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）招募单核细胞/巨噬细胞 下皮空间是血管之间过渡的强制性步骤 健康和动脉粥样硬化病变形成。脂质在 细胞质诱导巨噬细胞转化为代谢惰性 泡沫细胞。巨噬细胞的胆固醇外流不仅延迟泡沫 细胞形成，但也激活反向胆固醇的转运。载脂蛋白 （APO）AI是胆固醇外排的主要生理决定因素之一 来自细胞，但不受组织巨噬细胞的表达。在先前的研究中， 申请人表明巨噬细胞的产生APOE（另一个受体 细胞内胆固醇）直接影响近交的病变形成 C57BL/6鼠。法齐奥博士假设，如果有能力 apoai，巨噬细胞在摆脱胆固醇和中的效率更高 激活HDL代谢。为此，他的小组制作了几行 在A的控制下表达人apoAI的转基因小鼠 巨噬细胞特异性启动子。此外，他们开发了一种可行的方法 用于骨髓转导，并带有带有apoai cDNA的逆转录病毒，并且 表明将转导的骨髓移植到辐照小鼠中 导致巨噬细胞表达apoai。这项研究的目标 程序是：i）创建和表征具有的转基因小鼠的能力 从巨噬细胞产生apoai； ii）评估巨噬细胞的影响 C57BL/6小鼠的脂质和动脉粥样硬化的APOAI表达以及小鼠 缺乏apoai或apoe基因； iii）评估 ACAT-1 - / - 小鼠中的巨噬细胞apoai，一种游离胆固醇毒性的模型和 不适当的排出； iv）评估骨髓转导的可行性 ApoAI向巨噬细胞进行体内递送的一种方法。这些研究可以是 预计将描述泡沫细胞形成的生物学以及 动脉粥样硬化中的胆固醇外排。此外，这些研究可能是基础 用于动脉粥样硬化的基因治疗方法。