Determining the mechanisms of vascular CD8 T cell activation in CMV and HIV infections

确定 CMV 和 HIV 感染中血管 CD8 T 细胞激活的机制

基本信息

  • 批准号:
    10461964
  • 负责人:
  • 金额:
    $ 20.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-04 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Persons living with HIV infection (PWH) on antiretroviral therapy (ART) are succumbing earlier to many of the same complications that plague the HIV-uninfected elderly. This elevated CVD risk in PWH is at least partly due to persistently increased inflammation and activation of CD8 T cells and monocytes that our group has identified and characterized. Many elderly and nearly all PWH are coinfected with cytomegalovirus (CMV), which we have shown is associated with inflammation and dramatic expansion of CD8 T cells in PWH, and has been independently linked to CVD. Activated CD8 T cells accumulate at sites of endothelial dysfunction in vivo, promote atherosclerotic CVD (ASCVD) in animal models, and can trigger a proatherogenic phenotype on monocytes in vitro – yet whether CD8 T cells infiltrating the vasculature recognize cognate antigenic peptides has never been definitively shown in vivo, nor have antigen-nonspecific activating pathways been rigorously evaluated. In this proposal, we seek to identify how CMV and activated T cells conspire to exacerbate CVD beyond traditional risk factors in HIV-uninfected persons, and to understand if and how activated T cells further promote CVD risk in PWH with CMV coinfection. We hypothesize that active CMV replication within atherosclerotic lesions provides antigen for infiltrating CMV-reactive T cells and that additional antigen- nonspecific signals (including IL-15 and the CD2/LFA-3 axis) further shape the T cell response. We propose that these signals exacerbate ASCVD in HIV-uninfected persons and that they are further elevated in those with HIV infection. We will test these hypotheses with the following specific aims: Aim 1: To define the mechanisms of plaque CD8 T cell activation in vivo. We will use bulk and single cell RNA-sequencing coupled with barcoded- antibody and multimer labeling to test the hypothesis that CD8 T cells recovered from atherosclerotic plaques of CMV+ donors exhibit a more proinflammatory transcriptional program than plaque CD8 T cells from CMV- donors, and we will identify the activating pathways involved. We will then use immunofluorescence imaging and fluorescence in situ hybridization to confirm spatial relationships with activating signals such as IL-15, LFA-3, and CMV. Aim 2: To define the effect of HIV infection on the activation and in situ localization of vascular CD8 T cells. We will use RNA-sequencing to identify and characterize the mechanisms of activation and antigen- specificity of vascular CD8 T cells. We will also use immunofluorescence imaging to test the hypothesis that aortas from PWH will have increased activating signals and additional pro-inflammatory factors that bolster T cell activation compared to aortas from age- and gender-matched controls. Our studies will define mechanisms whereby chronic viral infection drives CD8 T cell-mediated vascular pathology and may identify novel targets beyond traditional risk factors to prevent/treat ASCVD in PWH and the HIV-uninfected elderly.
项目总结/文摘

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Emerging antibody products and Nicotiana manufacturing.
新兴抗体产品和烟草制造。
  • DOI:
    10.4161/hv.7.3.14266
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Whaley,KevinJ;Hiatt,Andrew;Zeitlin,Larry
  • 通讯作者:
    Zeitlin,Larry
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Michael L Freeman其他文献

Differential impact of ageing on cellular and humoral immunity to a persistent murine γ-herpesvirus
  • DOI:
    10.1186/1742-4933-7-3
  • 发表时间:
    2010-02-02
  • 期刊:
  • 影响因子:
    5.600
  • 作者:
    Eric J Yager;In-Jeong Kim;Michael L Freeman;Kathleen G Lanzer;Claire E Burkum;Tres Cookenham;David L Woodland;Marcia A Blackman
  • 通讯作者:
    Marcia A Blackman

Michael L Freeman的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Michael L Freeman', 18)}}的其他基金

Determining the mechanisms of vascular CD8 T cell activation in CMV and HIV infections
确定 CMV 和 HIV 感染中血管 CD8 T 细胞激活的机制
  • 批准号:
    10326617
  • 财政年份:
    2021
  • 资助金额:
    $ 20.13万
  • 项目类别:
CD* T cell responses to gamma-herpesviral infection
CD* T 细胞对 γ-疱疹病毒感染的反应
  • 批准号:
    7929661
  • 财政年份:
    2009
  • 资助金额:
    $ 20.13万
  • 项目类别:

