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.

人类过早冠状动脉粥样硬化的发生率人口。高度相关的高浓度密度脂蛋白或其主要载脂蛋白A-I，这种情况被称为降低脂肪蛋白血症。目标的目标在此应用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Apo-A-I基因表达水平上。为了明确定义基于APO A-I基因的差异表达并将这些差异与apo a-的变化联系起来 I生产，将使用最近描述的模型系统。它已经很好地表明，非洲绿猴的发展较少严重的高胆固醇血症和动脉粥样硬化比cynomolgus 当喂胆固醇和脂肪的水平类似于北部时，猴子美国饮食。这种差异的一个重要特征是非洲绿色猴子的水平更高（3倍）血浆HDL和APO A-I浓度比Cynomolgus猴子的浓度，可能有助于其更大能力抵抗的因素动脉粥样硬化的发展。此外，apo a-i mRNA 发现肝脏和小肠中的丰度与肝APO A-1产生和apo A-的水平相关 I非洲绿色和cynomolgus的血浆浓度猴。因此，在本应用中提出的研究将试图确定这种物种特定水平的差异是否组织apo a-i mRNA反映了调节的差异和灵长类动物A-I基因的表达。为此，apo a-i 基因将与非洲绿色和 cynomolgus猴子。序列同源性的程度将比较两个物种，以及人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基因转录率相关两种物种中的小肠。 5'Flanking Apo的序列非洲绿色和cynomolgus猴子的A-I基因将是通过删除映射分析分析以识别调节负责物种特异性表达的元素灵长类动物A-I基因。整个Apo A-I基因簇将是在两个灵长类动物中进行了研究，以确定Apo A-I是否是否 APO C-III和APO A-VI作为一个多基因家庭存在。这通过完成这些研究获得的知识将被使用制定治疗降低脂肪蛋白血症的策略和冠心病。