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

• 批准号: 10464928
• 负责人: Patrick Robert Lundgren
• 金额: $ 1.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10464928
• 关键词: Ablation; Academia; Address; Adipocytes; Adipose tissue; Agonist; Antibodies; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Bioinformatics; Biological; Bone Marrow; Cardiovascular Diseases; Cathepsins; Cells; Chemicals; Clinical Research; Combined Modality Therapy; Data; Development; Disease; Fatty Liver; Functional disorder; Future; Gene Expression; Gene Expression Profile; Generations; Genetic Models; Goals; Histology; Homeostasis; Human; Hypertrophy; Immune; Immune response; Immunology; Immunophenotyping; Immunotherapy; In Vitro; Infiltration; Inflammation; Inflammatory; Integral Membrane Protein; Knock-out; Knockout Mice; Knowledge; Laboratories; Link; Lipase; Lipids; Lipoproteins; Malignant Neoplasms; Metabolic; Metabolism; Methods; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Obesity; PPAR gamma; Pathologic; Pattern recognition receptor; Peptide Hydrolases; Phenotype; Physiology; Public Health; Receptor Signaling; Reporter; Role; Signal Transduction; Solid; TREM2 gene; Testing; Therapeutic; Tissues; Training; Work; base; career; cell type; extracellular; fatty acid-binding proteins; in vitro activity; inhibitor; lipid metabolism; macrophage; metabolomics; mortality; novel; novel therapeutics; nuclease; preclinical study; programs; response; sensor; tool

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.

项目概要 巨噬细胞是动脉粥样硬化富含脂质的斑块中的核心炎症细胞类型。然而， 巨噬细胞表型对斑块形成的影响仍不清楚。我们实验室的工作有 最近描述了出现在与细胞外脂质相关的环境中的组织巨噬细胞的子集 积累。这些巨噬细胞根据其特性被称为脂质相关巨噬细胞 (LAM) 通过单细胞分析和细胞外脂质周围的定位来分析基因表达谱。 LAM 的特点 通过单跨膜蛋白 Trem2 的表达，既作为标记又作为重要驱动因素 林一代。我们的研究结果表明 Trem2 驱动脂质代谢相关基因的表达。 此外，Trem2 还被发现可以作为脂质和脂蛋白的传感器。因此，Trem2 可能充当 细胞外脂质积累信号的模式识别受体，这反过来又驱动保守的 免疫反应旨在减少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，该提案的中心假设 Trem2 驱动巨噬细胞的组织特异性表达谱，该表达谱可以响应 细胞外脂质积累的信号，该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积累。为了检验这一假设，提出了两个具体目标： 目标 1 是通过比较动脉粥样硬化负荷和免疫细胞来确定 Trem2 在动脉粥样硬化中的作用 遗传性缺乏 Trem2 的小鼠及其同窝对照小鼠的动脉粥样硬化斑块表型 Ldlr-/- 和 Apoe-/- 动脉粥样硬化模型。在目标 2 中，将使用 新型Trem2报告小鼠，结合体外巨噬细胞培养和治疗条件。我有 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。总而言之，这些研究的完成将从根本上增进我们对新事物的认识。 发现了组织代谢失调背景下的免疫反应，并开创了可操作的目标 由此可以通过疾病中的免疫疗法来调节组织生理学。此外，这项工作也符合我的 通过允许我使用尖端的实验、计算和概念工具来实现培训目标 连接免疫学和新陈代谢的跨学科领域的最前沿，开启了我的学术生涯。