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：
RISHENG XU
金额：
$ 19.95万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
https://reporter.nih.gov/project-details/10644182
关键词：
Address Agonist Animal Model Asthma Attenuated Biochemical Blood Brain Brain Injuries Brain Ischemia CCL2 gene Cell Death Cell Degranulation Central Nervous System Cerebral Ischemia Cerebrovascular Disorders Cerebrum Cessation of life Charge Chymase Clinical Cocaine Dependence Connective Tissue Data Development Effector Cell Ethics Exhibits FDA approved Fellowship Female Fluorescence G-Protein-Coupled Receptors Genetic Transcription Goals Heparin Hypersensitivity IgE Immune system Immunohistochemistry Immunologic Surveillance Immunologics Immunology In Vitro Individual Infiltration Inflammation Injury Innate Immune System Intervention Invaded Investigation Ischemic Stroke K-Series Research Career Programs Kallidin Knowledge Label Leukocytes Ligands Location Macrophage Activation Measures Mechanics Mediating Mediator Meningeal Meninges Mentors Microdissection Microglia Middle Cerebral Artery Occlusion Modeling Molecular Medicine Morbidity - disease rate Mucous Membrane Mus Myelogenous Natural Killer Cells Neuroimmune Neurological outcome Neuronal Injury Neurosciences Neutrophil Activation Neutrophil Infiltration Outcome Pathology Pathway interactions Patients Pattern Peptides Peripheral Pharmacology Physiological Play Population Prevalence Production Proteins Reaction Regulation Reporter Research Role Scientist Stains Stimulus Stroke Stroke Volume Substance P Surface Surgeon T-Lymphocyte Techniques Testing Therapeutic Thermal Hyperalgesias Thrombectomy Time Tissues Training Tryptase Wild Type Mouse animal imaging blood-brain barrier disruption career cerebrovascular cortistatin disability-adjusted life years experience experimental study first responder glial activation immune activation improved in vivo inhibitor innate immune pathways male mast cell medical schools monocyte mortality multidisciplinary neuroinflammation neurosurgery neutrophil novel novel strategies novel therapeutics pathogen pharmacologic post stroke pre-clinical professor receptor recruit response responsible research conduct screening sensor stroke 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）找到通过筛查TMCAO后已知的MRGPRB2激动剂筛选脑缺血中MRGPRB2的内源配体，以及将MRGPRB2抑制剂作为中风的潜在疗法的测试。