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
- 来源:
- 关键词:Acute DiseaseAdhesionsAldosteroneApolipoprotein EArterial Fatty StreakAtherosclerosisAttenuatedBindingBiological AssayBlood PressureBlood VesselsBlood flowBromodeoxyuridineCardiovascular systemCause of DeathCell Adhesion MoleculesCell CommunicationCell physiologyCellsChronicClinicalClinical TrialsCoculture TechniquesConfocal MicroscopyCytokine SignalingDataDiseaseEndothelial CellsEndotheliumEnvironmentEventFlow CytometryFluorescenceFunctional disorderGene ExpressionGenetic TranscriptionGoalsHelper-Inducer T-LymphocyteHistologyHomeostasisHypersensitivityImmunoblottingImmunotherapeutic agentImmunotherapyIn VitroInfiltrationInflammationInflammatoryIntegrinsKidneyLeadLeukocyte RollingLeukocytesLuciferasesLymphocyteMaintenanceMeasuresMediatingMesenteryMineralocorticoid ReceptorModelingMusMyelogenousMyeloid CellsMyocardial InfarctionOrganOutcomePathway interactionsPatientsPeritonealPhenotypePhysiciansPlant RootsPlasmaPreventionReceptor InhibitionReporterResolutionReverse Transcriptase Polymerase Chain ReactionRoleRuptureScientistSepsisSodiumStrokeT-Cell ActivationT-Cell ProliferationT-LymphocyteT-Lymphocyte SubsetsTNF geneTestingTherapeuticThrombusTrainingWateraortic archblood pressure regulationcardiovascular disorder preventioncardiovascular risk factorcareerchronic inflammatory diseaseeffector T cellexperimental studyimprovedin vivoinsightinterestintravital microscopymRNA Expressionmacrophagemortalitymouse modelpolarized cellpreventprotein expressionrecruitresponsesextraffickingtraining opportunitytranscription factorvascular inflammation
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
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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