ATHEROSCLEROSIS AND APOLIPOPROTEIN A-I REGULATION

动脉粥样硬化和载脂蛋白 A-I 调节

基本信息

批准号：
2220202
负责人：
Mary G Sorci-Thomas
金额：
$ 10.25万
依托单位：
WAKE FOREST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-12-01 至 1994-11-30
项目状态：
已结题

项目摘要

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.

人类冠状动脉粥样硬化过早发生率人口。与高浓度的降低高度相关密度脂蛋白或其主要载脂蛋白A-I，这种情况被称为低α脂蛋白血症。的目标本申请中提出的研究旨在阐明分子负责调节生产的机制 apo-A-I 基因表达水平的高密度脂蛋白。为了清楚地定义基于apo A-I基因的差异表达并将这些差异与 apo A 的变异联系起来我的制作中，将使用最近描述的模型系统。它众所周知，非洲绿猴发育较弱高胆固醇血症和动脉粥样硬化比食蟹猴严重喂食的猴子胆固醇和脂肪水平与北方相似美国饮食。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 HDL 和 apo A-I 浓度高于食蟹猴，可能有助于增强其抵抗力的因素动脉粥样硬化的发展。此外，apo A-I mRNA 已发现肝脏和小肠中的丰富性与肝脏 apo A-I 产生和 apo A- 水平相关 I 非洲绿猴和食蟹猴的血浆浓度猴。因此，本申请中提出的研究将试图确定这种水平是否存在物种特异性差异组织apo A-I mRNA的差异反映了调节和灵长类 apo A-I 基因的表达。为此，apo A-I 基因将从非洲绿和食蟹猴。之间的序列同源性程度将比较两个物种以及人类 apo A-I 基因顺序。将测量 apo A-I 转录的相对速率并且，apo A-I mRNA 稳态丰度测量值将是与肝脏的 apo A-I 基因转录率相关两个物种的小肠。 apo 的 5' 侧翼序列非洲绿猴和食蟹猴的 A-I 基因将通过删除图谱分析来识别监管负责物种特异性表达的元件灵长类动物 apo A-I 基因。整个apo A-I基因簇将是在两种灵长类动物中进行了研究，以确定 apo A-I 是否 apo C-III 和 apo A-VI 作为多基因家族存在。这完成这些研究所获得的知识将被使用制定治疗低α脂蛋白血症的策略和冠心病。