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LOCALLY PRODUCED APOLIPOPROTEIN E IN ATHEROSCLEROSIS

局部产生的载脂蛋白 E 在动脉粥样硬化中的作用

基本信息

批准号：
6184197
负责人：
WILLIAM A BOISVERT
金额：
$ 12.72万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 2002-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6184197
关键词：
T lymphocyte apolipoprotein E atherosclerosis bone marrow transplantation cholesterol disease /disorder etiology gene targeting high density lipoproteins laboratory mouse low density lipoprotein macrophage pathologic process phenotype

项目摘要

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.

描述（改编自研究者摘要）：虽然apoE是在动脉粥样硬化病变中由常驻巨噬细胞大量表达，这种蛋白质在病变环境中的特异性功能及其对动脉粥样硬化形成作用尚未确定。为了解决的作用 apoE特异性地存在于病变中，这是野生型小鼠的一种表型，其中apoE 基本上从病变中消除了。这是通过用apoE-/-小鼠的骨髓移植辐射小鼠，导致这些小鼠的巨噬细胞（M）重新增殖，在病变中表达apoE。显著减少饮食引起的在这些小鼠中观察到动脉粥样硬化，正常M的小鼠，尽管脂质和apoE的循环水平相似。这有力地表明，病变中的apoE是由M ，并提供了令人信服的证据表明，病变apoE促进动脉粥样硬化因为负责观察的机制已知病变apoE的促动脉粥样硬化作用，该建议涉及前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的上述观察的替代解释。这第一个目标将测试假设，病变apoE促进通过保留致动脉粥样硬化的脂蛋白以有利于泡沫细胞而导致动脉粥样硬化阵这将通过产生LDL-R/-小鼠进行测试，载脂蛋白E在病变中的表达，并比较动脉粥样硬化程度和脂质在血管壁中积聚。第二个目标将确定apoE是否是促进胆固醇流出病变所必需的。与apoE促进HDL介导的胆固醇的流行观点相反，外排，apoE的致动脉粥样硬化作用表明它可能不是对胆固醇从病变流出至关重要。这一假设将是在LDL-R-/-小鼠和LDL-R-/-、apoAI-/-双敲除小鼠中进行了测试，产生四种有和无病变apoE和/或HDL的表型。因为 apoE已被证明抑制T细胞功能，第三个目标将测试，如果病变apoE通过改变T细胞功能发挥促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的小鼠动脉粥样硬化的减少 apoE-/-骨髓的患者不一定是由于apoE的缺乏，病变，但由于转移居民提供的动脉粥样硬化保护骨髓记忆细胞对某些循环抗原敏感，高脂血症apoE-/-小鼠。 apoE在病变中的作用的鉴定可能导致旨在预防动脉粥样硬化的干预措施。