CETP, HDL AND ATHEROGENESIS

我们最近的研究显示冠心病的发病率增加 基因突变的日裔美国男性的冠心病（CHD） 胆固醇酯转移蛋白（CETP）基因，尽管HDL增加 程度. 同样，我们观察到早期动脉粥样硬化的减少， 在具有降低的HDL水平的CETP转基因（Tg）小鼠中。 一起 这些发现表明CETP表达的显性效应 可以是抗动脉粥样硬化的。 然而，抗动脉粥样硬化 在Tg小鼠中CETP表达的影响仅在 apoCIII转基因表达导致的高脂血症背景。 总体目标是进一步评估CETP与 高密度脂蛋白对人类和小鼠动脉粥样硬化形成的影响， 基本机制。 具体目标是：（1）评估 CETP在apoB Tg易感小鼠动脉粥样硬化形成中的表达及其与动脉粥样硬化的关系 定义与高脂血症相关的潜在机制，或 逆转胆固醇转运; 2）评价新的抗动脉粥样硬化药物 CETP和HDL在动脉壁水平介导的作用， 动脉壁细胞表达CETP或apoA-I的apoB Tg小鼠 过度表达或糖尿病;和3）研究机制 负责增加冠心病在人类遗传CETP缺乏症， 鉴定CETP或肝脂酶基因的常见变体， 与CHD相关的变体。 拟议的研究涉及合作 与项目19 HDL/CETP对LDL聚集的影响， 动脉潴留），2（脂蛋白大小与apoCIII基因的关系 VLDL动脉流入和动脉粥样硬化形成的变化），4（ HDL和脂质转移对糖尿病小鼠动脉粥样硬化形成的影响）和5（作用 高密度脂蛋白介导干扰素-γ降低动脉粥样硬化形成 受体0/apoE 0小鼠）;并使用分子生物学核心， 开发Tg小鼠和对人类DNA样品进行基因分型， 用于表征和定量的病理学核心 小鼠动脉粥样硬化病变和临床/生物统计学核心 人类研究 该项目与SCOR的两个主要主题有关： 使用诱导突变小鼠研究动脉粥样硬化形成的机制 并鉴定基因变异， 关于人类CHD风险的新信息。

Our recent studies reveal an increased prevalence of coronary heart disease (CHD) in Japanese-American men with mutations in the cholesteryl ester transfer protein (CETP) gene despite increased HDL levels. Similarly, we have observed a decrease in early atherosclerosis in CETP transgenic (Tg) mice with decreased HDL levels. Together these findings suggest that the dominant effects of CETP expresssion in vivo may be anti-atherogenic. However, the anti-atherogenic effects of CETP expression in Tg mice were only observed int he context of hypertriglyceridemia due to apoCIII transgene expression. The overall goals are to evaluate further the relationship of CETP and HDL to atherogenesis in humans and mice and to define the underlying mechanisms. The specific aims are 1) to assess effects of CETP expression on atherogenesis in susceptible apoB Tg mice and to define underlying mechanisms related to hypertriglyceridemia or reverse cholesterol transport; 2) to evaluate novel anti-atherogenic effects of CETP and HDL mediated at the level of the arterial wall in apoB Tg mice with expression CETP in arterial wall cells or apoA-I overexpression or diabetes; and 3) to investigate mechanisms responsible for increased CHD in human genetic CETP deficiency, to identify common variants of CETP or hepatic lipase genes and to relate variants to CHD. The proposed research involves collaborations with Projects 1 9effects of HDL/CETP on LDL aggregation and arterial retention), 2 (relationship of lipoprotein size and apoCIII gene variation to VLDL arterial influx and atherogenesis), 4 (effects of HDL and lipid transfer on atherogenesis in diabetic mice) and 5 (role of HDL in mediating decreased atherogenesis in interferon-gamma receptor 0/apoE0 mice); and uses the Molecular Biology Core for development of Tg mice and for genotyping human DNA samples, the Pathology Core for the characterizaiton and quantitation of atherosclerotic lesions in mice and the Clinical/Biostatistics Core for human studies. The project is tied to two major SCOR themes: the use of induced mutant mice to investigate mechanisms of atherogenesis in the vessel wall and the identification of gene variants that provide novel information on human CHD risk.