MACROPHAGE EXPRESSION OF APOAI AND ATHEROSCLEROSIS

APOAI 和动脉粥样硬化的巨噬细胞表达

• 批准号: 6760012
• 负责人: SERGIO FAZIO
• 金额: $ 33.98万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6760012
• 关键词: apolipoprotein E; apolipoproteins; atherosclerosis; blood lipoprotein metabolism; bone marrow transplantation; cellular pathology; cholesterol; complementary DNA; disease /disorder model; gene expression; gene targeting; gene therapy; genetically modified animals; high density lipoproteins; laboratory mouse; leukocyte activation /transformation; lipid metabolism; lipid transport; lipoprotein lipase; low density lipoprotein receptor; macrophage; model design /development; molecular pathology; tissue /cell culture; vascular endothelium

DESCRIPTION: (adapted from abstract) Recruitment of monocyte/macrophages into the subendothelial space is a mandatory step in the transition between vascular health and atherosclerotic lesion formation. Accumulation of lipids within the cytoplasm induces the transformation of macrophages into metabolically inert foam cells. Efflux of cholesterol from the macrophages cannot only delay foam cell formation but also activates reverse cholesterol transport. Apolipoprotein (apo) AI is one of the major physiologic determinants of cholesterol efflux from cells, but is not expressed by tissue macrophages. In previous studies, the applicant has shown that macrophage production of apoE (another acceptor of intracellular cholesterol) directly influences lesion formation in inbred C57BL/6 mice. Dr. Fazio hypothesizes that, if given the ability to produce apoAI, macrophages would be more efficient in getting rid of cholesterol and in activating HDL metabolism. To this end, his group has produced several lines of transgenic mice expressing the human apoAI under the control of a macrophage-specific promoter. In addition, they have developed a viable method for transduction of bone marrow with a retrovirus carrying the apoAI cDNA, and shown that transplantation of transduced marrow into irradiated mice will result in expression of apoAI from macrophages. The objectives of this research program are: i) To create and characterize transgenic mice with the ability to produce apoAI from the macrophage; ii) To evaluate the effect of macrophage apoAI expression on lipids and atherosclerosis in C57BL/6 mice and in mice lacking either the apoAI or the apoE gene; iii) To evaluate the effect of macrophage apoAI in ACAT-1-/- mice, a model of free cholesterol toxicity and inappropriate efflux; iv) To evaluate the feasibility of marrow transduction as a method for ex vivo delivery of apoAI to the macrophage. These studies can be expected to delineate the biology of foam cell formation and the importance of cholesterol efflux in atherogenesis. Moreover, these studies may lay the basis for a gene therapy approach to atherosclerosis.

描述：（改编自摘要）单核细胞/巨噬细胞招募至 内皮下间隙是血管与内皮细胞之间过渡的必要步骤， 健康和动脉粥样硬化病变形成。脂质在体内的积累 细胞质诱导巨噬细胞转化为代谢惰性细胞， 泡沫细胞胆固醇从巨噬细胞中流出不仅可以延缓泡沫形成， 细胞形成，而且还激活胆固醇逆向转运。载脂 (apo)AI是胆固醇流出的主要生理决定因素之一 从细胞，但不表达的组织巨噬细胞。在以前的研究中， 本申请人已经表明巨噬细胞产生apoE（apoE另一种受体） 细胞内胆固醇）直接影响近交系中病变的形成 c57 bl/6小鼠法齐奥博士假设，如果有能力产生 apoAI，巨噬细胞将更有效地摆脱胆固醇， 激活HDL代谢。为此，他的团队制作了几条线， 表达人apoAI的转基因小鼠在一种 巨噬细胞特异性启动子。此外，他们还开发了一种可行的方法， 用于用携带apoAI cDNA的逆转录病毒转导骨髓，和 表明将转导的骨髓移植到受辐射的小鼠中将 导致巨噬细胞表达apoAI。本研究的目标 i）创建和表征具有以下能力的转基因小鼠： 从巨噬细胞产生apoAI; ii）评估巨噬细胞的作用 载脂蛋白AI在C57 BL/6小鼠和小鼠脂质和动脉粥样硬化中的表达 缺乏apoAI或apoE基因; iii）评估apoAI或apoE基因的影响 ACAT-1-/-小鼠中的巨噬细胞apoAI，游离胆固醇毒性模型， iv）评估骨髓转导作为治疗的可行性， 一种将apoAI离体递送至巨噬细胞的方法。这些研究可以 期望描绘泡沫细胞形成的生物学和 动脉粥样硬化形成中的胆固醇流出。此外，这些研究可能奠定了基础， 动脉粥样硬化的基因治疗方法