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烈的致病因素之一 动脉粥样硬化的发展和早期动脉粥样硬化病变到晚期的进展 脆弱的斑块。然而，目前尚不清楚血管胆固醇的积累是否直接导致 血管炎症，特别是巨噬细胞向炎症表型的极化。在这 项目中，我们将研究两种导致胆固醇介导的炎症反应的机制。 并将确定它们在动脉粥样硬化发展过程中的定量意义。 小鼠模型和相关新生物标记物和治疗方法的翻译潜力。在一个 动脉粥样硬化形成机制，氧化胆固醇酯(OxCE)诱导Toll样受体-4(TLR4)二聚化， 它反过来在巨噬细胞中介导炎症和致动脉粥样硬化反应。在一种动脉粥样硬化保护剂中 机制，我们已经确定分泌的apoA-I结合蛋白(AIBP)是一个因子，它显著地 通过加速胆固醇外流来改善高密度脂蛋白功能，从而破坏脂筏依赖 巨噬细胞中TLR4二聚化和炎症反应减少。我们将检验假设 OxCE促进和抑制炎性巨噬细胞极化、泡沫细胞形成和 动脉硬化。我们已经产生了一种阻断OxCE的单抗，以及系统和 巨噬细胞特异性载脂蛋白1BP-/-小鼠来验证这些假说。在补充实验中，我们将使用 注射重组AIBP和/或表达AIBP的腺相关病毒可提高AIBP 并有望抑制动脉粥样硬化的进展。重要的是，与其他机构的协同研究 PPG项目将研究OxCE和AIBP机制与致动脉粥样硬化或动脉粥样硬化保护的相关性 不同单核细胞和T、B细胞群的功能。为了将我们的发现转化为临床，我们将使用 冠状动脉抬高的动脉粥样硬化(MESA)受试者的多种族研究的血浆 钙或经历过重大心血管不良事件，以评估诊断和预后价值 新的OxCE和AIBP生物标志物。这些结果将与由 PPG调查员。为了研究抑制胆固醇引起的炎症的新的治疗方法，我们 将检验在低AIBP血浆中升高AIBP和在高OxCE血浆中阻断OxCE的假设 在台地人群中发现的药物将减少血浆对人类巨噬细胞的致动脉粥样硬化作用。建议数 研究将加强我们对动脉粥样硬化中胆固醇介导的炎症的机制的理解 并将提出新的心血管疾病生物标志物和治疗策略。