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

基本信息

  • 批准号:
    10224646
  • 负责人:
  • 金额:
    $ 5.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-16 至 2023-07-15
  • 项目状态:
    已结题

项目摘要

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.
项目总结/文摘

项目成果

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Joshua James Man其他文献

Joshua James Man的其他文献

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{{ truncateString('Joshua James Man', 18)}}的其他基金

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
  • 财政年份:
    2020
  • 资助金额:
    $ 5.1万
  • 项目类别:

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