulation of the miRNAs, let-7a and miR125-b, that modulate the expression of VEGF and nerve growth factor (NGF) as well as the other potential target genes such as Bcl-2;and (iii) the serum levels of SEC are reduced in PBC and PSC patients indicating that dysregulation of the SEC/SR axis may be key in the pathogenesis of these cholangiopathies. We propose the overall hypothesis that the SEC/SR axis is a key pathway responsible for mediating biliary proliferation/damage during liver diseases. Our long-term objective is to define the therapeutic role of the SEC/SR axis in hepatobiliary disorders such as PBC/PSC. The overall hypothesis will be evaluated by three specific aims. First, we will demonstrate that the SEC/SR axis modulates cholangiocyte proliferation and damage during animal models of acute cholestasis through the activation of autocrine/paracrine mechanisms. Second, we will identify functional SEC-dependent miRNAs involved in the regulation of the expression levels of the pro-proliferative/protective neuroendocrine factors. Third, we will determine the trophic/protective SEC/SR axis that contributes to biliary damage/recovery during chronic cholestasis in animal models of PSC and PBC. Therapeutic effects of secretin dependent gene/miRNA manipulation on biliary cell growth and proliferation will be evaluated. Novel insights into the physiological roles and mechanisms of molecular and functional secretin signaling in human biliary epithelium will be obtained. Meanwhile, the fundamental knowledge obtained in the regulation of growth, proliferation and apoptosis in biliary tree is expected to advance the field of biliary biology/ pathophysiology. !

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 #
2I01BX000574-05
Application #
8633852
Study Section
Gastroenterology (GAST)
Project Start
2009-10-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Olin Teague Veterans Center
Department
Type
DUNS #
City
Temple
State
TX
Country
United States
Zip Code
76504
Francis, Heather; Kennedy, Lindsey; Alpini, Gianfranco (2018) Dual ablation of ?- and ?-catenin: Critical regulators of junctions and their functions. Hepatology 67:2079-2081
Zhou, Tianhao; Wu, Nan; Meng, Fanyin et al. (2018) Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/- mice by diminishing senescence of cholangiocytes. Lab Invest 98:1449-1464
Meng, Fanyin; Kennedy, Lindsey; Hargrove, Laura et al. (2018) Ursodeoxycholate inhibits mast cell activation and reverses biliary injury and fibrosis in Mdr2-/- mice and human primary sclerosing cholangitis. Lab Invest 98:1465-1477
Kennedy, Lindsey; Hargrove, Laura; Demieville, Jennifer et al. (2018) Knockout of l-Histidine Decarboxylase Prevents Cholangiocyte Damage and Hepatic Fibrosis in Mice Subjected to High-Fat Diet Feeding via Disrupted Histamine/Leptin Signaling. Am J Pathol 188:600-615
Ehrlich, Laurent; Scrushy, Marinda; Meng, Fanyin et al. (2018) Biliary epithelium: A neuroendocrine compartment in cholestatic liver disease. Clin Res Hepatol Gastroenterol 42:296-305
Lewis, Phillip L; Su, Jimmy; Yan, Ming et al. (2018) Complex bile duct network formation within liver decellularized extracellular matrix hydrogels. Sci Rep 8:12220
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Sato, Keisaku; Meng, Fanyin; Giang, Thao et al. (2018) Mechanisms of cholangiocyte responses to injury. Biochim Biophys Acta Mol Basis Dis 1864:1262-1269
Luo, Xianjun; Li, Honggui; Ma, Linqiang et al. (2018) Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice. Gastroenterology 155:1971-1984.e4
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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