Ethanol Hepatotoxicity and NO-Dependent Mitochondrial Dysfunction

描述（由申请方提供）：乙醇引起的缺氧增加通过尚不清楚的机制导致肝毒性。线粒体功能障碍和相关的活性氧和氮物质（ROS/RNS）的形成似乎是酒精暴露在肝脏中的后果。我们假设，乙醇依赖性缺氧涉及一氧化氮（NO）与线粒体呼吸链相互作用的贡献，这已得到支持的研究在以前的资助期。在这种竞争性更新中，我们建立在这些发现的基础上，这些发现表明：a）对线粒体呼吸的NO依赖性抑制的敏感性增强发生在暴露于酒精的早期B）这种反应在缺乏诱导型NO合酶同种型的小鼠中被消除c）这些变化与线粒体蛋白质组的变化以及蛋白质和线粒体DNA的氧化修饰有关。这些数据导致了这样的假设，即酒精肝毒性通过增加线粒体功能障碍而加剧，并且这些影响将通过靶向抗氧化剂来改善。这一概念将通过追求以下具体目标来检验：1.确定脑靶向抗氧化剂（MTA）对酒精依赖性肝毒性和缺氧发展的影响。第二章：确定MTA对线粒体蛋白活性的慢性酒精依赖性变化的影响，对NO抑制呼吸链的敏感性和对mtDNA的损伤。3：确定MTA对线粒体蛋白质组的乙醇依赖性修饰的影响。该项目将通过定义导致慢性酗酒引起的肝脏损伤的机制来为公共卫生做出贡献。此外，将测试使用一类新药物的可能性，这些药物针对产生能量的细胞部分，以逆转或防止酒精的这些毒性作用。

DESCRIPTION (provided by applicant): Increased hypoxia in response to ethanol contributes to hepatotoxicity through mechanisms that are not understood in detail. Mitochondrial dysfunction and the associated formation of reactive oxygen and nitrogen species (ROS/RNS) appear to be a consequence of alcohol exposure in the liver. We hypothesized that ethanol-dependent hypoxia involved a contribution from the nitric oxide (NO) interaction with the mitochondrial respiratory chain, and this has been supported by studies undertaken in the previous funding period. In this competing renewal, we build upon these findings that demonstrate a) enhanced sensitivity to the NO-dependent inhibition of mitochondrial respiration occurs early on exposure to alcohol b) this response is ablated in mice lacking the inducible NO synthase isoform c) these changes are associated with changes in the mitochondrial proteome and oxidative modification of proteins and mitochondrial DNA. These data have led to the hypothesis that alcohol hepatotoxicity is exacerbated through increased mitochondrial dysfunction and these effects will be ameliorated by mitochondrially targeted antioxidants. This concept will be tested by pursuit of the following Specific Aims: 1. Determine the effect of mitochondrially targeted antioxidants (MTA) on the development of alcohol-dependent hepatoxicity and hypoxia. 2: Determine the effects of MTA on the chronic alcohol-dependent changes in activity of mitochondrial proteins, sensitivity to inhibition of the respiratory chain by NO and damage to mtDNA. 3: Determine the effects of MTA on the ethanol dependent modifications of the mitochondrial proteome. This project will contribute to public health through defining the mechanisms that lead to the liver damage that occurs in response to chronic alcoholism. In addition, the possibility of using a new class of drugs directed to the parts of the cell that produce energy to reverse or prevent these toxic effects of alcohol will be tested.