相似国自然基金

靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
  • 批准年份:
    2024
  • 资助金额:
    0 万元
  • 项目类别:
    面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
  • 批准号:
    2023JJ50274
  • 批准年份:
    2023
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
  • 批准号:
  • 批准年份:
    2022
  • 资助金额:
    33 万元
  • 项目类别:
    地区科学基金项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
  • 批准号:
    n/a
  • 批准年份:
    2022
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
  • 批准号:
    81973577
  • 批准年份:
    2019
  • 资助金额:
    55.0 万元
  • 项目类别:
    面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
  • 批准号:
    81602908
  • 批准年份:
    2016
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
  • 批准号:
    81501928
  • 批准年份:
    2015
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Effect of tea flavonoids and low dose estrogen on bone metabolism in an animal model for age-related bone loss
茶黄酮和低剂量雌激素对年龄相关性骨质流失动物模型骨代谢的影响
  • 批准号:
    488140-2016
  • 财政年份:
    2018
  • 资助金额:
    $ 20.13万
  • 项目类别:
    Postdoctoral Fellowships
The Structural and Metabolic Changes Associated with Ependymal Layer Disruption in the Age Continuum of Hydrocephalus - A Human and Animal Model Study
脑积水年龄连续体中与室管膜层破坏相关的结构和代谢变化 - 人类和动物模型研究
  • 批准号:
    376678
  • 财政年份:
    2017
  • 资助金额:
    $ 20.13万
  • 项目类别:
    Studentship Programs
Effect of tea flavonoids and low dose estrogen on bone metabolism in an animal model for age-related bone loss
茶黄酮和低剂量雌激素对年龄相关性骨质流失动物模型骨代谢的影响
  • 批准号:
    488140-2016
  • 财政年份:
    2017
  • 资助金额:
    $ 20.13万
  • 项目类别:
    Postdoctoral Fellowships
Effect of tea flavonoids and low dose estrogen on bone metabolism in an animal model for age-related bone loss
茶黄酮和低剂量雌激素对年龄相关性骨质流失动物模型骨代谢的影响
  • 批准号:
    488140-2016
  • 财政年份:
    2016
  • 资助金额:
    $ 20.13万
  • 项目类别:
    Postdoctoral Fellowships
Animal model of impaired autoregulation for study of age related vascular cognitive impairment
用于研究年龄相关血管认知障碍的自动调节受损动物模型
  • 批准号:
    9197938
  • 财政年份:
    2016
  • 资助金额:
    $ 20.13万
  • 项目类别:
The domestic cat as an animal model for age-related neurofibrillary tangles
家猫作为年龄相关神经原纤维缠结的动物模型
  • 批准号:
    24780283
  • 财政年份:
    2012
  • 资助金额:
    $ 20.13万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Identification of candidate genes responsible for an increased susceptibility of age-related macular degeneration using an animal model and its application to gene diagnosis.
使用动物模型鉴定导致年龄相关性黄斑变性易感性增加的候选基因及其在基因诊断中的应用。
  • 批准号:
    22591939
  • 财政年份:
    2010
  • 资助金额:
    $ 20.13万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
MT1-MMP-based Animal Model of Age-related Macular Degeneration (AMD)
基于 MT1-MMP 的年龄相关性黄斑变性 (AMD) 动物模型
  • 批准号:
    8101435
  • 财政年份:
    2008
  • 资助金额:
    $ 20.13万
  • 项目类别:
MT1-MMP-based Animal Model of Age-related Macular Degeneration (AMD)
基于 MT1-MMP 的年龄相关性黄斑变性 (AMD) 动物模型
  • 批准号:
    7481783
  • 财政年份:
    2008
  • 资助金额:
    $ 20.13万
  • 项目类别:
A novel molecular paradigm of age-related macular degeneration in view of the social trend in nocturnal: An approach using an animal model
鉴于夜间活动的社会趋势,年龄相关性黄斑变性的新分子范式:使用动物模型的方法
  • 批准号:
    20791248
  • 财政年份:
    2008
  • 资助金额:
    $ 20.13万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了