Alcoholic liver disease affects millions of people worldwide and it remains to be a therapeutic challenge for clinicians. Activation of the inflammatory cascade via gut-derived lipopolysaccharide (LPS) contributes to alcoholic liver disease via induction of pro-inflammatory cytokines induction in Kupffer cells. Micro-RNA-155 (miR-155), small non-coding RNA molecule, is important in regulation of inflammation. Our preliminary data demonstrate that chronic alcohol up-regulates miR155 in macrophages in vitro as well as in vivo in the liver and in isolated Kupffer cells and this miR155 increase contributes to inflammation in alcoholic liver disease. We hypothesize that miRNAs not only play a role in the pathomechanism of alcoholic liver disease but also represent therapeutic targets and potential biomarkers. Specifically, we postulate that alcohol-induced miR-155 is a mediator of KC sensitization to gut-derived LPS, and that alcohol-induced miR-155 increase leads to amplification of pro-inflammatory cytokine production by KC. We further hypothesize that inhibition of miR-155 in the liver and/or in Kupffer cells will ameliorate alcohol-induced liver disease. Based on our preliminary data demonstrating increased serum levels of miR-155 and miR-122 in alcohol-induced liver injury, we propose that these serum miRNAs may serve as biomarkers of alcohol-induced liver damage. These hypotheses will be tested in the following Specific Aims: 1. To evaluate the mechanistic role of miR155 in alcoholic liver injury;2. To delineate the mechanisms by which chronic alcohol increases miR-155 levels in alcoholic liver disease;3. To explore the therapeutic potential of in vivo inhibition of miR155 in the development of alcoholic liver disease. Results from the proposed experiments will provide new insights into the role of miRNAs in alcoholic liver disease, identify potential early biomarkers of inflammation and liver damage in ALD and provide reclinical evaluation of novel therapeutic intervention via target-specific and cell-specific delivery of a miRNA-antagonist.

Public Health Relevance

The impact of new discoveries from this proposed research is expected to be highly significant. For example, identification of miRNAs as biomarkers of liver damage could revolutionalize clinical diagnostics and disease prognosis. The proposed therapeutic intervention, if successful could be then directly translated into human clinical trials in the underserved area of alcoholic steatohepatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020744-02
Application #
8330791
Study Section
Special Emphasis Panel (ZAA1-JJ (01))
Program Officer
Murray, Gary
Project Start
2011-09-10
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$370,125
Indirect Cost
$145,125
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Satishchandran, Abhishek; Ambade, Aditya; Rao, Sitara et al. (2018) MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients From Ethanol-Induced Liver Disease. Gastroenterology 154:238-252.e7
Wang, Xiaojing; de Carvalho Ribeiro, Marcelle; Iracheta-Vellve, Arvin et al. (2018) Macrophage-Specific Hypoxia-Inducible Factor-1? Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis. Hepatology :
Bala, Shashi; Szabo, Gyongyi (2018) TFEB, a master regulator of lysosome biogenesis and autophagy, is a new player in alcoholic liver disease. Dig Med Res 1:
Bala, Shashi; Csak, Timea; Kodys, Karen et al. (2017) Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease. J Leukoc Biol 102:487-498
Iracheta-Vellve, Arvin; Petrasek, Jan; Gyongyosi, Benedek et al. (2016) Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes. J Biol Chem 291:26794-26805
Ambade, Aditya; Satishchandran, Abhishek; Szabo, Gyongyi (2016) Alcoholic hepatitis accelerates early hepatobiliary cancer by increasing stemness and miR-122-mediated HIF-1? activation. Sci Rep 6:21340
Bala, Shashi; Csak, Timea; Saha, Banishree et al. (2016) The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis. J Hepatol 64:1378-87
Saha, Banishree; Bala, Shashi; Hosseini, Nooshin et al. (2015) Krüppel-like factor 4 is a transcriptional regulator of M1/M2 macrophage polarization in alcoholic liver disease. J Leukoc Biol 97:963-973
Sanyal, Arun J; Gao, Bin; Szabo, Gyongyi (2015) Gaps in Knowledge and Research Priorities for Alcoholic Hepatitis. Gastroenterology 149:4-9
Bala, Shashi; Csak, Timea; Momen-Heravi, Fatemeh et al. (2015) Biodistribution and function of extracellular miRNA-155 in mice. Sci Rep 5:10721

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