SPECIFIC MYOCARDIAL METABOLITES OF ETHANOL

此续期申请中建议的研究针对的是 酒精所致终末器官的分子病理生理研究 疾病，尤其是与非氧化乙醇代谢有关的疾病 肝外器官。脂肪酸乙酯合成酶，发现于 1981年在首席研究员的实验室中发现了心肌组织， 催化乙醇生成脂肪酸乙酯。这些 脂肪在人体器官中积累，最常见的是酗酒造成的损害， 它们在这些器官中的合成速度最快，它们导致 线粒体功能受损，这是酒精性终末的标志 器官受损。由于心脏和胰腺等许多器官缺乏氧化 酒精的新陈代谢，这一途径可能在 酒精摄入与酒精诱导的遗传易损性 终末器官疾病，如胰腺炎和心肌病。建议 研究将集中在人类的生化特征上 胰腺次要脂肪酸乙酯合成酶，因为该酶是 现在已知在胰腺中含量最多(科学 231：497,1986)，因为次要合成酶占大多数 合酶活性。其四种分子形式(200、100、67和52 kDa) 将全部提纯到同质，表征和蛋白质序列 确定的部分原因是允许使用重组DNA技术。这些遗嘱 用于检测限制性片段长度多态，克隆 合成酶，并提供其基因的染色体定位。这个 结果直接与在植物体内建立分子连接有关 酒精性终末器官损害的遗传病理生理学研究。

Proposed studies in this renewal application are directed at investigating the molecular pathophysiology of alcohol-induced end organ disease, especially as it relates to non-oxidative ethanol metabolism in extra-hepatic organs. Fatty acid ethyl ester synthases, discovered in myocardium in the laboratory of the principal investigator in 1981, catalyze the formation of fatty acid ethyl esters from ethanol. These lipids accumulate in human organs most commonly damaged by alcohol abuse, their rates of synthesis are greatest in these organs and they cause impairment of mitochondrial function, a hallmark of alcohol-induced end organ damage. Since many organs such as heart and pancreas lack oxidative metabolism of alcohol, this pathway may provide a crucial link between ethanol ingestion and genetic vulnerabilities found in alcohol-induced end-organ diseases, such as pancreatitis and cardiomyopathy. Proposed studies will focus on the biochemical characterization of the human pancreatic minor fatty acid ethyl ester synthase because the enzyme is now known to be present in the greatest amount in pancreas (Science 231:497, 1986) and because the minor synthase accounts for the majority of synthase activity. Its four molecular forms (200, 100, 67 and 52 kDa) will be all purified to homogeneity, characterized and protein sequences determined in part to allow use of recombinant DNA techniques. These will be employed to detect restriction fragment length polymorphisms, clone the synthases and provide chromosomal localization of their genes. The results directly relate to establishing molecular links in the pathophysiology of alcohol-induced end organ damage at the genetic level.