Impact of conformationally specific human anti-NMDA receptor antibodies on NMDA receptors and neuronal function

构象特异性人抗 NMDA 受体抗体对 NMDA 受体和神经元功能的影响

基本信息

批准号：
9224296
负责人：
Jessica Anne Panzer
金额：
$ 18.75万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2017-05-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9224296
关键词：
Acute Advisory Committees Agonist Animal Model Antibodies Antiepileptic Agents Autoantibodies Autoimmune Diseases Autoimmune Process Autonomic Dysfunction Binding Biological Assay Biology Brain Brain Diseases Calcium Catatonia Cells Central Nervous System Diseases Child Care Chronic Clinical Dangerousness Data Data Analyses Degenerative Disorder Development Disabled Persons Disease Dyskinetic syndrome Electrophysiology (science)Encephalitis Environment Epilepsy Epitopes Equilibrium Experimental Designs Faculty Fc Receptor Fellowship Foundations Functional disorder Future Glutamate Receptor Goals Grant Hippocampus (Brain)Human Huntington Disease Image Immune System Diseases Immunohistochemistry Immunotherapy Impairment Knockout Mice Left Literature Maps Mediating Mental disorders Mentors Modality Modification Molecular Conformation Movement Disorders Mutation N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neurologist Neurology Neurons Neurotransmitter Receptor Pathogenesis Patients Pediatric Hospitals Pediatric Neurology Pennsylvania Pharmacology Philadelphia Physicians Probability Property Psychotic Disorders Publishing Rattus Receptor Signaling Recovery Research Residencies Resistance Resources Role Sampling Schizophrenia Scientist Seizures Signal Transduction Signal Transduction Pathway Site Specificity Surface Synapses Synaptic plasticity Therapeutic Therapeutic immunosuppression Training Training Programs Translations Universities Work Writing base career career development cell type clinical effect excitotoxicity extracellular knock-down nervous system disorder neural circuit neuronal circuitry optical imaging programs receptor response skills synaptic function trafficking

Acute Advisory Committees Agonist Animal Model Antibodies Antiepileptic Agents Autoantibodies Autoimmune Diseases Autoimmune Process Autonomic Dysfunction Binding Biological Assay Biology Brain Brain Diseases Calcium Catatonia Cells Central Nervous System Diseases Child Care Chronic Clinical Dangerousness Data Data Analyses Degenerative Disorder Development Disabled Persons Disease Dyskinetic syndrome Electrophysiology (science)Encephalitis Environment Epilepsy Epitopes Equilibrium Experimental Designs Faculty Fc Receptor Fellowship Foundations Functional disorder Future Glutamate Receptor Goals Grant Hippocampus (Brain)Human Huntington Disease Image Immune System Diseases Immunohistochemistry Immunotherapy Impairment Knockout Mice Left Literature Maps Mediating Mental disorders Mentors Modality Modification Molecular Conformation Movement Disorders Mutation N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neurologist Neurology Neurons Neurotransmitter Receptor Pathogenesis Patients Pediatric Hospitals Pediatric Neurology Pennsylvania Pharmacology Philadelphia Physicians Probability Property Psychotic Disorders Publishing Rattus Receptor Signaling Recovery Research Residencies Resistance Resources Role Sampling Schizophrenia Scientist Seizures Signal Transduction Signal Transduction Pathway Site Specificity Surface Synapses Synaptic plasticity Therapeutic Therapeutic immunosuppression Training Training Programs Translations Universities Work Writing base career career development cell type clinical effect excitotoxicity extracellular knock-down nervous system disorder neural circuit neuronal circuitry optical imaging programs receptor response skills synaptic function trafficking

