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

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
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-15 至 2018-07-31

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中文摘要
翻译
项目总结/摘要 心血管疾病(CVD)正在成为HIV-1感染者死亡的主要原因。的 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。尽管有有效的抗逆转录病毒治疗(ART), 与CVD进展相关的激活。越来越清楚的是, 单核细胞/巨噬细胞(M/M)比T细胞参数更准确地预测发病率和死亡率 在ART治疗的个体中。M/M与氧化脂质(oxPL)共定位于组织如动脉和肠道中, 是HIV-1感染的最大宿主之一,体内大部分M/M都在其中。新出现的证据 表明肠道氧化脂质的形成可能调节炎症和CVD。M/M还与 氧化脂蛋白,并处于HIV-1感染、肠道相关和全身性 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新的治疗方法来管理HIV相关的CVD。此类疗法 包括高密度脂蛋白(HDL)模拟肽,其模拟HDL的正常功能 oxPLs和抗炎特性。我们假设HIV-1和氧化脂质形成了一个恶性循环 HIV-1增强的M/M激活和炎症导致HIV-1感染者的CVD。整体 目的是探索HIV-1感染是否会增加氧化脂质的形成,并促进炎症反应。 尽管有效的ART,但仍存在促动脉粥样硬化M/M。该项目分为两个目标。Aim 1将在 人源化小鼠体内模型中,尽管ART有效,HIV-1是否直接诱导氧化的 被HDL模拟物衰减的脂质。目的2将使用相同的小鼠模型在体内确定HDL 模拟物改善慢性炎症患者M/M的促氧化、促炎、活化和促动脉粥样硬化表型 治疗HIV-1感染。鉴于接受抗逆转录病毒治疗的艾滋病毒1感染者的M/M可能继续升高, 激活和氧化脂质,这种方法可以减少剩余的过量发病率和死亡率, 尽管如此。这项工作具有创新性,对公共卫生产生影响,并直接解决研究优先事项 关于艾滋病相关的合并症
英文摘要
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.
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Mitoquinone/mitoquinol mesylate as oral and safe Postexposure Prophylaxis for Covid-19
  • 批准号:
    10727092
  • 项目类别:
  • 资助金额:
    $24.6万
  • 财政年份:
    2023
  • 负责人:
    Theodoros Kelesidis
  • 依托单位:
Targeting early instigators of vascular inflammation to prevent and/or delay vascular aging in chronic treated HIV
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Targeting early instigators of vascular inflammation to prevent and/or delay vascular aging in chronic treated HIV
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