ATHEROSCLEROSIS AND APOLIPOPROTEIN A-I REGULATION

人早发冠状动脉粥样硬化的发病率 人口 与高浓度 密度脂蛋白或其主要载脂蛋白A-I，这种情况 称为低脂蛋白血症。 的目标 在本申请中提出的研究是为了阐明 负责管理生产的机制 高密度脂蛋白在apo-A-I基因表达水平。 为了明确定义基于载脂蛋白A-I基因的差异， 表达，并将这些差异与载脂蛋白A的变化联系起来。 在生产中，将使用最近描述的模型系统。 它 非洲绿色猴的发育速度 严重的高胆固醇血症和动脉粥样硬化比食蟹猴 猴子当喂养的胆固醇和脂肪水平类似北方 美国饮食 这种差异的一个重要特征是， 非洲绿色猴的水平高得多（3倍） 血浆HDL和apo A-I浓度的显著性差异， 这些因素可能有助于他们更大的抵抗能力， 动脉粥样硬化的发展。 此外，载脂蛋白A-I mRNA 在肝脏和小肠中的丰度被发现， 与肝脏apo A-I产生水平和apo A-相关 非洲绿色和食蟹猴的I血浆浓度 猴子. 因此，本申请中提出的研究将 试图确定这种物种特异性的水平差异 组织载脂蛋白A-I mRNA的表达反映了调节的差异， 灵长类apo A-I基因的表达。 为此，载脂蛋白A-I 将从非洲绿色和 食蟹猴 序列之间的同源性程度 两个物种将进行比较，以及人类载脂蛋白A-I基因 顺序 将测量载脂蛋白A-I转录的相对速率 并且，载脂蛋白A-I mRNA稳态丰度测量将是 与肝脏载脂蛋白A-I基因转录速率相关， 两个物种的小肠。 载脂蛋白5 '侧翼序列 非洲绿色猴和食蟹猴的A-I基因将被 通过缺失作图分析进行分析，以鉴定调控基因。 元件负责物种特异性表达的 灵长类载脂蛋白A-I基因。 整个载脂蛋白A-I基因簇 在两种灵长类动物中进行研究以确定载脂蛋白A-I， apo C-III和apo A-VI作为多基因家族存在。 的 通过完成这些研究获得的知识将被用于 制定治疗低脂蛋白血症的策略， 和冠心病。

The incidence of premature coronary atherosclerosis in the human population. Highly correlated to decreased concentrations of high density lipoprotein or its major apolipoprotein A-I, this condition is referred to as hypoalphalipoproteinemia. The goal of the studies proposed in this application are to elucidate the molecular mechanisms which are responsible for regulating the production of high density lipoproteins at the level of apo-A-I gene expression. In order to clearly define differences based on apo A-I gene expression and to relate these differences to variation in apo A- I production, a recently described model system will be used. It is well established that the African green monkey develops a less severe hypercholesterolemia and atherosclerosis than the cynomolgus monkey when fed levels of cholesterol and fat resembling the North American diet. An important feature of this difference is that African green monkeys have a substantially higher (3 fold) level of plasma HDL and apo A-I concentration than cynomolgus monkeys, factors which may contribute to their greater ability to resist the development of atherosclerosis. Furthermore, apo A-I mRNA abundance in both the liver and small intestine have been found to correlate with the level of hepatic apo A-I production and apo A- I plasma concentration for both the African green and cynomolgus monkey. The studies proposed in this application, therefore, will seek to determine if this species-specific difference in the levels of tissue apo A-I mRNA reflect differences in the regulation and expression of the primate apo A-I gene. To do this, the apo A-I gene will be isolated and sequenced from both African green and cynomolgus monkeys. The degree of sequence homology between the two species will be compared, as well as to the human apo A-I gene sequence. Relative rates of apo A-I transcription will be measured and, the apo A-I mRNA steady state abundance measurements will be correlated to the rates of apo A-I gene transcription for liver and small intestine in both species. 5'flanking sequences of the apo A-I gene for both the African green and cynomolgus monkey will be analyzed by deletion mapping analysis to identify regulatory elements which responsible for species-specific expression of the primate apo A-I gene. The entire apo A-I gene cluster will be investigated in both primate species to determine whether apo A-I, apo C-III and apo A-VI exists as a multi-gene family. The knowledge gained by the completion of these studies will be used to develop strategies for the treatment of hypoalphalipoproteinemia and coronary heart disease.