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展，但心血管缺血事件仍然是 世界上的死亡。盐皮质激素受体(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 破裂和随后流向目标器官的血流闭塞。MR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以及减少动脉粥样硬化的斑块大小和炎症 小鼠模型不受血压变化的影响。以前的研究已经探索了 MR在血管细胞中对动脉粥样硬化的作用。血管内皮细胞而不是平滑肌细胞的MR缺乏 减轻动脉粥样硬化斑块炎症，但这两种药物都没有复制前- 全身性MR阻断所见斑块内炎性髓细胞。髓系细胞中的MR (My-MR)已被证明在体外调节巨噬细胞(MΦ)的促炎基因表达，并 在小鼠模型中影响斑块大小，但My-MR直接影响血管大小的机制 动脉粥样硬化中的炎症作用尚不清楚。我们已经证明了缓慢滚动的白细胞的数量 肠系膜血管对肿瘤坏死因子的反应中，随着My-MR缺陷，α减少。此外，这些数字 随着My-MR缺乏，动脉粥样硬化斑块中M、Φ和T细胞的数量减少。因此，我们假设 My-MR通过调节髓样细胞向血管壁的募集而促进斑块炎症，MΦ M-Φ与斑块中效应T细胞的相互作用我们已经开发出 一种动脉粥样硬化小鼠模型，其中MR在髓系细胞中特异性缺失(而不是在淋巴细胞或 任何其他维管细胞)。在目标1中，我们将确定My-MR在管理MΦ招聘到和 活体显微镜、流式细胞仪和组织学研究动脉粥样硬化斑块内的增殖。在AIM 2，我们将探讨My-MR在调节M-Φ共刺激分子和细胞因子信号转导中的作用 因此，利用流式细胞术、条件培养液和共培养，T细胞在体内和体外都能发挥作用 实验。这些目的的成功完成将阐明My-MR介导的调节MΦ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方法。 预防心血管疾病的目标。该提案还包括详细的培训计划和 整合临床培训，为PI作为独立内科科学家的职业生涯做好准备。