Mrgprb2 mediated neuroinflammation after cerebral ischemia
Mrgprb2介导脑缺血后的神经炎症
基本信息
- 批准号:10644182
- 负责人:
- 金额:$ 19.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-15 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAgonistAnimal ModelAsthmaAttenuatedBiochemicalBloodBrainBrain InjuriesBrain IschemiaCCL2 geneCell DeathCell DegranulationCentral Nervous SystemCerebral IschemiaCerebrovascular DisordersCerebrumCessation of lifeChargeChymaseClinicalCocaine DependenceConnective TissueDataDevelopmentEffector CellEthicsExhibitsFDA approvedFellowshipFemaleFluorescenceG-Protein-Coupled ReceptorsGenetic TranscriptionGoalsHeparinHypersensitivityIgEImmune systemImmunohistochemistryImmunologic SurveillanceImmunologicsImmunologyIn VitroIndividualInfiltrationInflammationInjuryInnate Immune SystemInterventionInvadedInvestigationIschemic StrokeK-Series Research Career ProgramsKallidinKnowledgeLabelLeukocytesLigandsLocationMacrophage ActivationMeasuresMechanicsMediatingMediatorMeningealMeningesMentorsMicrodissectionMicrogliaMiddle Cerebral Artery OcclusionModelingMolecular MedicineMorbidity - disease rateMucous MembraneMusMyelogenousNatural Killer CellsNeuroimmuneNeurological outcomeNeuronal InjuryNeurosciencesNeutrophil ActivationNeutrophil InfiltrationOutcomePathologyPathway interactionsPatientsPatternPeptidesPeripheralPharmacologyPhysiologicalPlayPopulationPrevalenceProductionProteinsReactionRegulationReporterResearchRoleScientistStainsStimulusStrokeStroke VolumeSubstance PSurfaceSurgeonT-LymphocyteTechniquesTestingTherapeuticThermal HyperalgesiasThrombectomyTimeTissuesTrainingTryptaseWild Type Mouseanimal imagingblood-brain barrier disruptioncareercerebrovascularcortistatindisability-adjusted life yearsexperienceexperimental studyfirst responderglial activationimmune activationimprovedin vivoinhibitorinnate immune pathwaysmalemast cellmedical schoolsmonocytemortalitymultidisciplinaryneuroinflammationneurosurgeryneutrophilnovelnovel strategiesnovel therapeuticspathogenpharmacologicpost strokepre-clinicalprofessorreceptorrecruitresponseresponsible research conductscreeningsensorstroke model
项目摘要
ABSTRACT
I am finishing my cerebrovascular fellowship in the department of neurosurgery at the Johns Hopkins School of
Medicine, where I will start as an assistant professor of neurosurgery with a practice focused on cerebrovascular
diseases. I am applying for a mentored surgeon-scientist career development award (CDA) to obtain further
training in neuroscience, immunology, and animal models of cerebral ischemia. This will further my long-term
career goals of exploring neuro-immunologic mechanisms underlying cerebral ischemia, and hopefully provide
a basis for new investigations in patients experiencing ischemic stroke.
A major mechanism underlying stroke pathology involves neuroinflammation, where activation of
microglia and infiltration of peripheral leukocytes worsen neuronal injury and cell death. Despite substantial pre-
clinical efforts, there exists no efficacious therapeutic in limiting post-stroke neuroinflammatory damage. Mast
cells are tissue specific, long-lived immunologic effector cells which are thought to be one of the first-responders
in immune surveillance and activation, activating multiple pathways of the innate immune system. As such, the
ability to suppress mast cell activation may broadly attenuate multiple pathways of cerebral inflammation after
stroke. Recently, Mrgprb2 was identified as a mast cell-specific G-coupled protein receptor for basic
secretagogues, mediating IgE-independent activation. I have shown preliminarily that deletion of Mrgprb2 results
in decreased stroke volume after transient middle cerebral artery occlusion (tMCAO), with decreased
transcription and production of TNFa and CCL2 after stroke, and decreased neutrophil recruitment into the
ischemic brain. This CDA proposes building upon my pharmacology graduate training in mechanisms of cell
death and cocaine addiction, towards a new direction at the interface of neuroscience and immunology. I hope
this CDA will allow me to receive multidisciplinary training in the Departments of Neuroscience and Cellular and
Molecular Medicine. Specific training goals include: (1) Training in advanced basic neuroscience techniques
including dural and meningeal microdissection, and in-vivo live-animal imaging (2) Training in animal models
of cerebral ischemia including photo-thrombotic stroke (3) Didactic and experimental training in immunology
and neuro-immune interactions (4) Additional training in the ethical and responsible conduct of research.
