AOP2 AND ATHEROSCLEROSIS RESISTANCE AND MICE

AOP2 和动脉粥样硬化抵抗与小鼠

• 批准号: 6139127
• 负责人: Shelley A Phelan
• 金额: $ 3.67万
• 依托单位: FAIRFIELD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-12 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6139127
• 关键词: animal breeding; atherosclerosis; disease /disorder model; gene expression; genetic promoter element; genetic susceptibility; genetically modified animals; in situ hybridization; laboratory mouse; model design /development; molecular cloning; nucleic acid sequence; oxidative stress; polymerase chain reaction; tissue /cell culture

DESCRIPTION Previous studies from our laboratory have demonstrated that susceptibility to atherosclerosis differs significantly between inbred strains of mice, suggesting a strong genetic component to the disease. Athl is a quantitative trait locus that we found to be associated with decreased plasma HDL-cholesterol levels and increased atherosclerotic lesion formation in susceptible strains of mice when fed a high fat diet. We have recently identified a Athl candidate gene, Aop2, which is a member of the thiol-specific antioxidant family. We believe Aop2 mediates protection from atherosclerosis based on its chromosomal co-localization with Athl, mRNA induction by high fat diet, amino acid and expression differences between resistant and susceptible strains, and the proposed role of LDL oxidation in the pathogenesis of atherosclerosis. I propose three specific aims toward the characterization of AOP2 in atherosclerosis resistance: 1) obtain definitive proof that AOP2 confers resistance to atherosclerosis by transgenic rescue; 2) characterize expression of AOP2 in the arterial wall; and 3) determine the molecular basis for the regulatory differences observed between atherosclerosis resistant and susceptible strains.

描述 我们实验室以前的研究表明， 对动脉粥样硬化的影响在近交系小鼠之间有显著差异， 这表明这种疾病有很强的遗传因素Athl是一个 数量性状基因座，我们发现与减少 血浆HDL-胆固醇水平和动脉粥样硬化病变增加 当喂食高脂肪饮食时，在易感品系的小鼠中形成。我们有 最近发现了一个Athl候选基因Aop 2，它是一个成员， 巯基特异性抗氧化剂家族。我们认为Aop 2介导了保护作用， 基于其与Athl的染色体共定位， 高脂饲料对mRNA的诱导、氨基酸及表达差异 耐药和敏感菌株之间的关系，以及LDL的作用 氧化在动脉粥样硬化的发病机制。我建议三个具体的 目的在于表征AOP 2在动脉粥样硬化抗性中的作用：1） 获得AOP 2赋予抗动脉粥样硬化的确切证据， 转基因拯救; 2）表征动脉中AOP 2的表达 壁;和3）确定调节差异的分子基础 观察动脉粥样硬化抵抗和敏感株之间。