Impact of human anti-NMDA receptor antibodies on glutamate receptor signaling, calcium mobilization, and hippocampal neuronal circuits in autoimmune encephalitis
人抗 NMDA 受体抗体对自身免疫性脑炎中谷氨酸受体信号传导、钙动员和海马神经元回路的影响
基本信息
- 批准号:10019421
- 负责人:
- 金额:$ 19.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAffectAgitationAlzheimer&aposs DiseaseAnimal ModelAntibodiesAreaAutoimmune encephalitisAutonomic DysfunctionBehavioralBindingBiochemicalBrainBrain DiseasesCa(2+)-Calmodulin Dependent Protein KinaseCalciumCell Surface ProteinsCellsCessation of lifeClinicalCognitiveComaComplexCyclic AMP-Dependent Protein KinasesDataDevelopmentDevelopment PlansDiseaseDoctor of MedicineDoctor of PhilosophyDrug usageEducational workshopElementsEncephalitisEpilepsyFc ReceptorFunctional disorderFutureGenetic Predisposition to DiseaseGlutamate ReceptorGlutamatesGoalsHippocampus (Brain)HumanImageImmuneImmune responseImmune systemIndividualInstructionIntuitionKnowledgeLeadLearningLeftLinkMarylandMeasuresMediatingMembrane ProteinsMemoryMemory impairmentMentorsMentorshipMicroscopyMolecularMorbidity - disease rateMotorMovement DisordersMultiple SclerosisMusN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeuraxisNeurodegenerative DisordersNeurologyNeuronal PlasticityNeuronsNeurophysiology - biologic functionNeurosciencesNeurosciences ResearchNeurotransmitter ReceptorOutcomeParalysedPathogenicityPathway interactionsPatientsPerformancePhosphoric Monoester HydrolasesPhosphorylationPhysiciansPositioning AttributePrincipal InvestigatorProgram DevelopmentProtein KinaseProtein-Serine-Threonine KinasesProteomicsPsychotic DisordersPublic HealthReceptor SignalingRegulationResearchResearch PersonnelResearch Project GrantsResearch TrainingResourcesRodentScientistSeizuresSeveritiesSignal PathwaySignal TransductionSiteSurfaceSurvivorsSymptomsSynapsesSynaptic TransmissionSynaptic plasticitySystemTechnologyTimeTrainingTranslational ResearchUnited States National Institutes of HealthUniversitiesWorkcalmodulin-dependent protein kinase IIcareercareer developmentcognitive taskdisabilityexperiencehigh riskimmunoregulationin vivoin vivo imaginginnovationinsightlive cell microscopymedical schoolsmemory processmortalitynervous system disorderneural networkneurobehavioralneuroimmunologyneuronal circuitryneuroregulationneurotransmissionnew therapeutic targetnovelnovel therapeuticsobject recognitionpostsynaptic neuronsprofessorprotein complexrelease of sequestered calcium ion into cytoplasmtargeted treatmenttraffickingtranslational neurosciencetreatment strategy
项目摘要
This is a proposal for a five year research career development program focused on the study of human antibodies
binding to neuronal cell surface proteins in autoimmune encephalitis. The goal is to gain understanding of the
pathophysiology of autoimmune encephalitis and identify novel targets for therapy in neurological disease. The
principal investigator, David R. Benavides, M.D., Ph.D., is an Assistant Professor of Neurology at University of
Maryland School of Medicine. My long term career goal is to become an independent investigator in translational
research focused on immune regulation of neural function in neurological disease. To accomplish this goal, I
propose a research project and training plan in proteomics, advanced live cell microscopy, and in vivo miniscope
technology, which is integral to addressing the central research question posed here. The research project builds
on my previous research in signal transduction and molecular neuroscience and clinical experience in
neuroimmunology and integrates innovative approaches in areas of expertise represented by my mentor team
at University of Maryland School of Medicine. I propose a comprehensive development plan, combining didactic
instruction overseen by my mentors, formal coursework, applied training experiences with individual advisors,
and participation in seminars and workshops. The proposed project and development plan will position me with
a unique skillset that will enable me to transition to independence as a physician-scientist in translational
neuroscience research.
Encephalitis is a brain disease with significant morbidity and mortality. Anti-NMDA receptor (NMDAR)
encephalitis is the most common form of autoimmune encephalitis and accounts for nearly 4% of all cases of
encephalitis. Excitatory synaptic transmission and plasticity in the central nervous system are governed, in part,
by a class of glutamate neurotransmitter receptors known as NMDARs. NMDAR dysfunction can cause
psychosis, impaired memory, agitation, movement disorders, seizures, and coma and may result from many
conditions, such as drug use, genetic predisposition, and antibody targeting (e.g., anti-NMDAR encephalitis).
