Plaque and blood derived macrophages: a multi-omic assessment of CVD pathogenesis in PLWH

斑块和血液来源的巨噬细胞：PLWH CVD 发病机制的多组学评估

• 批准号: 10275181
• 负责人: Mark James Cameron
• 金额: $ 74.4万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10275181
• 关键词: Arterial Fatty Streak; Atherosclerosis; Biological Assay; Biological Markers; Blood; Blood Vessels; CD14 gene; Cardiovascular Diseases; Carotid Endarterectomy; Cause of Death; Cells; Cessation of life; Clinical; Complex; Data; Data Set; Disease; Event; Exposure to; FCGR3B gene; Fatty Acids; Gene Expression; Gene Expression Profile; Genetic Transcription; HIV; HIV Seronegativity; Homing; Immune signaling; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Interleukin-6; Leukocytes; Link; Lipids; Macrophage Activation; Matrix Metalloproteinases; Measures; Mediator of activation protein; Mitochondria; Modeling; Myeloid Cell Activation; Nucleosides; Outcome; Oxidative Phosphorylation; Participant; Pathogenesis; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Polyunsaturated Fatty Acids; Population; Prevalence; Production; Reverse Transcriptase Inhibitors; Risk; Saturated Fatty Acids; Signal Transduction; TNFRSF1A gene; Testing; United States; Viral; Work; antiretroviral therapy; base; cardiovascular disorder risk; clinically relevant; coronary artery calcification; experimental study; fatty acid oxidation; immune activation; improved; in vivo; inflammatory marker; inhibitor/antagonist; lipid I; lipidome; lipidomics; macrophage; mitochondrial dysfunction; monocyte; mortality; multiple omics; pre-exposure prophylaxis; recruit; therapeutic target; transcriptomics; uptake

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death in the United States; and there is ~2-fold greater risk for CVD events for people living with HIV (PLWH).1,2 The mechanisms underlying increased CVD prevalence in PLWH are not fully understood, but likely involve heightened activation of monocytes and macrophages. We hypothesize that monocytes will be exposed to disparate inflammatory signals during differentiation in PLWH; as a result, macrophages will be functionally and phenotypically different and exacerbate CVD in this population. Our data suggest that alterations in the lipidome may influence inflammation, monocyte activation, and the differentiation of macrophages. Antiretroviral therapy may alter lipid profiles by reducing oxidative phosphorylation (OxPHOS) and fatty acid oxidation (FAO) as a consequence of ART-induced mitochondrial dysfunction. Our studies have identified differences in the lipidomes of HIV- and HIV+ populations, even when traditional lipid panels in these groups were similar22. Biomarkers associated with CVD risk (IL-6, sCD14, TNFR1),10-15 were directly related to fatty acid composition and pro-inflammatory lipid classes in PLWH. We have also identified an expansion of pro-coagulant, vascular homing monocytes in PLWH42-44 and linked monocyte activation to altered lipid profiles19,20,45-47. Aim 1: To identify unique and common phenotypic, transcriptomic, and functional MDM profiles associated with the presence or absence of ASCVD in PLWH and HIV- individuals. 1A: To compare MDM phenotypic, functional, and transcriptomic profiles across our 4 groups. 1B: To sort and differentiate monocyte subsets (based on CD14 and CD16 expression)43,49,50 into MDMs in order to determine whether subset origin determines differential functional and phenotypic outcome. 1C: To sort macrophages from atherosclerotic plaques (carotid endarterectomies) and compare the transcriptional profiles of these cells to the profiles identified in MDMs from our 4 participant groups. Aim 2: To characterize drivers of MDM activation in PLWH and HIV- persons with and without ASCVD. 2A: To characterize the plasma lipid profiles of participants using advanced lipidomics (Lipidyzer) as well as the lipidomic profiles of atherosclerotic plaques collected from carotid endarterectomies. 2B: To explore the consequences of in vivo and in vitro lipid profile modulation on MDM gene expression and functional capabilities; statin treatment will improve the lipidome51 and as a consequence, decrease MDM activation, and in vitro exposure of MDMs to proinflammatory lipids (i.e CERs, SaFAs) will activate these cells. 2C: To determine the drug-specific effects of ART exposure on MDM profiles. Aim3: To elucidate profiles associated with ASCVD in HIV- and HIV+ individuals using a comprehensive, multi-dimensional approach and in vitro pathway inhibitor experiments to explore differential drivers and inhibitors of signaling cascades on MDM transcription and functional profiles.

动脉粥样硬化性心血管疾病（ASCVD）是美国的主要死亡原因; HIV感染者（PLWH）发生CVD事件的风险约为2倍。1，2 尚不完全清楚PLWH中CVD患病率的增加，但可能涉及 单核细胞和巨噬细胞。我们假设单核细胞将暴露于不同的炎症介质中， 在PLWH分化过程中的信号;因此，巨噬细胞将在功能和表型上 不同并加重CVD。我们的数据表明，脂质体的改变可能 影响炎症、单核细胞活化和巨噬细胞的分化。抗逆转录病毒治疗可能 通过减少氧化磷酸化（OxPHOS）和脂肪酸氧化（FAO）来改变脂质谱， ART诱导的线粒体功能障碍的后果。我们的研究已经确定了 HIV-和HIV+人群的脂质体，即使这些人群中的传统脂质组相似22。 与CVD风险相关的生物标志物（IL-6、sCD 14、TNFR 1）10 -15与脂肪酸组成直接相关 和促炎脂质类。我们还发现了促凝血剂，血管 PLWH 42 -44中的归巢单核细胞，并将单核细胞活化与改变的脂质分布相关联19，20，45-47。 目的1：鉴定独特和常见的表型、转录组学和功能性MDM谱 与PLWH和HIV-个体中ASCVD的存在或不存在相关。 1A：比较我们4组中的MDM表型、功能和转录组学特征。 1B：将单核细胞亚群（基于⑶ 14和⑶ 16表达）43、49、50分选和分化成MDM， 以确定是否亚群起源决定了不同的功能和表型结果。 图1C：从动脉粥样硬化斑块（颈动脉内膜切除术）中分选巨噬细胞，并比较巨噬细胞的 将这些细胞的转录谱与我们4个参与者组的MDM中鉴定的谱进行比较。 目的2：表征PLWH和HIV患者中MDM激活的驱动因素-伴和不伴ASCVD。 2A：使用高级脂质组学（Lipidyzer）以及 从颈动脉内膜切除术中收集的动脉粥样硬化斑块的脂质组学特征。 2B：探索体内和体外脂质分布调节对MDM基因表达的影响， 功能能力;他汀类药物治疗将改善脂质体51，从而减少MDM 激活，并且MDM体外暴露于促炎脂质（即CER、SaFA）将激活这些细胞。 2C：确定ART暴露对MDM特征的药物特异性影响。 目的3：使用一种新的方法阐明HIV-和HIV+个体中与ASCVD相关的特征， 全面、多维度的途径和体外抑制剂实验探索 在MDM转录和功能谱上的信号级联的差异驱动剂和抑制剂。