鼠尾草酸调控miR-34a/SIRT1-p66shc信号通路抗酒精性肝损伤的分子机制研究

项目名称： 鼠尾草酸调控miR-34a/SIRT1-p66shc信号通路抗酒精性肝损伤的分子机制研究

项目编号： No.81473266

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 姚继红

作者单位： 大连医科大学

项目金额： 67万元

中文摘要： 酒精性肝病发病机制复杂，线粒体氧化应激所致ROS失衡是其损伤的重要因素。近期研究显示，这种ROS失衡受某些信号通路的调控。鼠尾草酸为迷迭香中抗氧化成分最丰富的提取物, 我们前期研究首次发现其对大鼠慢性酒精性肝损伤具有明显的保护作用。深入研究发现，该保护作用与SIRT1的诱导进而抑制衔接蛋白p66shc调节的肝细胞线粒体氧化应激凋亡有关，与其对miRNA-34a的抑制作用有关。结合生物信息学结果和研究报道,首次提出：调控miR-34a/SIRT1-p66shc通路可能是酒精性肝损伤防治的重要策略，也是鼠尾草酸发挥作用的关键分子机制。本研究采用分子生物学技术和体内外实验模型，探讨miR-34a/SIRT1-p66shc通路在慢性酒精性肝损伤中的作用及机制，探讨鼠尾草酸对该通路的调控作用。本研究对揭示酒精性肝损伤发病新机制及为鼠尾草酸的开发利用提供重要的药理学依据。

中文关键词： 微小RNA；沉默信息调节因子1；衔接蛋白p66shc；鼠尾草酸；酒精性肝损伤

英文摘要： Uncontrolled formation of reactive oxygen species (ROS) resulted by mitochondrial oxidative stress is a major cause of alcoholic liver disease(ALD) with complex pathogenesis. Recent studies suggested that the modification of ROS levels was modulated by specific signal pathways. Carnosic acid (CA), which is found in the extracts of rosemary leaves, has antioxidant properties. We firstly showed that CA protected rats against chronic alcohol-induced liver injury. And we further found that the protection of CA was related with the inhibition of p66shc expression as a potential molecular mediator of hepatocellular mitochondrial oxidative stress and apoptosis by activating SIRT1 and was involved in downregulating miR-34a. On the basis of bioinformatics and researches, we firstly point out that the miR-34a/SIRT1-p66shc pathway maybe an important prevention strategy against alcohol-induced liver injury and the pathway plays a key role in the molecular mechanism that CA modulates. In this study a variety of molecular biology methods will be used for focusing on the significant role of miR-34a/SIRT1-p66shc pathway in the mechanism of chronic alcoholic liver injury and the regulation of CA. The study may provide new mechanisms for therapeutic intervention of ALD and represent an attractive pharmacological target for the development of CA to arrest ALD.

英文关键词： miRNA;SIRT1;p66shc;carnosic acid;alcohol liver injury