Myocardial Protein Synthesis After Alcohol Intoxication

酒精中毒后心肌蛋白质的合成

基本信息

批准号：
7146446
负责人：
THOMAS C VARY
金额：
$ 31.13万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-22 至 2011-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the mechanisms by which alcohol consumption induces myofibrillar damage characteristic of alcoholic heart muscle disease. Alcoholism remains the most common form of drug abuse in the United States. Alcohol abuse is associated with an increased premature mortality partly resulting from the development of an alcohol-induced cardiomyopathy, a condition diagnosed in approximately 35% of whose individuals who chronically consume excessive amounts of alcohol. The mechanisms leading to alcohol-dependent myocardial dysfunction are multifactorial, but altered expression of myocardial proteins appears as a central mechanism. Studies completed during the current funding period established that alcohol consumption inhibits rates of protein synthesis in heart at the level of mRNA translation. By understanding the alterations in the process of mRNA translation it is hoped that new strategies could be developed to combat the pathologic derangements in cardiac muscle structure and function associated with chronic alcoholism. We delineated two regulatory steps in the process of protein synthesis, the formation of an active elF4E-elF4G complex and the process of elongation that are responsible, in part, for the inhibition of protein synthesis during chronic alcohol administration, whereas acute alcohol intoxication only affects the formation of an active elF4E-elF4G complex. We hypothesize that the normal signaling path-way through mTOR responsible for maintaining the functioning of these two steps in protein synthesis at rates observed in control animals is severely compromised by ethanol intake. The net effect is manifested through alterations in the expression of myocardial proteins including contractile proteins. We further hypothesize that provision of amino acids either through acute gavage or meal feeding to rats administered alcohol can stimulate mTOR leading to an acceleration of rates of protein synthesis. The experimental design for the forthcoming project period addresses the following Specific Aims in order to test the hypothesis that: 1) Alcohol consumption reduces mTOR activity resulting in dephosphorylation of 4E-BP1 and S6K1, thereby limiting myocardial protein synthesis by reducing formation of active elF4G-elF4E complex; 2) Stimulating mTOR activity with aminp acid supplementation reverses the alcohol-induced inhibition of myocardial protein synthesis; 3) Inhibition of protein synthesis in response to chronic alcohol feeding shifts myocardial protein expression; and 4) Genetic ablation of mTOR causes functional and biochemical derangements in the myocardium similar to those observed with chronic alcohol intake. Overall, the research design will establish the mechanism by which myocardial protein synthesis is reduced in response to alcohol abuse.

描述（由申请人提供）：该项目的长期目标是了解饮酒引起酒精性心肌病的肌原纤维损伤的机制。酗酒仍然是美国最常见的药物滥用形式。酒精滥用与过早死亡率增加有关，部分原因是酒精诱发的心肌病的发展，大约 35% 的长期过量饮酒的人被诊断出患有这种疾病。导致酒精依赖性心肌功能障碍的机制是多因素的，但心肌蛋白表达的改变似乎是一个核心机制。在当前资助期间完成的研究表明，饮酒会在 mRNA 翻译水平上抑制心脏中蛋白质的合成速率。通过了解 mRNA 翻译过程的变化，希望能够开发出新的策略来对抗与慢性酒精中毒相关的心肌结构和功能的病理紊乱。我们描述了蛋白质合成过程中的两个调节步骤，即活性 elF4E-elF4G 复合物的形成和延伸过程，它们在一定程度上负责长期饮酒期间蛋白质合成的抑制，而急性酒精中毒仅影响活性elF4E-elF4G复合物的形成。我们假设通过 mTOR 的正常信号通路负责维持蛋白质合成中这两个步骤的功能，在对照动物中观察到的速率受到乙醇摄入的严重损害。净效应通过心肌蛋白（包括收缩蛋白）表达的改变来体现。我们进一步假设，通过急性强饲法或膳食喂养给给予酒精的大鼠提供氨基酸可以刺激 mTOR，从而加速蛋白质合成速率。即将到来的项目期的实验设计解决了以下具体目标，以检验以下假设：1) 饮酒会降低 mTOR 活性，导致 4E-BP1 和 S6K1 去磷酸化，从而通过减少活性 eF4G- 的形成来限制心肌蛋白质合成。 eF4E复合体； 2）补充氨基酸刺激mTOR活性可逆转酒精引起的心肌蛋白质合成抑制； 3) 长期饮酒对蛋白质合成的抑制会改变心肌蛋白质的表达； 4) mTOR 的基因消融会导致心肌功能和生化紊乱，类似于长期饮酒时观察到的情况。总体而言，研究设计将建立因酗酒而减少心肌蛋白质合成的机制。