The role of Trem2-expressing macrophages in atherosclerosis

表达 Trem2 的巨噬细胞在动脉粥样硬化中的作用

基本信息

  • 批准号:
    10464928
  • 负责人:
  • 金额:
    $ 1.68万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-04-15 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Macrophages are the central inflammatory cell types in atherosclerotic lipid-laden plaques. However, the influence of macrophage phenotype on the development of plaques remains unclear. Work from our lab has recently described a subset of tissue macrophages that appears in contexts associated with extracellular lipid accumulation. These macrophages were termed Lipid-Associated Macrophages (LAMs) on the basis of their gene expression profile by single cell profiling and localization around extracellular lipids. LAMs are characterized by the expression of the single transmembrane protein Trem2, both as a marker and as an essential driver of LAM generation. Our findings suggest that Trem2 drives the expression of genes involved in lipid metabolism. In addition, Trem2 has been found to act as a sensor for lipids and lipoproteins. Thus, Trem2 may function as a pattern-recognition receptor for signals of extracellular lipid accumulation, which in turn drives a conserved immune response aimed to reduce the burden of extracellular lipid in a disease such as atherosclerosis. However, the role of Trem2-expressing macrophages in atherosclerosis remains unknown. In addition, the molecular mechanisms that induce Trem2 expression are unknown. Thus, the central hypothesis of this proposal is that Trem2 drives a tissue-specialized expression profile of macrophages that can be induced in response to a signal of extracellular lipid accumulation, and the function of this macrophage subset is to reduce the pathological accumulation of lipid in atherosclerosis. To test this hypothesis, two specific aims are proposed: Aim 1 is to determine the role of Trem2 in atherosclerosis by comparing atherosclerotic burden and immune cell phenotypes in atherosclerotic plaques of mice genetically lacking Trem2 and their littermate controls using both the Ldlr-/- and Apoe-/- model of atherosclerosis. In Aim 2, inducers of Trem2 expression will be identified using a novel Trem2 reporter mouse, combined with in vitro macrophage cultures and treatment conditions. I have already generated the toolbox needed to address my specific aims, including genetic models and preliminary data. Taken together, the completion of these studies will fundamentally advance our knowledge of a newly discovered immune response in the context of tissue metabolic dysregulation, and pioneer actionable targets whereby tissue physiology can be modulated by immunotherapy in disease. In addition, this work aligns with my training goals by allowing me to use cutting-edge experimental, computational, and conceptual tools at the forefront of an interdisciplinary field linking immunology and metabolism, to initiate my career in academia.
项目总结 巨噬细胞是动脉粥样硬化载脂斑块的中心炎性细胞类型。然而, 巨噬细胞表型对斑块形成的影响尚不清楚。我们实验室的工作已经完成 最近描述了出现在与细胞外脂质相关的上下文中的组织巨噬细胞的一个子集 积累。这些巨噬细胞被称为脂质相关巨噬细胞(LAM),其基础是它们的 单细胞图谱和细胞外脂定位的基因表达谱。LAM的特征是 通过单一跨膜蛋白TREM2的表达,既作为一种标记,也作为一种基本的驱动因素 林一代。我们的发现表明,TREM2驱动了与脂质代谢有关的基因的表达。 此外,TREM2还被发现是脂类和脂蛋白的传感器。因此,TREM2可以作为一种 细胞外脂质积聚信号的模式识别受体,这反过来又驱动保守的 免疫反应旨在减轻动脉粥样硬化等疾病中细胞外脂质的负担。 然而,表达TREM2的巨噬细胞在动脉粥样硬化中的作用仍不清楚。此外, 诱导TREM2表达的分子机制尚不清楚。因此,这一提议的中心假设 是TREM2驱动巨噬细胞的组织特异性表达谱,这种表达谱可以诱导对 细胞外脂质积聚的信号,这个巨噬细胞亚群的功能是减少 动脉粥样硬化中脂质的病理性堆积。为了验证这一假设,我们提出了两个具体目标: 目的1是通过比较动脉粥样硬化的负荷和免疫细胞来确定TREM2在动脉粥样硬化中的作用 TREM2基因缺失小鼠及其仔鼠对照动脉粥样硬化斑块的表型 动脉粥样硬化的LDLR-/-和APOE-/-模型。在目标2中,TREM2表达的诱导者将使用 新型TREM2报告小鼠,结合巨噬细胞体外培养和处理条件。我有过 我已经生成了解决我的特定目标所需的工具箱,包括遗传模型和初步 数据。综上所述,这些研究的完成将从根本上促进我们对一个新的 在组织代谢失调的背景下发现了免疫反应,并开创了可操作的靶点 在疾病中,组织生理学可以通过免疫疗法进行调节。此外,这项工作与我的 通过允许我使用尖端的实验、计算和概念工具 走在免疫学和新陈代谢交叉学科领域的前沿,开启了我在学术界的职业生涯。

项目成果

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Patrick Robert Lundgren其他文献

Patrick Robert Lundgren的其他文献

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