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项目摘要

Project Summary The goal of the proposed 5-year training program is the development of the applicant’s independent research career as an academic neurologist focused the mechanisms underlying autoimmune neurologic disorders associated with autoantibodies against synaptic components. Dr. Panzer completed residency training in Pediatric Neurology, clinical fellowship training in Movement Disorders and has joined the neurology faculty at the Children’s Hospital of Philadelphia (CHOP) focusing on the care of children afflicted with these disorders. Her near-term goals are to develop and refine the essential skills of experimental design, data interpretation, grant writing, and lab management that will be required to successfully transition to a career as an independent physician-scientist. The focus of her research program will be to define the effects of patient derived antibodies on synaptic and circuit function. Dr. David Lynch, an expert in N-methyl-D-aspartate receptor (NMDAR) biology and co-discoverer of the autoimmune disease anti-NMDAR encephalitis, will be her scientific mentor. Dr. Douglas Coulter, an expert in the optical imaging of neuronal circuit activity with be her co-mentor. In addition, a group of eminent physicians and scientists has been assembled to serve on a Scientific Advisory Committee to support her career development. She will draw upon their expertise and the outstanding and highly collaborative training environment and resources available at CHOP and the University of Pennsylvania as she advances toward her goal of becoming an academic neurologist and translation neuroscientist. The research goal of this proposal is to determine autoantibody mechanisms in anti-NMDAR encephalitis, an autoimmune brain disorder. Chronic treatment of neurons with these antibodies results in loss of NMDARs, an important brain neurotransmitter receptor, and reduced synaptic NMDAR currents. Despite this understanding, some features of anti-NMDAR encephalitis, such as seizures, are unexplained. Better understanding of this disease is critical for the development of new non-immunosuppressive therapies. The central hypothesis of this proposal that patients’ antibodies have unique conformational specificity and agonist effects, resulting in NMDAR dysfunction of select active neuronal circuits, rather than global receptor knockdown. This proposal will establish the role of the open conformation of the NMDAR in antibody binding, define the binding and effects of antibodies on NMDARs at synaptic and extrasynaptic sites, and map the cell-type specific and circuit level effects of anti-NMDAR antibodies.

项目摘要拟议的5年培训计划的目标是申请人独立的发展作为一名学术神经科医生的研究职业集中于自身免疫性神经系统的基础机制与突触组件相关的自身抗体相关的疾病。 Panzer博士完成了居住培训在小儿神经病学上，运动障碍的临床奖学金培训，并加入了神经病学系在费城儿童医院（CHOP），专注于对患有这些疾病的儿童的照顾。她的近期目标是发展和完善实验设计，数据解释，赠款写作和实验室管理将被要求成功过渡到职业为独立的职业身体科学家。她的研究计划的重点是定义患者衍生抗体的影响在突触和电路功能上。 David Lynch博士，N-甲基-D-天冬氨酸受体（NMDAR）生物学专家自身免疫性疾病抗NMDAR脑炎的共同发现将是她的科学心理。博士道格拉斯·库尔特（Douglas Coulter）是与她的同事的神经元电路活性光学成像的专家。此外，一群著名的医生和科学家已经组建了科学咨询委员会支持她的职业发展。她将借鉴他们的专业知识以及杰出而高度的 CHOP和宾夕法尼亚大学提供的协作培训环境和资源在她身上获得她成为一名学术神经科医生和翻译神经科学家的目标。该提案的研究目标是确定抗NMDAR脑炎的自身抗体机制，自身免疫性脑部疾病。用这些抗体对神经元的慢性治疗导致NMDAR的丧失，一个重要的脑神经递质接收器，并减少了突触NMDAR电流。尽管如此理解，抗NMDAR脑炎的某些特征（例如癫痫发作）是意外的。更好的对这种疾病的了解对于开发新的非免疫抑制疗法至关重要。这该提议的中心假设是，患者的抗体具有独特的构象特异性和激动剂效果，导致精选主动神经元电路的NMDAR功能障碍，而不是全局受体敲低。该建议将确定NMDAR在抗体结合中的开放构象的作用，定义抗体对合成和突触外位点NMDAR的结合和影响，并绘制细胞类型的特异性和抗NMDAR抗体的电路水平效应。