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.

项目摘要/摘要 心血管疾病（CVD）已成为HIV-1感染患者的主要死亡原因。这 将HIV-1感染，CVD和与HIV感染相关的免疫系统激活联系起来的机制 （免疫激活）仍然未知。尽管有效的抗逆转录病毒疗法（ART）仍有持续的免疫 与CVD进程相关的激活。越来越清楚激活标记 与T细胞参数相比，单核细胞/巨噬细胞（M/M）可以更准确地预测发病率和死亡率 在经过艺术治疗的个人中。 M/M与动脉和肠道等组织中的氧化脂质（OXPLS）共定位 HIV-1感染中最大的水库之一，它具有大部分人体M/m。新兴证据 表明肠道中氧化脂质的形成可能调节炎症和CVD。 M/M也与 氧化脂蛋白，在HIV-1感染，肠道相关和全身性之间的交点处 炎症，CVD和免疫激活。揭示氧化脂质如何影响M/M，CVD和HIV-1 发病机理可能有助于发展与HIV相关CVD的新疗法。这种疗法 包括高密度脂蛋白（HDL）模拟肽，模仿HDL等正常功能，例如结合 OXPLS和抗炎特性。我们假设HIV-1和氧化的脂质促进了一种恶性循环 HIV-1增强的M/M激活和炎症，使HIV-1感染的个体驱动CVD。总体 目标是探索HIV-1感染是否会增加氧化脂质和促炎/的形成/ 尽管有效，但仍具有促进性m/m。该项目分为两个目标。 AIM 1将在 人源化小鼠模型在体内是否有效HIV-1是否直接诱导氧化的形成 HDL Mimetics减弱的脂质。如果HDL，AIM 2将使用相同的鼠标模型确定体内 MIMETICS改善慢性M/M的促氧化剂，促炎，激活和促进​​质源性表型 治疗的HIV-1感染。鉴于HIV-1感染的ART的人可能会继续升高M/M 激活和氧化脂质，这种方法可以降低过量的发病率和死亡率 尽管。这项工作具有创新性，对公共卫生有影响，并直接解决了研究重点 关于HIV相关的合并症。