The role of the Aryl hydrocarbon receptor in antigen-presenting cells in atherosclerosis

抗原呈递细胞中芳基烃受体在动脉粥样硬化中的作用

基本信息

项目摘要

Atherosclerosis is the main cause of ischemic diseases such as myocardial infarction and stroke, which together constitute the leading cause of mortality worldwide. Recognized as a chronic inflammatory disease of the vascular wall, it involves innate as well as adaptive immune mechanisms. The ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which in addition to physiological ligands can function as a xenobiotic sensor, has been described to promote atherosclerosis in response to toxic environmental contaminants. The physiological role of Ahr and its cell-type specific functions in atherosclerosis, however, have not been investigated. In preliminary experiments we demonstrated that Ahr is highly expressed in a population of atherosclerosis-associated CD11c+ antigen-presenting immune cells and that Ahr deficiency in CD11c+ cells increases atherosclerosis in mice, which was associated with an increased tumor necrosis factor (TNF)-α production. We therefore hypothesize that Ahr expression in lesional CD11c+ APCs limits atherosclerosis by acting as a gatekeeper of inflammatory cell activation via inhibition of TNFα expression. In this project we will evaluate the role of Ahr in CD11c+ cells in lesion formation at different stages of atherosclerosis and perform a systematic analysis of how Ahr affects the accumulation of CD11c+ cells and their gene expression in atherosclerosis. Moreover, we will investigate the mechanisms underlying Ahr-mediated regulation of TNFα production in CD11c+ immune cells and target TNFα specifically in these cells to evaluate its cell-type specific contribution in atherosclerosis. Finally, we will also evaluate Ahr expression and associated effector molecules in human atherosclerosis in a translational approach.
动脉粥样硬化是心肌梗死和中风等缺血性疾病的主要原因,这些疾病共同构成全球死亡率的主要原因。它被认为是一种血管壁的慢性炎症性疾病,涉及先天性和适应性免疫机制。配体激活的转录因子芳烃受体(AhR),除了生理配体可以作为一个异生素传感器,已被描述为促进动脉粥样硬化响应有毒的环境污染物。然而,Ahr的生理作用及其在动脉粥样硬化中的细胞类型特异性功能尚未研究。在初步实验中,我们证明Ahr在动脉粥样硬化相关的CD 11 c+抗原呈递免疫细胞群体中高度表达,并且CD 11 c+细胞中的Ahr缺陷会增加小鼠的动脉粥样硬化,这与肿瘤坏死因子(TNF)-α产生增加有关。因此,我们推测,Ahr在病变的CD 11 c + APC表达限制动脉粥样硬化作为一个看门人的炎症细胞活化通过抑制TNFα的表达。在本项目中,我们将评估Ahr在CD 11 c+细胞中在动脉粥样硬化不同阶段病变形成中的作用,并对Ahr如何影响CD 11 c+细胞的积累及其基因表达进行系统分析。此外,我们将研究Ahr介导的调节CD 11 c+免疫细胞中TNFα产生的机制,并在这些细胞中特异性靶向TNFα,以评估其在动脉粥样硬化中的细胞类型特异性贡献。最后,我们还将评估Ahr表达和相关的效应分子在人类动脉粥样硬化的翻译方法。

项目成果

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Dr. Clement Cochain, Ph.D.其他文献

Dr. Clement Cochain, Ph.D.的其他文献

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{{ truncateString('Dr. Clement Cochain, Ph.D.', 18)}}的其他基金

Role and therapeutic targeting of TREM2 in monocyte/macrophage dependent ischemic heart repair
TREM2 在单核细胞/巨噬细胞依赖性缺血性心脏修复中的作用和治疗靶向
  • 批准号:
    458539578
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Tissue experienced resident macrophages of the perivascular niche in myocardial infarction
心肌梗塞血管周围微环境中的组织经历了常驻巨噬细胞
  • 批准号:
    471705758
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

相似国自然基金

N-芳基酰胺类惰性C(aryl)-N键直接活化/官能化反应研究
  • 批准号:
    21772032
  • 批准年份:
    2017
  • 资助金额:
    64.0 万元
  • 项目类别:
    面上项目

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The Role of CD96hi Cells Mediated by Transcription Factor Aryl Hydrocarbon Receptor (AHR) in HIV Pathogenesis.
转录因子芳基烃受体 (AHR) 介导的 CD96hi 细胞在 HIV 发病机制中的作用。
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了解芳烃受体混杂的起源和机制
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    10679532
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    2023
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芳基碳氢化合物受体信号传导对 Toll 样受体介导的炎症的影响
  • 批准号:
    10569113
  • 财政年份:
    2022
  • 资助金额:
    --
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The impact of Aryl hydrocarbon receptor signaling on Toll like receptor-mediated inflammation
芳基碳氢化合物受体信号传导对 Toll 样受体介导的炎症的影响
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    10367788
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    --
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Decoding microbial-Aryl Hydrocarbon Receptor interactions at the skin barrier interface
解码皮肤屏障界面处的微生物-芳基烃受体相互作用
  • 批准号:
    10689803
  • 财政年份:
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Decoding microbial-Aryl Hydrocarbon Receptor interactions at the skin barrier interface
解码皮肤屏障界面处的微生物-芳基烃受体相互作用
  • 批准号:
    10507321
  • 财政年份:
    2022
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    --
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Regulation of metabolism by the Aryl hydrocarbon receptor in hematopoietic and immune cell progenitors
芳基烃受体对造血和免疫细胞祖细胞代谢的调节
  • 批准号:
    10353238
  • 财政年份:
    2021
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    --
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Aryl hydrocarbon receptor and bilirubin as therapeutic target for ICH
芳烃受体和胆红素作为脑出血的治疗靶点
  • 批准号:
    10615880
  • 财政年份:
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  • 资助金额:
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Gut Microbiota Dysbiosis in Major Depressive Disorder is Associated with Altered Production of Aryl Hydrocarbon Receptor Ligands and Altered Microglia Function
重度抑郁症中的肠道微生物群失调与芳基烃受体配体的产生改变和小胶质细胞功能改变有关
  • 批准号:
    10371654
  • 财政年份:
    2021
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    --
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芳烃受体对 T 辅助细胞功能的调节
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  • 财政年份:
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