The overall objective of this research plan has been to define the mechanisms responsible for repair and regeneration of alcohol-injured livers. After demonstrating that chronic consumption of alcohol inhibited proliferation of mature hepatocytes, we began to investigate whether liver progenitors were responsible for regenerating livers with alcohol-induced damage. During the last funding period we discovered that the Hedgehog (Hh) pathway regulates the fate of adult liver progenitors, and showed that this pathway is dramatically induced during alcoholic liver disease (ALD). Although Hh signaling was known to play critical roles in embryonic tissue construction, certain types of adult tissue remodeling, and tumor metastasis, it had not been implicated in adult liver repair until our work. Further efforts focused on delineating the pathobiological relevance of Hh pathway activation during ALD. We proved that Hh pathway activation causes liver epithelial progenitors to undergo epithelial-to-mesenchymal transition (EMT) and demonstrated that mice with an overly-active Hh pathway develop excessive liver fibrosis when their livers are injured. Our most recent preliminary data identify a novel mechanism for Hh pathway inhibition by demonstrating that Tweak/Fn14 signaling (which is known to promote expansion of epithelial-type liver progenitors) antagonizes the EMT-promoting actions of the Hh pathway and permits mesenchymal-to-epithelial transition (MET) in progenitors. Therefore, this competing renewal application will evaluate the HYPOTHESIS that the Hh pathway and Tweak/Fn14 differentially regulate the fate of liver progenitors, and hence the outcomes of ALD.
Our Specific Aims are to 1) determine if dysregulated Hh signaling increases EMT and inhibits MET to promote fibrogeneic repair of ALD, 2) determine if Tweak/Fn14 inhibit EMT and promote non-fibrogenic repair of ALD by inhibiting Hh activity, and 3) determine if treatments that improve ALD decrease EMT and enhance MET because they inhibit Hh pathway activity and/or increase Tweak/Fn14 signaling. The results will clarify the relative significance of EMT/MET, and some of the mechanisms that regulate these processes, in controlling the divergent outcomes of ALD. This, in turn, might identify novel genetic susceptibility factors for alcohol-related cirrhosis, new biomarkers for ALD progression, and novel therapeutic targets for this common liver disease.

Public Health Relevance

The results will clarify the relative significance of EMT/MET, and some of the mechanisms that regulate these processes, in controlling the divergent outcomes of ALD. This, in turn, might identify novel genetic susceptibility factors for alcohol-related cirrhosis, new biomarkers for ALD progression, and novel therapeutic targets for this common liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA010154-17
Application #
8306351
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Gao, Peter
Project Start
1994-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
17
Fiscal Year
2012
Total Cost
$365,257
Indirect Cost
$131,118
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Chan, Isaac S; Guy, Cynthia D; Machado, Mariana V et al. (2014) Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis. Alcohol Clin Exp Res 38:787-800
Bohinc, Brittany N; Michelotti, Gregory; Xie, Guanhua et al. (2014) Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology 155:4591-601
Karaca, Gamze; Swiderska-Syn, Marzena; Xie, Guanhua et al. (2014) TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice. PLoS One 9:e83987
Swiderska-Syn, M; Syn, W K; Xie, G et al. (2014) Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 63:1333-44
Xie, Guanhua; Karaca, Gamze; Swiderska-Syn, Marzena et al. (2013) Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology 58:1801-13
Diehl, Anna Mae; Chute, John (2013) Underlying potential: cellular and molecular determinants of adult liver repair. J Clin Invest 123:1858-60
Michelotti, Gregory A; Xie, Guanhua; Swiderska, Marzena et al. (2013) Smoothened is a master regulator of adult liver repair. J Clin Invest 123:2380-94
Rangwala, Fatima; Guy, Cynthia D; Lu, Jiuyi et al. (2011) Increased production of sonic hedgehog by ballooned hepatocytes. J Pathol 224:401-10
Omenetti, Alessia; Choi, Steve; Michelotti, Gregory et al. (2011) Hedgehog signaling in the liver. J Hepatol 54:366-73
Choi, Steve S; Omenetti, Alessia; Syn, Wing-Kin et al. (2011) The role of Hedgehog signaling in fibrogenic liver repair. Int J Biochem Cell Biol 43:238-44

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