Humanized mice as a model to study the role of oxidized lipids in HIV-related cardiovascular disease

人源化小鼠作为模型研究氧化脂质在艾滋病毒相关心血管疾病中的作用

• 批准号: 9203331
• 负责人: Theodoros Kelesidis
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203331
• 关键词: AIDS/HIV problem; Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Antiviral Therapy; Apolipoprotein A-I; Arteries; Attenuated; Autologous; Binding; Biochemical; Biological Assay; Biology; CCL2 gene; CXCL10 gene; Cardiovascular Diseases; Cause of Death; Cell Adhesion Molecules; Cholesterol; Chronic; Comorbidity; Development; Disease Progression; F2-Isoprostanes; FCGR3B gene; Foam Cells; Fostering; General Population; Goals; HIV; HIV Infections; HIV-1; HLA-DR Antigens; High Density Lipoproteins; Human; ITGAM gene; Immune system; In Vitro; Individual; Infection; Inflammation; Inflammatory; LOX gene; Lead; Link; Lipids; Lipoprotein Binding; Lipoproteins; Longevity; Lysophosphatidylcholines; Macrophage Activation; Mediating; Membrane; Modeling; Morbidity - disease rate; NF-kappa B; NOS2A gene; Neopterin; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peptides; Peripheral; Persons; Phenotype; Play; Property; Public Health; Reactive Oxygen Species; Research Priority; Research Proposals; Role; Sampling; Site; System; T-Lymphocyte; TNF gene; Testing; Thromboplastin; Tissues; Toll-like receptors; Work; antiretroviral therapy; atherogenesis; base; chemokine; co-infection; cytokine; design; humanized mouse; immune activation; improved; in vitro Model; in vivo; innovation; macrophage; mimetics; monocyte; mortality; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; outcome forecast; oxidation; oxidized lipid; oxidized low density lipoprotein; peptidomimetics; receptor; scavenger receptor; self-renewal

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is becoming a major cause of death in persons with HIV-1 infection. The mechanisms that link HIV-1 infection, CVD and activation of the immune system associated with HIV infection (immune activation) remain unknown. Despite effective antiretroviral therapy (ART) there is persistent immune activation that is associated with CVD progression. It is becoming increasingly clear that markers of activation of monocyte/macrophages (M/M) may more accurately predict morbidity and mortality than T-cell parameters in ART-treated individuals. M/M co-localize with oxidized lipids (oxPLs) in tissues such as arteries and the gut, one of the largest reservoirs in HIV-1 infection that harbors most of the body's M/M. Emerging evidence suggests that formation of oxidized lipids in gut may regulate inflammation and CVD. M/M also interact with oxidized lipoproteins and are at the intersection between HIV-1 infection, gut related and systemic inflammation, CVD and immune activation. Unraveling how oxidized lipids affect M/M, CVD and HIV-1 pathogenesis may contribute to development of new therapies to manage HIV-related CVD. Such therapies include High Density Lipoprotein (HDL) mimetic peptides that mimic normal functions of HDL such as binding of oxPLs and anti-inflammatory properties. We hypothesize that HIV-1 and oxidized lipids foster a vicious cycle of HIV-1-enhanced M/M activation and inflammation that drive CVD in HIV-1 infected individuals. The overall goal is to explore whether HIV-1 infection drives increased formation of oxidized lipids and proinflammatory/ proatherogenic M/M despite effective ART. This project is organized into two aims. Aim 1 will explore in a humanized mouse model in vivo whether HIV-1, despite effective ART, directly induces formation of oxidized lipids that is attenuated by HDL mimetics. Aim 2 will determine in vivo using the same mouse model if HDL mimetics improve prooxidant, proinflammatory, activated and proatherogenic phenotype of M/M in chronic treated HIV-1 infection. Given that HIV-1-infected persons on ART may continue to have elevated M/M activation and oxidized lipids, such an approach could reduce the excess morbidity and mortality remaining despite. This work is innovative, has an impact on public health and directly addresses research priorities regarding HIV-associated comorbidities.

项目概要/摘要 心血管疾病 (CVD) 正在成为 HIV-1 感染者死亡的主要原因。这 HIV-1 感染、CVD 和与 HIV 感染相关的免疫系统激活之间的联系机制 （免疫激活）仍然未知。尽管抗逆转录病毒治疗（ART）有效，但免疫仍存在持续性 与 CVD 进展相关的激活。越来越明显的是，激活标记 单核细胞/巨噬细胞 (M/M) 的参数可能比 T 细胞参数更准确地预测发病率和死亡率 在接受 ART 治疗的个体中。 M/M 与动脉和肠道等组织中的氧化脂质 (oxPL) 共定位， HIV-1 感染的最大储存库之一，容纳着人体大部分的 M/M。新出现的证据 表明肠道中氧化脂质的形成可能调节炎症和心血管疾病。 M/M 还与 氧化脂蛋白，处于 HIV-1 感染、肠道相关感染和全身感染之间的交叉点 炎症、CVD 和免疫激活。揭示氧化脂质如何影响 M/M、CVD 和 HIV-1 发病机制可能有助于开发治疗艾滋病毒相关心血管疾病的新疗法。此类疗法 包括高密度脂蛋白 (HDL) 模拟肽，可模拟 HDL 的正常功能，例如结合 oxPLs 和抗炎特性。我们假设 HIV-1 和氧化脂质会形成恶性循环 HIV-1 增强的 M/M 激活和炎症导致 HIV-1 感染者发生 CVD。整体 目标是探索 HIV-1 感染是否会导致氧化脂质和促炎/促炎物质的形成增加 尽管 ART 有效，但促动脉粥样硬化 M/M。该项目有两个目标。目标 1 将探索 体内人源化小鼠模型，尽管 ART 有效，HIV-1 是否会直接诱导氧化 HDL 模拟物减弱的脂质。目标 2 将使用相同的小鼠模型在体内确定 HDL 模拟物改善慢性 M/M 的促氧化、促炎、激活和促动脉粥样硬化表型 治疗 HIV-1 感染。鉴于接受 ART 的 HIV-1 感染者的 M/M 值可能继续升高 活化和氧化脂质，这种方法可以减少剩余的过量发病率和死亡率 尽管。这项工作具有创新性，对公共卫生有影响，并直接解决研究重点 关于艾滋病毒相关的合并症。