NUTRITIONAL EFFECTS ON TRANSFER PROTEIN GENE EXPRESSION

营养对转移蛋白基因表达的影响

• 批准号: 3361681
• 负责人: ALAN richard TALL
• 金额: $ 19.01万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3361681
• 关键词: Cercopithecidae; Macaca fascicularis; animal tissue; atherosclerosis; blood lipoprotein metabolism; cholesterol esters; dietary lipid; gene expression; genetic mapping; genetic regulatory element; genetically modified animals; human genetic material tag; human tissue; in situ hybridization; laboratory mouse; messenger RNA; nucleic acid probes; nucleic acid sequence; nutrition related tag; pathogenic diet; protein transport; tissue /cell culture; transfection

The plasma cholesteryl ester transfer protein (CETP) promotes the transfer of neutral lipids between the plasma lipoproteins and may play a role in determining the susceptibility of different species to atherosclerosis. The objectives are to investigate nutritional influences on the expression of the CETP gene, to elucidate the structure of the human CETP gene and its regulatory elements, and to explore the role of CETP in lipoprotein physiology and atherosclerosis. Recent studies have shown that rabbits fed an atherogenic diet develop increased levels of CETP mRNA in their livers and an increased mass of CETP in plasma. In the proposed studies the effects of dietary cholesterol and saturated fat on CETP mRNA levels in liver and other tissues, and the relationship of CETP levels to atherosclerosis, will be investigated in Cynomolgus and African green monkeys. The transcription start site, intron/exon organization and flanking DNA sequences of the human CETP gene will be elucidated, and the gene will be transfected into cultured cells. Regulatory elements of the CETP gene, required for basal or lipoprotein-stimulated expression, will be defined in tissue culture. Mice lack an endogenous gene homologous to CETP, and are resistant to dietary atherosclerosis. In collaboration with Dr. J. Breslow, the human CETP gene, containing an inducible promoter, will be introduced into mice, and the effects of CETP induction on lipoprotein profiles and atherosclerosis will be determined. CETP transgenic mice will also be inbred with transgenic mice expressing high levels of human apoA-I or with other strains susceptible or resistant to dietary atherosclerosis. Finally, transgenic mice will be prepared using the natural promoter and enhancers of the CETP gene, in order to elucidate tissue-specific and diet-responsive elements of the CETP gene in vivo. These experiments will provide new information on the CETP gene and its regulation, especially by nutritional factors, and should help to elucidate the impact of CETP gene expression on lipoprotein physiology and atherosclerosis.

血浆胆固醇酯转移蛋白（CETP）促进 血浆脂蛋白之间中性脂质的转移，可能起到 在确定不同物种的易感性方面发挥着作用 动脉粥样硬化。 目的是研究营养 CETP基因表达的影响，以阐明 人类CETP基因及其调控元件的结构，以及 探讨CETP在脂蛋白生理学和动脉粥样硬化中的作用。 最近的研究表明，喂食致动脉粥样硬化饮食的兔子会出现动脉粥样硬化的情况。 肝脏中 CETP mRNA 水平增加，并且肝脏中的 CETP 质量增加 血浆中的CETP。 在拟议的研究中，饮食的影响 胆固醇和饱和脂肪对肝脏和其他部位CETP mRNA水平的影响 组织以及 CETP 水平与动脉粥样硬化的关系 在食蟹猴和非洲绿猴中进行了研究。 转录 起始位点、内含子/外显子组织和侧翼 DNA 序列 人类CETP基因将被阐明并转染该基因 进入培养细胞。 CETP 基因的调控元件，是 基础或脂蛋白刺激的表达，将在组织中定义 文化。 小鼠缺乏与CETP同源的内源基因，并且 抵抗饮食动脉粥样硬化。 与 J 博士合作 Breslow，人类 CETP 基因，含有诱导型启动子，将被 导入小鼠体内，以及CETP诱导对脂蛋白的影响 将确定概况和动脉粥样硬化。 CETP转基因小鼠 还将与表达高水平人类基因的转基因小鼠近交 apoA-I 或其他对饮食敏感或耐药的菌株 动脉粥样硬化。 最后，将使用以下方法制备转基因小鼠： CETP基因的天然启动子和增强子，以阐明 CETP 基因的体内组织特异性和饮食反应元件。 这些实验将提供有关CETP基因及其相关信息的新信息。 调节，尤其是营养因素的调节，应该有助于 阐明CETP基因表达对脂蛋白生理学的影响 和动脉粥样硬化。