The microRNA Control of Alcoholic Liver Injury and Hepatic Lipid Metabolism

摘要 酒精性肝病的患病率正在上升，发病率和死亡率也随之增加。 全世界。肝细胞内的脂滴积聚是脂肪变性的基本标志。 代表酒精性脂肪肝(AFL)的最初表现，可发展为严重的肝损伤 导致肝硬变和肝细胞癌。尽管AFL的患病率不断上升，但没有有效的 存在治疗方法或已有的医学治疗方法。MicroRNAs是由22个核苷酸组成的非编码小RNA 它们在各种癌症和其他与肝脏相关的疾病中扮演不同的角色。MIR-200C已经被 与非酒精性肝病的发展有关，然而，到目前为止还没有研究调查 MiR-200C在AFL中的作用我们对拟议研究的中心假设是miR-200C是一个关键的 酒精性肝损伤、炎症和脂质堆积的调节剂。我们的目标是：(1)确定 MiR-200C介导AFL的分子机制；(2)研究与 MIR-200C介导的酒精暴露时肝脏代谢的改变；(3)阐明 MiR-200C在酒精性炎症中的调节作用我们将利用基因， 解决miR-200C在AFL中作用的分子和药理学方法。向我们的 问题，我们将利用一种综合的实验方法，结合使用体外细胞 培养模型和体内小鼠模型相辅相成，允许高度靶向性 病理生理学和分子生物学方法。建议的研究已作好准备，可勾勒出 MiR-200C调节肝脏脂质堆积和炎症的机制 酒精暴露。

ABSTRACT The prevalence of alcoholic liver disease is rising with concomitant increase in morbidity and mortality rates worldwide. Accumulation of lipid droplets in hepatocytes is the fundamental hallmark of steatosis and represents the initial manifestation of alcoholic fatty liver (AFL), which can progress to severe liver injury leading to cirrhosis and hepatocellular carcinoma. Despite the increasing prevalence of AFL, no effective therapies or established medical treatments exist. microRNAs are small non coding RNAs of 22 nucleotides in length which have diverse roles in various cancers and other liver-related diseases. miR-200c has been implicated in the development of non-alcoholic liver disease, however no studies to date have investigated the role of miR-200c on AFL. Our central hypothesis of the proposed study is that miR-200c is a critical regulator of alcohol-induced liver injury, inflammation and lipid accumulation. We aim to: (1) Identify the molecular mechanisms by which miR-200c mediates AFL; (2) Investigate the pathways associated with miR-200c-mediated alterations in hepatic metabolism during alcohol exposure; (3) Elucidate that the regulatory function of miR-200c in alcohol-induced inflammation. We will take advantage of genetic, molecular and pharmacological approaches to address the role of miR-200c on AFL. To address our questions, we will utilize a comprehensive experimental approach that integrates the use of in vitro cell culture model and in vivo mouse models complementing each other, allowing for a highly targeted pathophysiological and molecular approach. The proposed studies are well equipped to delineate the underlying mechanisms by which miR-200c regulates hepatic lipid accumulation and inflammation during alcohol exposure.