Role of apolipoprotein E4 in the progression and regression of atherosclerosis

载脂蛋白E4在动脉粥样硬化进展和消退中的作用

• 批准号: 7642511
• 负责人: Robert Raffai
• 金额: $ 39.4万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-26 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642511
• 关键词: Address; Alleles; Apolipoprotein E; Apolipoproteins; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Binding; Cause of Death; Cholesterol; Endothelial Cells; Engineering; Foam Cells; Generations; Goals; High Density Lipoproteins; Human; Hyperlipidemia; Knowledge; Laboratories; Lesion; Lipids; Low Density Lipoprotein Receptor; Mediating; Modeling; Molecular; Mus; Physiological; Plasma; Population; Principal Investigator; Process; Protein Isoforms; Proteins; Research Personnel; Risk Factors; Role; Series; Signal Transduction; Source; Testing; United States; Variant; Very low density lipoprotein; apolipoprotein E-3; apolipoprotein E-4; clinically relevant; design; disability; fighting; gene repair; macrophage; migration; monocyte; mouse model; novel; preference; programs; research study; response; treatment strategy

DESCRIPTION (provided by applicant): Atherosclerosis and its complications remain leading causes of death and disability in the United States. Although promoting the regression of atherosclerosis has emerged as a promising treatment strategy for atherosclerosis, the molecular and cellular mechanisms that orchestrate this clinically relevant process are poorly understood. Moreover, the mechanisms by which the apolipoprotein 4 (apoE4) allele predisposes to symptomatic forms of atherosclerosis and whether it can impair its regression following plasma lipid lowering, remains largely unknown. To fill these gaps of knowledge, we propose a series of experiments with genetically engineered murine models of apoE4, conditional apoE expression, reversible hyperlipidemia, and atherosclerosis regression developed in our laboratory. Hypomorphic ApoeR61h/h mice express reduced levels of an apoE4-like form of murine apoE (Arg-61 apoE) that reproduces a unique biophysical feature of human apoE4 called "domain interaction". Our previous studies have shown that domain interaction in Arg- 61 apoE is sufficient to reproduce the VLDL-binding preference of human apoE4 in hyperlipidemic mouse plasma. Moreover, our studies of conditional expression of apoE in ApoeR61h/h mice has recently established the existence of a role for apoE in promoting the regression of atherosclerosis beyond lowering plasma cholesterol levels. Experiments detailed in this proposal will make use of ApoeR61h/h mice, as well as new variants of this model, to investigate mechanisms by which apoE accumulation in plasma and macrophage-derived apoE in lesions regulate the onset and progression of atherosclerosis in the setting of hyperlipidemia. We will also test the hypothesis that apoE4 domain interaction in Arg-61 apoE will accelerate the progression of atherosclerosis and impair its regression following sustained lipid lowering. Lastly, we will test the hypothesis that apoE expression levels influence the migration of monocytes into established lesions, and the egress of macrophages from lesions during the regression of atherosclerosis in an isoform-specific manner. Our long term goal is to clarify the molecular and cellular mechanisms by which apoE isoforms regulate the progression and regression of atherosclerosis. A better understanding of these mechanisms would help usher in a new generation of molecular therapies to fight atherosclerosis, particularly among apoE4 carriers who represent 20% of the global population.

描述（由申请人提供）：动脉粥样硬化及其并发症仍然是美国死亡和残疾的主要原因。虽然促进动脉粥样硬化的消退已成为动脉粥样硬化的一种有前途的治疗策略，但对协调这一临床相关过程的分子和细胞机制知之甚少。此外，载脂蛋白4（apoE 4）等位基因易患动脉粥样硬化的症状形式的机制，以及它是否可以削弱其消退后，血浆脂质降低，仍然在很大程度上是未知的。为了填补这些知识的空白，我们提出了一系列的实验与基因工程小鼠模型apoE 4，条件apoE表达，可逆性高脂血症，动脉粥样硬化消退在我们的实验室开发。亚纯型ApoeR 61 h/h小鼠表达降低水平的apoE 4样形式的鼠apoE（Arg-61 apoE），其再现了人apoE 4的独特生物物理特征，称为“结构域相互作用”。我们以前的研究表明，Arg- 61 apoE中的结构域相互作用足以重现高脂血症小鼠血浆中人apoE 4的VLDL结合偏好。此外，我们在ApoeR 61 h/h小鼠中apoE的条件性表达的研究最近确立了apoE在促进动脉粥样硬化消退中的作用，而不仅仅是降低血浆胆固醇水平。 本提案中详细描述的实验将利用ApoeR 61 h/h小鼠以及该模型的新变体来研究血浆中apoE蓄积和病变中巨噬细胞来源的apoE调节高脂血症背景下动脉粥样硬化的发生和进展的机制。我们还将检验以下假设：Arg-61 apoE中的apoE 4结构域相互作用将加速动脉粥样硬化的进展，并在持续降脂后损害其消退。最后，我们将测试的假设，apoE表达水平影响单核细胞迁移到建立的病变，和巨噬细胞从病变的消退过程中的动脉粥样硬化在亚型特异性的方式出口。 我们的长期目标是阐明apoE亚型调节动脉粥样硬化进展和消退的分子和细胞机制。更好地理解这些机制将有助于引入新一代分子疗法来对抗动脉粥样硬化，特别是在占全球人口20%的apoE 4携带者中。