The effects of NMDAR antibodies on brain function in autoimmune encephalitis remain incompletely defined. My
preliminary data show that NMDAR antibodies alter neuronal signaling and neuronal activity in primary rodent
dissociated neuron cultures. How exactly NMDAR antibodies do this in anti-NMDAR encephalitis is a question
that this proposal begins to address. Specifically, the aims of the proposal are: 1) define the effects of NMDAR
antibodies on glutamate receptor signaling pathways, 2) determine the effects of NMDAR antibodies on neuronal
calcium mobilization, and 3) determine the effect of NMDAR antibodies on hippocampal neuronal circuits in vivo.
Our long term goal of this work is to elucidate the effects of human NMDAR antibodies in autoimmune
encephalitis to advance novel therapeutics for neurological disease.
这是针对人类抗体研究的五年研究职业发展计划的提案
在自身免疫性脑炎中与神经元细胞表面蛋白结合。目的是了解
自身免疫性脑炎的病理生理学,并确定神经系统疾病治疗的新靶标。这
首席研究员David R. Benavides,医学博士,博士,是大学神经病学助理教授
马里兰医学院。我的长期职业目标是成为翻译的独立调查员
研究重点是神经疾病中神经功能的免疫调节。为了实现这一目标,我
提出蛋白质组学,高级活细胞显微镜和体内米斯科托的研究项目和培训计划
技术,这是解决此处提出的中心研究问题不可或缺的。研究项目建立
关于我先前在信号转导和分子神经科学和临床经验方面的研究
神经免疫学并整合了由我的导师团队代表的专业领域的创新方法
在马里兰大学医学院。我提出了一个全面的发展计划,结合了教学法
由我的导师,正式课程,与个人顾问的应用培训经验监督的指导,
并参加研讨会和研讨会。拟议的项目和开发计划将使我与
一个独特的技能,将使我能够转变为独立的医师科学家的独立
神经科学研究。
脑炎是一种脑部疾病,具有明显的发病率和死亡率。抗NMDA受体(NMDAR)
脑炎是自身免疫性脑炎的最常见形式,占所有病例的4%
脑炎。中枢神经系统中的兴奋性突触传播和可塑性部分受到控制
由一类称为NMDAR的谷氨酸神经递质受体。 NMDAR功能障碍可能导致
精神病,记忆力受损,躁动,运动障碍,癫痫发作和昏迷,可能是许多人造成的
诸如药物使用,遗传倾向和抗体靶向(例如抗NMDAR脑炎)之类的疾病。
NMDAR抗体对自身免疫性脑炎脑功能的影响尚未完全定义。我的
初步数据表明,NMDAR抗体会改变一级啮齿动物的神经元信号传导和神经元活性
解离神经元培养。 NMDAR抗体如何在抗NMDAR脑炎中做到这一点是一个问题
该建议开始解决。具体而言,该提案的目的是:1)定义NMDAR的影响
谷氨酸受体信号通路上的抗体,2)确定NMDAR抗体对神经元的影响
钙动员和3)确定NMDAR抗体对体内海马神经元回路的影响。
我们的这项工作的长期目标是阐明自身免疫中人类NMDAR抗体的影响
脑炎可以推进神经系统疾病的新型疗法。
项目成果
期刊论文数量(0)
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David Roger Benavides其他文献
David Roger Benavides的其他文献
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{{ truncateString('David Roger Benavides', 18)}}的其他基金
Impact of human anti-NMDA receptor antibodies on glutamate receptor signaling, calcium mobilization, and hippocampal neuronal circuits in autoimmune encephalitis
人抗 NMDA 受体抗体对自身免疫性脑炎中谷氨酸受体信号传导、钙动员和海马神经元回路的影响
- 批准号:
10473709 - 财政年份:2019
- 资助金额:
$ 19.13万 - 项目类别:
Impact of human anti-NMDA receptor antibodies on glutamate receptor signaling, calcium mobilization, and hippocampal neuronal circuits in autoimmune encephalitis
人抗 NMDA 受体抗体对自身免疫性脑炎中谷氨酸受体信号传导、钙动员和海马神经元回路的影响
- 批准号:
10237295 - 财政年份:2019
- 资助金额:
$ 19.13万 - 项目类别:
Impact of human anti-NMDA receptor antibodies on glutamate receptor signaling, calcium mobilization, and hippocampal neuronal circuits in autoimmune encephalitis
人抗 NMDA 受体抗体对自身免疫性脑炎中谷氨酸受体信号传导、钙动员和海马神经元回路的影响
- 批准号:
10674739 - 财政年份:2019
- 资助金额:
$ 19.13万 - 项目类别:
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