Impact of human anti-NMDA receptor antibodies on glutamate receptor signaling, calcium mobilization, and hippocampal neuronal circuits in autoimmune encephalitis

这是一个五年研究职业发展计划的建议，重点是人类抗体的研究 自身免疫性脑炎中与神经细胞表面蛋白的结合。目的是了解 自身免疫性脑炎的病理生理学和鉴定用于治疗神经系统疾病的新靶点。的 首席研究员，大卫R。Benavides，医学博士，哲学博士、是美国密歇根大学的神经病学助理教授， 马里兰州医学院。我的长期职业目标是成为翻译领域的独立调查员。 研究集中在神经系统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、先进活细胞显微镜和体内微型显微镜方面的研究项目和培训计划 技术，这是解决这里提出的中心研究问题的组成部分。研究项目建立 基于我以前在信号转导和分子神经科学方面的研究以及在 神经免疫学，并整合了我的导师团队所代表的专业领域的创新方法 在马里兰州大学医学院。我提出了一个全面的发展计划，结合教学 我的导师监督的指导，正式的课程，与个别顾问的应用培训经验， 以及参加研讨会和讲习班。拟议的项目和发展计划将使我与 一个独特的技能，使我能够过渡到独立作为一个物理学家，科学家在翻译 神经科学研究。 脑炎是一种具有显著发病率和死亡率的脑部疾病。抗NMDA受体（NMDAR） 脑炎是自身免疫性脑炎最常见的形式，占所有脑炎病例的近4%。 脑炎中枢神经系统中的兴奋性突触传递和可塑性在一定程度上， 被称为NMDAR的谷氨酸神经递质受体所控制。NMDAR功能障碍可导致 精神病，记忆力受损，激动，运动障碍，癫痫发作和昏迷，并可能导致许多 条件，如药物使用，遗传易感性，和抗体靶向（例如，抗NMDAR脑炎）。 NMDAR抗体对自身免疫性脑炎脑功能的影响仍不完全确定。我 初步数据显示NMDAR抗体改变了初级啮齿动物中的神经元信号传导和神经元活性 分离的神经元培养物。NMDAR抗体在抗NMDAR脑炎中究竟是如何做到这一点的， 这一建议开始解决。具体而言，该提案的目的是：1）定义NMDAR的效果 抗体对谷氨酸受体信号通路的影响，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。 我们这项工作的长期目标是阐明人NMDAR抗体在自身免疫性疾病中的作用。 脑炎，以推进神经系统疾病的新疗法。

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.