Micro-RNA's in Alcoholic Liver Disease

酒精性肝病影响着全世界数百万人，它仍然是临床医生的治疗挑战。肠源性脂多糖（LPS）激活炎症级联反应，通过诱导枯否细胞中的促炎细胞因子诱导而导致酒精性肝病。Micro-RNA-155（miR-155）是一种非编码RNA小分子，在炎症反应中起重要作用。我们的初步数据表明，慢性酒精上调巨噬细胞中的miR 155在体外以及在肝脏和分离的枯否细胞中的体内，这种miR 155的增加有助于酒精性肝病的炎症。我们推测miRNAs不仅在酒精性肝病的病理机制中发挥作用，而且还代表了治疗靶点和潜在的生物标志物。具体而言，我们假设酒精诱导的miR-155是KC对肠源性LPS敏感的介导物，并且酒精诱导的miR-155增加导致KC产生促炎细胞因子的放大。我们进一步假设，抑制肝脏和/或枯否细胞中的miR-155将改善酒精诱导的肝脏疾病。基于我们的初步数据表明，在酒精诱导的肝损伤中，血清中miR-155和miR-122的水平增加，我们建议这些血清miRNA可以作为酒精诱导的肝损伤的生物标志物。这些假设将在以下具体目标中进行检验：1.探讨miR 155在酒精性肝损伤中的作用机制; 2.阐明慢性酒精增加酒精性肝病中miR-155水平的机制; 3.探索体内抑制miR 155在酒精性肝病发展中的治疗潜力。拟议实验的结果将为miRNAs在酒精性肝病中的作用提供新的见解，确定ALD中炎症和肝损伤的潜在早期生物标志物，并通过靶向特异性和细胞特异性递送miRNAs拮抗剂提供新的治疗干预的再临床评估。

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.