ATHEROSCLEROSIS AND APOLIPOPROTEIN A-I REGULATION

早期冠状动脉粥样硬化在人类中的发生率 人口。高度相关的是高浓度的 密度脂蛋白或其主要载脂蛋白A-I，这种情况 被称为低脂蛋白血症。的目标是 在本申请中提出的研究是为了阐明分子 负责调节生产的机制 高密度脂蛋白在载脂蛋白A-I基因表达水平。 为了明确载脂蛋白A-I基因的差异 并将这些差异与载脂蛋白A的变异联系起来。 我生产时，将使用最近描述的模型系统。它 公认的是，非洲绿猴发展出的 比食蟹猴严重的高胆固醇血症和动脉粥样硬化 猴子喂食时的胆固醇和脂肪水平与北方相似 美式饮食。这种差异的一个重要特征是 非洲绿猴的水平要高得多(3倍)。 血浆高密度脂蛋白和载脂蛋白A-I浓度高于食蟹猴， 可能有助于他们更强地抵抗 动脉粥样硬化的发展。此外，载脂蛋白A-I的mRNA 在肝脏和小肠中都发现了丰富的 与肝脏载脂蛋白A-I生成及载脂蛋白A-I水平相关 I非洲绿和食蟹鱼的血浆浓度 猴子。因此，在本申请中提出的研究将 试图确定这种特定物种的水平差异是否 反映了组织载脂蛋白A-I的不同调控和 灵长类载脂蛋白A-I基因的表达。为了做到这一点，载脂蛋白A-I 将从非洲绿和非洲绿中分离并测序 食蟹猴。序列之间的同源性程度 将对两个物种以及人类载脂蛋白A-I基因进行比较 序列。将测量载脂蛋白A-I转录的相对速率 而且，载脂蛋白A-I mRNA的稳态丰度测量将是 与肝组织载脂蛋白A-I基因转录速率相关 两种动物的小肠。载脂蛋白基因5‘侧翼序列 非洲绿猴和食蟹猴的A-I基因将是 通过删除映射分析进行分析，以确定监管 负责物种特异性表达的元件 灵长类载脂蛋白A-I基因。整个载脂蛋白A-I基因簇将是 在两个灵长类物种中进行研究，以确定载脂蛋白A-I， 载脂蛋白C-III和载脂蛋白A-VI是一个多基因家族。这个 通过完成这些研究所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.