Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis

动脉粥样硬化中炎症巨噬细胞的胆固醇调节

• 批准号: 10188606
• 负责人: Yury Miller
• 金额: $ 35.12万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188606
• 关键词: Adhesions; Antibodies; Apolipoprotein A-I; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; B-Lymphocytes; Binding Proteins; Biological Markers; Blocking Antibodies; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cell membrane; Cell physiology; Cells; Cholesterol; Cholesterol Esters; Clinic; Dependovirus; Development; Diagnostic; Diagnostic tests; Dimerization; Disease; Endothelial Cells; Epitopes; Event; Excision; Foam Cells; Genes; Goals; High Density Lipoproteins; Human; Immune; Immunoglobulin M; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Laboratories; Lipids; Lipoproteins; Low-Density Lipoproteins; Macrophage Activation; Measures; Mediating; Membrane Microdomains; Monoclonal Antibodies; Multi-Ethnic Study of Atherosclerosis; Mus; Myocardial Infarction; Names; Oxides; Patients; Phenotype; Plasma; Plasma Proteins; Population; Process; Protein Deficiency; Recombinant Proteins; Recombinants; Regulation; Research; Research Personnel; Rupture; Sampling; Stroke; Study models; T-Lymphocyte; TLR4 gene; Testing; Therapeutic; Tissues; Translating; atheroprotective; coronary artery calcium; experience; experimental study; human study; hypercholesterolemia; immunoregulation; improved; in vivo evaluation; macrophage; monocyte; mouse model; novel; novel therapeutic intervention; oxidation; prognostic value; protein biomarkers; response; vascular inflammation

Project Summary Hypercholesterolemia and vascular inflammation are among the strongest causative factors in the development of atherosclerosis and in the progression of early atherosclerotic lesions into advanced vulnerable plaques. However, it is yet unclear whether vascular cholesterol accumulation directly contributes to vascular inflammation and, specifically, to polarization of macrophages into inflammatory phenotypes. In this project, we will investigate two mechanisms, which contribute to cholesterol-mediated inflammatory responses by macrophages, and will determine their quantitative significance in the development of atherosclerosis in a mouse model and the translational potential of relevant new biomarkers and therapeutic approaches. In an atherogenic mechanism, oxidized cholesteryl esters (OxCE) induce dimerization of toll-like receptor-4 (TLR4), which in turn mediates inflammatory and atherogenic responses in macrophages. In an atheroprotective mechanism, we have identified the secreted apoA-I binding protein (AIBP) as a factor, which significantly improves HDL function by accelerating cholesterol efflux, resulting in the disruption of lipid raft-dependent TLR4 dimerization and reduced inflammatory responses in macrophages. We will test the hypotheses that OxCE promotes and AIBP inhibits inflammatory macrophage polarization, foam cell formation and atherosclerosis. We have generated a monoclonal antibody blocking OxCE, as well as systemic and macrophage-specific Apoa1bp-/- mice to test these hypotheses. In complementary experiments, we will use infusions of recombinant AIBP and/or an AIBP-expressing adeno-associated virus to achieve increased AIBP levels in plasma and expect to inhibit atherosclerosis progression. Importantly, synergistic studies with other PPG Projects will examine the relevance of OxCE and AIBP mechanisms to atherogenic or atheroprotective functions of different monocyte and T and B cell populations. To translate our findings into clinic, we will use plasma from Multi-Ethnic Study of Atherosclerosis (MESA) subjects, who have elevated coronary artery calcium or have experienced major adverse cardiovascular events, to evaluate diagnostic and prognostic value of new OxCE and AIBP biomarkers. These results will be integrated with other biomarkers identified by the PPG Investigators. To examine novel therapeutic approaches to restrain cholesterol-induced inflammation, we will test the hypothesis that raising AIBP in the low-AIBP plasma and blocking OxCE in the high-OxCE plasma found in MESA populations will reduce plasma's atherogenic effects on human macrophages. The proposed studies will enhance our mechanistic understanding of cholesterol-mediated inflammation in atherosclerosis and will advance new biomarker and therapeutic strategies for cardiovascular disease.

项目摘要 高胆固醇血症和血管炎症是最强的致病因素之一 动脉粥样硬化的发展以及早期动脉粥样硬化病变发展为晚期 脆弱的斑块。但是，目前尚不清楚血管胆固醇积累是否直接有助于 血管炎症，特别是将巨噬细胞极化为炎症表型。在这个 项目，我们将研究两种机制，这些机制有助于胆固醇介导的炎症反应 通过巨噬细胞，并将确定它们在Atherosclosis的发展中的定量意义 小鼠模型以及相关新生物标志物和治疗方法的翻译潜力。在 动脉粥样硬化机制，氧化的胆固醇酯（OXCE）诱导了Toll样受体-4（TLR4）的二聚化， 这反过来介导了巨噬细胞中的炎症和动脉粥样硬化反应。在动脉保护区 机制，我们已经将分泌的ApoA-I结合蛋白（AIBP）确定为一个因素，这显着 通过加速胆固醇外排来改善HDL功能，从而导致脂质筏依赖性的破坏 TLR4二聚化并减少巨噬细胞的炎症反应。我们将测试假设 OXCE促进和AIBP抑制炎症性巨噬细胞极化，泡沫细胞的形成和 动脉粥样硬化。我们已经产生了一种单克隆抗体阻断OXCE，以及​​全身和 巨噬细胞特异性的apoA1bp - / - 小鼠以检验这些假设。在补充实验中，我们将使用 重组AIBP和/或表达AIBP的腺相关病毒的输注以增加AIBP 血浆中的水平并期望抑制动脉粥样硬化的进展。重要的是，与其他的协同研究 PPG项目将检查OXCE和AIBP机制与动脉粥样硬化或动脉保护性的相关性 不同的单核细胞和T细胞群体的功能。为了将我们的发现转化为诊所，我们将使用 冠状动脉升高的动脉粥样硬化（MESA）多种族研究的血浆 钙或经历了重大不良心血管事件，以评估诊断和预后价值 新的OXCE和AIBP生物标志物。这些结果将与其他生物标志物集成 PPG调查人员。为了检查新的治疗方法来抑制胆固醇引起的炎症，我们 将检验以下假设，即在低AIBP等离子体中升高AIBP并阻止高粘体等离子体中的OXCE 在梅萨种群中发现的将减少血浆对人巨噬细胞的动脉粥样硬化作用。提议 研究将增强我们对胆固醇介导的动脉粥样硬化炎症的机械理解 并将推进心血管疾病的新生物标志物和治疗策略。