The microRNA Control of Alcoholic Liver Injury and Hepatic Lipid Metabolism

microRNA 控制酒精性肝损伤和肝脂质代谢

• 批准号: 9427529
• 负责人: Dong Ju Shin
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9427529
• 关键词: Address; Affect; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Cell Culture Techniques; Chronic; Cirrhosis; Complement; Development; Diet; Disease; Ethanol; Experimental Designs; Family member; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Heavy Drinking; Hepatic; Hepatocyte; Human; In Vitro; Incidence; Inflammation; Inflammatory Response; Injury; Insulin Resistance; Investigation; Kupffer Cells; Lead; Lecithin; Length; Lipids; Liquid substance; Liver; Liver Dysfunction; Liver diseases; Macrophage Activation; Malignant Neoplasms; Mediating; Medical; Metabolic; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Outcome Study; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Pharmacology; Physiological; Physiological Processes; Prevalence; Primary carcinoma of the liver cells; Regulation; Risk; Role; Supplementation; Triglycerides; Untranslated RNA; alcohol exposure; alcohol response; base; chronic alcohol ingestion; effective therapy; glucose tolerance; improved; in vivo; innovation; insight; insulin sensitivity; insulin signaling; lipid metabolism; liver injury; liver metabolism; mortality; mouse model; non-alcoholic; non-alcoholic fatty liver; novel; novel therapeutics; prevent

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.

摘要 酒精性肝病的发病率和死亡率都在上升 国际吧肝细胞中脂滴的积累是脂肪变性的基本标志， 代表酒精性脂肪肝（AFL）的初始表现，可进展为严重的肝损伤 导致肝硬化和肝细胞癌。尽管AFL的患病率越来越高，但没有有效的 存在治疗或已建立的医学治疗。microRNA是22个核苷酸的小的非编码RNA 其在各种癌症和其它肝脏相关疾病中具有不同的作用。miR-200 c已被 与非酒精性肝病的发展有关，但迄今为止还没有研究调查 miR-200 c在AFL中的作用我们提出的研究的中心假设是，miR-200 c是一个关键的 酒精诱导的肝损伤、炎症和脂质积累的调节剂。我们的目标是：（1）确定 miR-200 c介导AFL的分子机制;（2）研究与AFL相关的途径。 miR-200 c介导的酒精暴露过程中肝脏代谢的改变;（3）阐明了miR-200 c介导的酒精暴露过程中肝脏代谢的改变。 miR-200 c在酒精诱导的炎症中的调节功能。我们将利用基因， 分子和药理学方法来解决miR-200 c在AFL中的作用。解决我们 问题，我们将利用一个综合的实验方法，整合使用体外细胞 培养模型和体内小鼠模型相互补充，允许高度靶向 病理生理学和分子生物学方法。拟议的研究有充分的准备来描绘 miR-200 c调节肝脏脂质蓄积和炎症的潜在机制 酒精暴露