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.
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.
|Csak, Timea; Bala, Shashi; Lippai, Dora et al. (2015) microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver Int 35:532-41|
|Lippai, Dora; Bala, Shashi; Catalano, Donna et al. (2014) Micro-RNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice. Alcohol Clin Exp Res 38:2217-24|
|Momen-Heravi, Fatemeh; Bala, Shashi; Bukong, Terence et al. (2014) Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages. Nanomedicine 10:1517-27|
|Lippai, Dora; Bala, Shashi; Csak, Timea et al. (2013) Chronic alcohol-induced microRNA-155 contributes to neuroinflammation in a TLR4-dependent manner in mice. PLoS One 8:e70945|
|Szabo, Gyongyi; Bala, Shashi (2013) MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 10:542-52|