Bio distribution and function of alcohol-induced exRNA

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DESCRIPTION (provided by applicant): Extracellular miRNAs (ex-miRs) have unique roles in cell-cell and inter-organ communications. Our preliminary data demonstrate that both acute alcohol binge drinking in humans and chronic alcohol administration in mice result in increased level of extracellular micoRNAs (ex-miR). We found that miR-155, a major regulator of inflammation, is increased by chronic alcohol in mice in the liver and this correlated with both liver inflammation and increased miR-155 in the circulation. Our results also demonstrate that acute alcohol binge in humans and in mice results in a significant increase in the number of circulating exosomes that are "loaded" with miR-155. Based on these findings we hypothesize that both acute alcohol binge and chronic alcohol consumption result in exosome release to the circulation and that that the frequency and ex-miR and/or the ex-miR "cargo" of exosomes might be different after acute and chronic alcohol consumption. Using miR-155 deficient mice we found that exosomes loaded with mature miR-155 deliver detectable levels of miR-155 to the plasma and liver of recipient mice suggesting a wide biological distribution of exosome-packaged ex-miRs. We hypothesize that exosomes provide a unique vehicle for transferring functionally potent ex-miRs induced by alcohol. We postulate that the alcohol-induced ex-miRs in exosomes have functional effects on the liver and/or in other organs. The Specific Aims are: 1. To test the effects of acute alcohol binge and chronic alcohol administration on the in vivo biodistribution of exosome-packaged miR-155 in the plasma and different organs using miR-155- deficient mice, 2. To delineate the biological effects of exosome-packaged miR-155 in vitro and in vivo, 3. To evaluate the effects of acute alcohol binge and chronic alcohol consumption on circulating ex-miR profile in mice and humans. These experiments will characterize plasma ex-miR profile after acute alcohol binge in comparison with chronic alcohol use in mice and this will be compared to data from human volunteers after acute alcohol binge drinking. Our experiments will reveal determinants of biodistribution, tissue localization of exosome-delivered ex-miRNAs, and reveal tissue targets and functions of alcohol-induced ex-miR-155.