Role of the myeloid mineralocorticoid receptor in vascular inflammation in atherosclerosis

骨髓盐皮质激素受体在动脉粥样硬化血管炎症中的作用

• 批准号: 10408135
• 负责人: Joshua James Man
• 金额: $ 5.18万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-16 至 2023-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408135
• 关键词: Acute Disease; Adhesions; Aldosterone; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attenuated; Binding; Biological Assay; Blood Pressure; Blood Vessels; Blood flow; Bromodeoxyuridine; Cardiovascular system; Cause of Death; Cell Adhesion Molecules; Cell Communication; Cell physiology; Cells; Chronic; Clinical; Clinical Trials; Coculture Techniques; Confocal Microscopy; Cytokine Signaling; Data; Disease; Endothelial Cells; Endothelium; Environment; Event; Flow Cytometry; Fluorescence; Functional disorder; Gene Expression; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Histology; Homeostasis; Hypersensitivity; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Inflammation; Inflammatory; Integrins; Kidney; Lead; Leukocyte Rolling; Leukocytes; Luciferases; Lymphocyte; Maintenance; Measures; Mediating; Mesentery; Mineralocorticoid Receptor; Modeling; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; Organ; Outcome; Pathway interactions; Patients; Peritoneal; Phenotype; Physicians; Plant Roots; Plasma; Prevention; Receptor Inhibition; Reporter; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Rupture; Scientist; Sepsis; Sodium; Stroke; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Therapeutic; Thrombus; Training; Water; Western Blotting; antagonist; aortic arch; blood pressure regulation; cardiovascular disorder prevention; cardiovascular risk factor; career; chronic inflammatory disease; effector T cell; experimental study; improved; in vivo; insight; interest; intravital microscopy; mRNA Expression; macrophage; mortality; mouse model; polarized cell; prevent; protein expression; recruit; response; sex; trafficking; training opportunity; transcription factor; vascular inflammation

PROJECT SUMMARY/ABSTRACT Despite advances in therapeutics and prevention, cardiovascular ischemic events remain the leading cause of death in the world. Activation of the mineralocorticoid receptor (MR) is associated with chronic inflammation of the blood vessel wall and formation of atherosclerotic plaques that lead to such ischemic events following their rupture and subsequent occlusion of blood flow to target organs. MR antagonists have been shown to reduce cardiovascular-related mortality in clinical trials as well as reduce plaque size and inflammation in atherosclerosis mouse models independently of changes in blood pressure. Previous studies have explored the contributions of MR in vascular cells to atherosclerosis. Deficiency of MR in endothelial cells but not smooth muscle cells attenuates atherosclerotic plaque inflammation, but neither reproduced changes in the proportion of pro- inflammatory myeloid cells in the plaque as seen with systemic MR blockade. MR in cells of the myeloid lineage (My-MR) has been shown to regulate pro-inflammatory gene expression in macrophages (MΦ) in vitro and contribute to plaque size in mouse models, but the mechanisms by which My-MR directly contributes to vascular inflammation in atherosclerosis are not known. We have demonstrated that the number of slow-rolling leukocytes in the mesenteric vasculature in response to TNFα decreases with My-MR deficiency. Additionally, the numbers of MΦ and T cells in atherosclerotic plaque decrease with My-MR deficiency. Therefore, we hypothesize that My-MR contributes to plaque inflammation by modulating myeloid cell recruitment to the vessel wall, MΦ polarization and proliferation, and MΦ interactions with effector T cells in the plaque in vivo. We have developed an atherosclerosis mouse model in which MR is specifically deleted in myeloid cells (and not in lymphocytes or any other vascular cells). In Aim 1, we will determine the role of My-MR in regulating MΦ recruitment to and proliferation within atherosclerotic plaques in vivo by intravital microscopy, flow cytometry, and histology. In Aim 2, we will explore the role of My-MR in regulating MΦ co-stimulatory molecule and cytokine signaling and therefore T cell function both in vivo and in vitro using flow cytometry, conditioned media, and co-culture experiments. Successful completion of these aims will elucidate My-MR-mediated pathways that regulate MΦ function and the overall plaque environment. These studies are expected to reveal potential immunotherapeutic targets for the prevention of cardiovascular disease. This proposal also includes a detailed training plan and integration of clinical training to prepare the PI for a career as an independent physician scientist.

项目摘要/摘要 尽管在治疗和预防方面取得了进步，但心血管缺血事件仍然是 世界上的死亡。矿物皮质激素受体（MR）的激活与慢性炎症有关 血管壁和动脉粥样硬化斑块的形成，导致这种缺血事件之后 破裂和随后的血液流向靶器官。先生的拮抗剂已被证明可以减少 临床试验中的心血管相关死亡率，并减少动脉粥样硬化的斑块大小和炎症 小鼠模型独立于血压变化。以前的研究探讨了 在血管硬化的血管细胞中MR。内皮细胞中MR的缺乏，但没有平滑肌细胞 减弱动脉粥样硬化斑块炎症，但两者都没有再现 全身性MR封锁可见，斑块中的炎性髓样细胞。 MR在髓样谱系的细胞中 （My-Mr）已显示出在体外和 在鼠标模型中有助于斑块大小，但My-MR直接有助于血管的机制 动脉粥样硬化中的炎症尚不清楚。我们已经证明了缓慢的白细胞数量 在肠系膜脉管系统中，响应TNFα的脉管系统会随着My-MR缺乏而降低。另外，数字 动脉粥样硬化斑块中的Mφ和T细胞随着My-MR缺乏而减少。因此，我们假设 My-MR通过调节粒子细胞募集到血管壁Mφ来促进斑块注射 极化和增殖，并与体内斑块中的效应T细胞相互作用。我们已经发展了 动脉粥样硬化小鼠模型，其中MR在髓样细胞中特异性删除（而不是在淋巴细胞或 任何其他血管细胞）。在AIM 1中，我们将确定My-MR在确定Mφ募集到和的作用 通过插入显微镜，流式细胞仪和组织学在体内动脉粥样硬化斑块中的增殖。目标 2，我们将探讨My-MR在调节Mφ共刺激分子和细胞因子信号以及的作用 因此，使用流式细胞仪，条件培养基和共培养 实验。这些目标的成功完成将阐明调节Mφ的My-MR介导的途径 功能和整体斑块环境。这些研究有望揭示潜在的免疫治疗性 预防心血管疾病的靶标。该建议还包括一个详细的培训计划和 整合临床培训，为PI做准备，成为独立物理科学家的职业。