MACROPHAGE EXPRESSION OF APOAI AND ATHEROSCLEROSIS

APOAI 和动脉粥样硬化的巨噬细胞表达

• 批准号: 6390892
• 负责人: SERGIO FAZIO
• 金额: $ 34.09万
• 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/6390892
• 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：(摘自摘要)将单核/巨噬细胞募集到 内皮下间隙是血管和血管之间过渡的必经步骤 健康和动脉粥样硬化病变的形成。脂肪在体内的堆积 细胞质诱导巨噬细胞转变为代谢惰性细胞 泡沫细胞。巨噬细胞胆固醇的外流不仅能延缓泡沫 细胞形成，但也激活了胆固醇的反向运输。载脂蛋白 载脂蛋白AI是胆固醇外流的主要生理决定因素之一 来自细胞，但不由组织巨噬细胞表达。在之前的研究中， 申请人已经证明，apoE(另一种受体)的巨噬细胞产生 细胞内胆固醇)直接影响近交系的损伤形成 C57BL/6小鼠。法齐奥博士假设，如果有能力生产 ApoAI，巨噬细胞将更有效地清除胆固醇和在 激活高密度脂蛋白代谢。为此，他的团队已经制作了几行 A基因控制下表达人载脂蛋白AI的转基因小鼠 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 用携带载脂蛋白AI基因的逆转录病毒转导骨髓，以及 表明将被转导的骨髓移植到受辐射的小鼠体内将 导致巨噬细胞表达载脂蛋白AI。这项研究的目的 计划是：i)创造和鉴定具有以下能力的转基因小鼠 巨噬细胞产生载脂蛋白AI；II)评价巨噬细胞的作用 载脂蛋白AI在C57BL/6小鼠和小鼠体内的表达与动脉粥样硬化 缺乏载脂蛋白AI或载脂蛋白E基因；iii)评估 ACAT-1-/-小鼠巨噬细胞载脂蛋白AI的研究 不适当的外排；iv)评估骨髓转导的可行性 一种体外向巨噬细胞递送载脂蛋白AI的方法。这些研究可以是 希望描绘泡沫细胞形成的生物学和泡沫细胞的重要性 胆固醇在动脉粥样硬化形成中的外流。此外，这些研究可能会奠定基础 用于动脉粥样硬化的基因治疗方法。