CETP, HDL AND ATHEROGENESIS

我们最近的研究显示冠心病患病率增加。 基因突变的日裔美国男性的疾病(CHD) 胆固醇酯转运蛋白(CETP)基因，尽管高密度脂蛋白升高 级别。同样，我们也观察到早期动脉粥样硬化的减少。 在高密度脂蛋白水平降低的CETP转基因(TG)小鼠中。同舟共济 这些发现表明CETP表达的显性效应 体内可能具有抗动脉粥样硬化作用。然而，抗动脉粥样硬化 仅观察到转基因小鼠CETP表达的影响 载脂蛋白CIII转基因表达引起的高甘油三酯血症。 总体目标是进一步评估CETP与 高密度脂蛋白在人类和小鼠动脉粥样硬化形成中的作用 潜在的机制。具体目标是：1)评估 CETP在载脂蛋白B-TG易感小鼠动脉粥样硬化形成中的表达 明确与高甘油三酯血症相关的潜在机制 胆固醇逆向转运；2)评价新型抗动脉粥样硬化药物 CETP和高密度脂蛋白在动脉壁水平的作用 动脉壁细胞或载脂蛋白A-I表达CETP的载脂蛋白B转基因小鼠 过度表达或糖尿病；以及3)研究机制 对人类CETP基因缺陷导致的CHD增加负责， 确定CETP或肝脂酶基因的常见变体并 将变异与CHD联系起来。拟议的研究涉及合作 与项目19高密度脂蛋白/CETP对低密度脂蛋白聚集和 2(脂蛋白大小与apoCIII基因的关系 变异到极低密度脂蛋白动脉内流和动脉粥样硬化)，4(影响 高密度脂蛋白和脂质转移在糖尿病小鼠动脉粥样硬化形成中的作用)和5(作用 高密度脂蛋白在干扰素-γ降低动脉粥样硬化形成中的作用 受体0/apoE0小鼠)；并使用分子生物学核心 转基因小鼠的发育和人类DNA样本的基因分型 定性和定量研究的病理学核心 小鼠动脉粥样硬化病变及其临床/生物统计学核心 人体研究。该项目与SCOR的两个主要主题有关： 利用诱变小鼠研究动脉粥样硬化的发生机制 在血管壁和鉴定基因变种提供 关于人类冠心病风险的新信息。

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.