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

这是一项为期五年的研究职业发展计划的建议，重点是研究人类抗体。 自身免疫性脑炎与神经细胞表面蛋白的结合。我们的目标是了解 自身免疫性脑炎的病理生理学，并确定治疗神经疾病的新靶点。这个 首席研究员大卫·R·贝纳维德斯，医学博士，加州大学神经学助理教授 马里兰医学院。我的长期职业目标是成为一名翻译领域的独立调查员 研究主要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活体微型显微镜的研究项目和培训计划。 技术，这对于解决这里提出的中心研究问题是不可或缺的。研究项目建立了 根据我以前在信号转导和分子神经科学方面的研究和临床经验 神经免疫学，并在我的导师团队代表的专业领域整合创新方法 在马里兰大学医学院。我提出了一个全面的发展计划，结合说教 由我的导师监督的指导，正式的课程作业，与个人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的内科医生-科学家在翻译 神经科学研究。 脑炎是一种发病率和死亡率都很高的脑部疾病。抗NMDA受体(NMDAR) 脑炎是最常见的自身免疫性脑炎，占所有脑炎病例的近4%。 脑炎。中枢神经系统的兴奋性突触传递和可塑性在一定程度上受到 通过一类被称为NMDAR的谷氨酸神经递质受体。NMDAR功能障碍可导致 精神病、记忆力减退、烦躁不安、运动障碍、癫痫发作和昏迷，可能由许多原因引起 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患者脑功能的影响尚不完全清楚。我的 初步数据显示，NMDAR抗体改变了初级啮齿动物的神经元信号转导和神经元活动 分离的神经元培养。NMDAR抗体在抗NMDAR脑炎中究竟是如何做到这一点的是一个问题 这项提案开始解决的问题。具体地说，该提案的目的是：1)确定NMDAR的影响 谷氨酸受体信号通路上的抗体，2)NMDAR抗体对神经元的影响 3)确定NMDAR抗体对活体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类NMDAR抗体在自身免疫中的作用 脑炎将推动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.