PREVENTION OF ATHEROSCLEROSIS BY GENE TRANSFER

通过基因转移预防动脉粥样硬化

• 批准号: 3426095
• 负责人: RICHARD H. GOODMAN
• 金额: $ 5.04万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-25 至 1988-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3426095
• 关键词: apolipoproteins; atherosclerosis; cardiovascular disorder prevention; coronary disorder; disease /disorder model; gene expression; gene therapy; genetic manipulation; high density lipoproteins; tissue /cell culture

Coronary artery disease (CAD) due to atherosclerosis is the leading cause of death and disability in our society. Plasma HDL cholesterol is the best available biochemical predictor of CAD. Low HDL levels are correlated with an increased incidence of premature CAD and high HDL levels are thought to be protective. Apolipoprotein Al (Apo Al) is the major protein constituent of HDL particles. Infusion of Apo Al into animals leads to an elevation in plasma levels of HDL. The timecourse for development of atherosclerosis makes it impractical to administer Apo Al by infusion however. We propose to use gene transfer techniques to test whether mice predisposed to atherosclerosis can be protected by over-expressing the gene for human Apo Al. One of the most common and easily available inbred strains of mice, C57/BL6, is the ideal model for our studies. We have already demonstrated in tissue culture that mouse fibroblasts transfected with an Apo Al expression vector produce HDL. We have also developed the capacity to produce lines of transgenic mice. We now propose to construct additional Apo Al expression vectors based on viral promoters and test these vectors in fibroblast and hepatoma cells. The viral promoter-Apo Al fusion genes will subsequently be used to produce lines of transgenic mice that express high levels of Apo Al. Mice that express high levels of HDL will be assayed for their resistance to atherosclerosis.

由动脉粥样硬化引起的冠状动脉疾病（CAD）是 我们社会死亡和残疾的主要原因。 血浆高密度脂蛋白 胆固醇是 CAD 的最佳生化预测因子。 低 HDL 水平与以下疾病的发生率增加相关： 过早发生 CAD 和高 HDL 水平被认为具有保护作用。 载脂蛋白 Al (Apo Al) 是 高密度脂蛋白颗粒。 将 Apo Al 输注到动物体内会导致 血浆高密度脂蛋白水平升高。 时间进程为 动脉粥样硬化的发展使得给药变得不切实际 然而，通过输注 Apo Al。 我们建议使用基因转移 测试小鼠是否易患动脉粥样硬化的技术 可以通过过度表达人 Apo Al 基因来保护。 最常见和最容易获得的近交系之一 小鼠 C57/BL6 是我们研究的理想模型。 我们有 已经在组织培养中证明小鼠成纤维细胞 用Apo A1表达载体转染产生HDL。 我们 还开发了生产转基因品系的能力 老鼠。 我们现在建议构建额外的 Apo Al 表达 基于病毒启动子的载体并在中测试这些载体 成纤维细胞和肝癌细胞。 病毒启动子-Apo Al融合体 基因随后将被用于生产转基因品系 表达高水平 Apo Al 的小鼠。 表达高的小鼠 HDL 水平将被测定其抵抗力 动脉粥样硬化。