Novel pathways controlling macrophage inflammation and resolution in atherosclerosis

控制巨噬细胞炎症和动脉粥样硬化消退的新途径

• 批准号: 10216329
• 负责人: GOKHAN S HOTAMISLIGIL
• 金额: $ 72.1万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216329
• 关键词: Anti-Inflammatory Agents; Atherosclerosis; Blood Vessels; Bone Marrow; Cardiac; Cardiovascular Diseases; Cell model; Cells; Cholesterol; Cholesterol Homeostasis; Chronic; Clinical Trials; Coupled; DNA sequencing; Data; Dependovirus; Disease; Genes; Genomics; Goals; Hepatocyte; Immune; Immunoprecipitation; Immunosuppression; Impairment; Inflammation; Inflammatory; Intervention; Lesion; Light; Link; Lipids; Low-Density Lipoproteins; Mediating; Mediator of activation protein; Metabolism; Methodology; Mission; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Outcome; Output; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Post-Translational Protein Processing; Process; Progressive Disease; Proteins; Public Health; Publishing; Regulation; Research; Research Proposals; Resolution; Role; Stimulus; System; Testing; Therapeutic; Tissues; United States National Institutes of Health; Work; atherogenesis; atheroprotective; base; gain of function; global health; in vivo; innovation; insight; lipid metabolism; loss of function; macrophage; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; nuclear factor-erythroid 2; overexpression; prevent; response; therapeutic target; tissue repair; transcription factor; western diet

Summary In-spite of effective strategies for lowering cholesterol, atherosclerosis and associated cardiovascular diseases remain a major global health burden. Work in recent years has highlighted the exciting therapeutic potential for interventions that reduce inflammation, as well as the need for identifying novel and selective targets. Our long term goal is to understand how lipid metabolism and inflammation interact, and how these interactions can be useful therapeutically. The objective of the current research proposal is to determine the role of the transcription factor Nuclear factor erythroid 2 related factor-1 (Nrf1; also known as Nfe2L1) in linking these two processes. The central hypothesis is that Nrf1 in the macrophage is a critical factor for preventing chronic inflammation and maintaining cholesterol homeostasis, and that enhancing these actions of Nrf1 may be beneficial in atherosclerosis. This is based on compelling new preliminary data showing that Nrf1 is activated in macrophages in response to inflammatory stimuli and is necessary for the expression of lipid metabolism pathway genes that are crucial for proper resolution of the inflammatory state. Previous results also showed that deletion of Nrf1 drastically impairs cellular cholesterol homeostasis.The rationale for the proposed research is that understanding the function and mechanism of macrophage Nrf1 may provide important insight into regulation of macrophage inflammation and resolution in general and reveal a novel therapeutic target for the treatment of atherosclerosis. The central hypothesis will be tested by pursuing three specific aims: 1) Examine the function of Nrf1 in macrophages; 2) Elucidate the molecular mechanism of Nrf1 action in macrophages; and 3) Explore the importance of macrophage-Nrf1 in atherosclerosis in-vivo. Under the first aim, tissue-specific inducible deletion models established and tested in the applicant's lab will be used for a thorough characterization of the function of Nrf1 in inflammatory output, lipid metabolism and resolution of inflammation. This aim will also explore the impact of cholesterol on Nrf1 function, and the reciprocal role of Nrf1 in regulating cholesterol homeostasis in macrophages. In the second aim, immunoprecipitation of readily available tagged protein coupled to DNA sequencing and MS/MS analysis will identify, protein interactors and post translational modifications of Nrf1 potentially mediating its function. The third aim will test the impact of Nrf1 deficiency and overexpression on atherosclerosis in-vivo using already established Western-diet fed Ldlr-deficient mice with either macrophage specific deletion of Nrf1, or adeno-associated-virus (AAV) mediated macrophage specific overexpression of Nrf1. The approach is innovative because it attempts to overcome issues of pro-resolving mediator delivery by using naturally existing systems within macrophages. The proposed research is significant, because current approaches to activate endogenous resolution of inflammation in the context of atherosclerosis are limited, and this study might provide important insight into the role of the resolution in atherosclerosis and reveal a novel therapeutic target.

概括 降低胆固醇，动脉粥样硬化和相关心血管疾病的有效策略 仍然是全球重大的健康负担。近年来的工作强调了令人兴奋的治疗潜力 减少炎症的干预措施，以及识别新颖和选择性目标的需求。我们的漫长 术语目标是了解脂质代谢和炎症如何相互作用，以及这些相互作用如何 有用的治疗。当前研究建议的目的是确定转录的作用 因子核因子红系2相关因子1（NRF1；也称为NFE2L1）在连接这两个过程时。 中心假设是巨噬细胞中的NRF1是预防慢性炎症和 维持胆固醇稳态，并增强NRF1的这些动作可能有益 动脉粥样硬化。这是基于引人注目的新初步数据，表明NRF1在巨噬细胞中被激活 响应炎症性刺激，对于表达脂质代谢途径基因的表达是必不可少的 对于正确解决炎症状态至关重要。先前的结果还表明NRF1的缺失 大大损害了细胞胆固醇的稳态。拟议的研究的基本原理是理解 巨噬细胞NRF1的功能和机制可以为巨噬细胞的调节提供重要的见解 一般而言，炎症和分辨率揭示了治疗动脉粥样硬化的新型治疗靶标。 中心假设将通过追求三个具体目的来检验：1）检查NRF1在 巨噬细胞； 2）阐明巨噬细胞中NRF1作用的分子机制； 3）探索 巨噬细胞-NRF1在体内动脉粥样硬化中的重要性。在第一个目标下，组织特异性诱导删除 在申请人实验室中建立和测试的模型将用于彻底表征该功能 NRF1在炎症输出，脂质代谢和炎症的分辨率中的of。这个目标也将探索 胆固醇对NRF1功能的影响，以及NRF1在调节胆固醇稳态中的相互作用 巨噬细胞。在第二个目标中，随时可用的标记蛋白与DNA的免疫沉淀 测序和MS/MS分析将识别NRF1的蛋白质相互作用者和后翻译变化 潜在地介导其功能。第三个目标将测试NRF1缺乏症和过表达对 动脉粥样硬化在体内使用已经建立的西部饮食的LDLR缺陷小鼠，这两种巨噬细胞 NRF1的特定缺失，或与NRF1介导的巨噬细胞特异性过表达。 这种方法具有创新性，因为它试图通过使用来克服促进调解员交付的问题 巨噬细胞内的自然存在系统。拟议的研究很重要，因为目前 在动脉粥样硬化的情况下激活内源性炎症的内源性分辨率的方法是有限的，并且 这项研究可能会为分辨率在动脉粥样硬化中的作用提供重要的见解，并揭示了一种新颖的 治疗靶标。