The research plan seeks to address the hypothesis that Mrgprb2 is a critical mast cell specific receptor
which upregulates the initial immunologic activation response after cerebral ischemia, and that inhibition of the
physiologic ligand for Mrgprb2 may decrease neuroinflammation after stroke. The Specific Aims of the proposal
are to: (1) Investigate which subset of mast cell mediators are regulated by Mrgprb2 in ischemic stroke (2)
Determine the localization and expression pattern of Mrgprb2 in central nervous system mast cells (3) Find the
endogenous ligand for Mrgprb2 in cerebral ischemia by screening of known Mrgprb2 agonists after tMCAO,
along with testing of inhibitors of Mrgprb2 as potential therapeutics of stroke.
抽象的
我正在约翰·霍普金斯学校的神经外科部门完成脑血管奖学金
医学,我将在那里开始担任神经外科助理教授,以脑血管的重点
疾病。我正在申请指导的外科医生职业发展奖(CDA),以进一步获得
脑缺血的神经科学,免疫学和动物模型的培训。这将进一步我的长期
探索脑缺血背后的神经免疫机制的职业目标,并希望提供
在患有缺血性中风的患者中进行新调查的基础。
中风病理学基础的主要机制涉及神经炎症,其中激活
小胶质细胞和周围白细胞的浸润恶化了神经元损伤和细胞死亡。尽管大量预先
临床努力,在限制中风后神经炎症性损害方面没有有效的治疗性。桅杆
细胞是组织特异性的,长寿命的免疫效应细胞,被认为是第一反应者之一
在免疫监视和激活中,激活先天免疫系统的多个途径。因此,
抑制肥大细胞激活的能力可能会大大减弱多种脑炎症的途径
中风。最近,MRGPRB2被鉴定为基本肥大细胞特异性G偶联蛋白受体
秘密的促进,介导了与IgE无关的激活。我已经初步向MRGPRB2结果删除了
瞬时脑动脉闭塞(TMCAO)的中风体积减少,降低
中风后TNFA和CCL2的转录和生产,并减少中性粒细胞募集到
缺血性大脑。该CDA提出了基于我的药理学研究生培训的细胞机理培训
死亡和可卡因成瘾,朝着神经科学和免疫学界面的新方向发展。我希望
该CDA将使我能够在神经科学和细胞部门接受多学科培训,
分子医学。具体培训目标包括:(1)高级基本神经科学技术中的培训
包括硬脑膜和脑膜的微解剖和体内活体成像(2)动物模型训练
脑缺血的脑缺血,包括光血性中风(3)免疫学中的教学和实验训练
和神经免疫相互作用(4)在伦理和负责任的研究中进行的额外培训。
该研究计划旨在解决MRGPRB2是关键肥大细胞特异性受体的假设
它上调了脑缺血后的初始免疫激活反应,并抑制
MRGPRB2的生理配体可能会减少中风后神经炎症。提案的具体目的
为:(1)研究哪些肥大细胞介质的子集受缺血性中风中MRGPRB2调节(2)
确定MRGPRB2在中枢神经系统肥大细胞中的定位和表达模式(3)找到
通过在TMCAO之后筛选已知的MRGPRB2激动剂,MRGPRB2的内源配体用于脑缺血
以及将MRGPRB2抑制剂作为中风的潜在疗法的测试。
项目成果
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