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

项目摘要 拟议的为期5年的培训计划的目标是发展申请人的独立性 作为一名学术神经学家，他的研究生涯专注于自身免疫神经学的潜在机制 与针对突触组件的自身抗体相关的疾病。潘泽博士完成了住院医师培训 在儿科神经学，在运动障碍方面的临床团契培训，并加入了神经病学教员 在费城儿童医院(CHOP)，重点关注患有这些疾病的儿童的护理。 她近期的目标是发展和完善实验设计、数据解释、 成功过渡到独立职业生涯所需的授权写作和实验室管理 医生兼科学家。她的研究计划的重点将是确定患者来源的抗体的效果 关于突触和回路的功能。大卫·林奇博士，N-甲基-D-天冬氨酸受体(NMDAR)生物学专家 以及自身免疫性疾病抗NMDAR脑炎的共同发现者，将成为她的科学导师。Dr。 道格拉斯·库尔特和她的共同导师道格拉斯·库尔特是神经元回路活动光学成像的专家。此外, 一群著名的医生和科学家聚集在一个科学咨询委员会任职 来支持她的事业发展。她将利用他们的专业知识和杰出的、高度 CHOP和宾夕法尼亚大学提供的协作培训环境和资源 她朝着成为一名学术神经学家和翻译神经学家的目标前进。 这项建议的研究目标是确定抗NMDAR脑炎的自身抗体机制， 一种自身免疫性脑部疾病。用这些抗体长期治疗神经元会导致NMDAR的丢失， 一种重要的脑神经递质受体，并减少突触NMDAR电流。尽管如此 据了解，抗NMDAR脑炎的一些特征，如癫痫发作，尚不清楚。更好 了解这种疾病对于开发新的非免疫抑制疗法是至关重要的。这个 这一建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 影响，导致NMDAR功能障碍的选择活跃的神经元电路，而不是全球受体击倒。 这项建议将确定NMDAR的开放构象在抗体结合中的作用，定义 抗体在突触和突触外部位对NMDAR的结合和影响，并映射细胞类型特异性 以及抗NMDAR抗体的电路水平效应。

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.