LOCALLY PRODUCED APOLIPOPROTEIN E IN ATHEROSCLEROSIS

描述(改编自调查人员摘要)：尽管apoE是 常驻巨噬细胞在动脉粥样硬化病变中大量表达， 该蛋白在损伤环境中的特定功能及其作用 对动脉粥样硬化形成的影响尚未确定。解决……的作用 ApoE在皮损中特异，这是一种野生型小鼠的表型，在这种情况下apoE 基本上从病变中消除了。这是由以下人员完成的 用apoE-/-小鼠的骨髓移植受照射的小鼠 导致这些小鼠的巨噬细胞(M)重新繁殖，而不是 在皮损中表达载脂蛋白E。饮食诱导的显著减少 与类似的治疗相比，在这些小鼠中观察到了动脉粥样硬化。 M正常的小鼠，尽管血脂和载脂蛋白E循环水平相似。 这强烈表明，皮损中的载脂蛋白E是由M ，并提供了令人信服的证据表明病变apoE促进 动脉硬化。因为负责观察到的 病变载脂蛋白E的致动脉粥样硬化作用是已知的，这项建议解决了 前3个具体目标中的几种可能的机制，并探讨了 第四个目标中上述意见的另一种解释。 这第一个目标将检验病变载脂蛋白E促进 动脉粥样硬化通过保留致动脉粥样硬化的脂蛋白而有利于泡沫细胞 队形。这将通过产生有和没有低密度脂蛋白受体的小鼠来进行测试 APOE，比较动脉粥样硬化和血脂的程度 在血管壁上堆积。第二个目标将决定载脂蛋白E 是促进胆固醇流出病变所必需的。 与普遍认为的载脂蛋白E促进高密度脂蛋白介导的胆固醇相反 外排，载脂蛋白E的致动脉粥样硬化作用表明它可能不是 对于胆固醇从皮损中流出是必不可少的。这一假设将是 在低密度脂蛋白-R-/-小鼠和低密度脂蛋白-R-/-，载脂蛋白AI-/-双基因敲除小鼠中进行测试 产生有和没有病变的载脂蛋白E和/或高密度脂蛋白的四种表型。因为 APOE已被证明可以抑制T细胞功能，第三个目标将测试是否 病变载脂蛋白E通过改变T细胞功能发挥其致动脉粥样硬化作用 被认为是抗动脉粥样硬化的。第四个目标将审查 移植小鼠动脉粥样硬化减轻的可能性 ApoE-/-骨髓不一定是由于ApoE缺失所致 损伤，但由于居民转移所提供的动脉粥样硬化保护 骨髓记忆细胞对体内循环的某些抗原敏感 高脂血症apoE-/-小鼠。载脂蛋白E在皮损中的作用鉴定 可能导致旨在预防动脉粥样硬化的干预措施。

DESCRIPTION (Adapted from Investigator's Abstract): Although apoE is expressed abundantly in atherosclerotic lesions by the resident macrophages, the specific function of this protein in the lesion environment and its effect on atherogenesis have not been identified. To address the role of apoE specifically in lesions, a phenotype of wild-type mice in which apoE was essentially eliminated from the lesion was developed. This was done by transplanting irradiated mice with bone marrow from apoE-/- mice, which resulted in repopulation of these mice with macrophages (M) that did not express apoE in lesions. A significant reduction in diet-induced atherosclerosis was observed in these mice compared to similarly treated mice with normal M , despite similar circulating levels of lipids and apoE. This is strongly suggests that apoE in lesions is produced locally by the M , and provides compelling evidence that lesion apoE promotes atherosclerosis. Because the mechanisms responsible for the observed proatherogenic role of lesion apoE are known, this proposal addresses several possible mechanisms in the first 3 Specific Aims, and probes an alternative explanation underlying the above observation in the fourth aim. This first aim will test the hypothesis that lesion apoE promotes atherosclerosis by retaining atherogenic lipoproteins to favor foam cell formation. This will be tested by generating LDL-R/-mice with and without apoE in their lesions, and comparing the extent of atherosclerosis and lipid accumulation in the vascular walls. The second Aim will determine if apoE is necessary for facilitating cholesterol efflux out of the lesion. Contrary to popular belief that apoE facilitates HDL-mediated cholesterol efflux, the proatherogenic role of apoE suggests that it may not be essential for cholesterol efflux from lesions. This hypothesis will be tested in LDL-R-/- mice and LDL-R-/-, apoAI-/- double knockout mice by generating four phenotypes with and without lesion apoE and/or HDL. Because apoE has been shown to inhibit T cell function, the third Aim will test if lesion apoE exerts it proatherogenic effect by altering T cell functions considered to be atheroprotective. The fourth Aim will examine the possibility that the reduction in atherosclerosis of the mice transplanted with apoE-/- bone marrow was not necessarily due to the absence of apoE in the lesion, but was due to atheroprotection offered by transfer of resident bone marrow memory cells sensitized to certain antigens circulating in the hyperlipidemic apoE-/- mice. Identification of the role of apoE in lesions may lead to interventions aimed at preventing atherosclerosis.