MYOCARDIAL PROTEIN SYNTHESIS AFTER ALCOHOL INTOXICATION

酒精中毒后心肌蛋白质的合成

• 批准号: 6533642
• 负责人: THOMAS C VARY
• 金额: $ 27.41万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-22 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533642
• 关键词: alcoholism /alcohol abuse; ethanol; gender difference; genetic translation; heart pharmacology; laboratory rat; myocardium disorder; protein biosynthesis; protein metabolism disorder

The objective of the studies described herein are to gain a better understanding of the mechanisms by which chronic alcohol feeding induces derangements in myocardial protein metabolism. Alcoholism remains the most common form of drug abuse in the United States. Alcohol abuse is associated with an increased premature mortality. A leading etilogy of mortality is the development of a cardiomyopathy, diagnosed in approximately 35% of whose individuals who chronically abuse alcohol. The degree of cardiac dysfunction is proportional to the duration and severity of the alcohol consumption. Histological examination of biopsy specimens obtained from humans reveals a thinning of the ventricular wall, myocyte degeneration, loss of striations, and myofilament dissolution, consistent with alterations in structural and myofibrillar proteins. The underlying mechanisms responsible for these alterations remain unknown. It is our hypothesis that chronic alcohol consumption induces specific defects in the regulation of protein synthesis in cardiac muscle that ultimately are responsible for the histologic changes of the alcoholic cardiomyopathy. Preliminary studies have shown a 25% loss of cardiac protein/heart from animals consuming alcohol for 12 weeks. The loss of protein mass resulted, in part, from a diminished (30%) rate of protein synthesis. The block in protein synthesis occurred through an inhibition of translational efficiency, rather than a loss of ribosomes. Furthermore, the diminished translational efficiency is a result of proportional decreases in both peptide-chain initiation and elongation. Currently, there is no information concerning the biochemical loci or mechanism responsible for the inhibition of translational efficiency and hence protein synthesis following chronic ethanol intoxication. The experimental design addresses the following Specific Aims: (1) to determine the mechanism by which chronic alcohol consumption reduces peptide-chain initiation in heart; (2) to determine the mechanism by which chronic alcohol consumption reduces myocardial peptide-chain elongation; 3) to determine the mechanism by which acute alcohol consumption reduces translational efficiency for protein synthesis in heart.; (3) to investigate the expression of specific myocardial proteins following chronic alcohol consumption; and 4) to determine if there is a differential response in protein metabolism to chronic alcohol consumption between male and female rats. Overall, the research design will establish the processes by which myocardial protein synthesis is reduced following long and short term alcohol intoxication.

本文所述研究的目的是更好地了解长期饮酒引起心肌蛋白质代谢紊乱的机制。酗酒仍然是美国最常见的药物滥用形式。酗酒与过早死亡率增加有关。死亡的一个主要病因是患上心肌病，大约 35% 的长期酗酒者被诊断出患有心肌病。心脏功能障碍的程度与饮酒的持续时间和严重程度成正比。对人类活检标本的组织学检查显示心室壁变薄、肌细胞变性、条纹消失和肌丝溶解，这与结构和肌原纤维蛋白的变化一致。造成这些改变的潜在机制仍然未知。我们的假设是，长期饮酒会引起心肌蛋白质合成调节的特定缺陷，最终导致酒精性心肌病的组织学变化。初步研究表明，连续 12 周饮酒的动物的心脏蛋白/心脏会损失 25%。蛋白质质量的损失部分是由于蛋白质合成率降低（30%）造成的。蛋白质合成的阻碍是通过抑制翻译效率而不是核糖体的损失而发生的。此外，翻译效率的降低是肽链起始和延伸成比例减少的结果。目前，还没有关于慢性乙醇中毒后抑制翻译效率并因此抑制蛋白质合成的生化位点或机制的信息。实验设计致力于以下具体目标：（1）确定长期饮酒减少心脏肽链起始的机制； (2) 确定长期饮酒减少心肌肽链伸长的机制； 3) 确定急性饮酒降低心脏蛋白质合成转化效率的机制。 (3)研究长期饮酒后特定心肌蛋白的表达； 4) 确定雄性和雌性大鼠之间的蛋白质代谢对长期饮酒是否存在差异反应。总体而言，研究设计将建立长期和短期酒精中毒后心肌蛋白质合成减少的过程。