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：
10674739
负责人：
David Roger Benavides
金额：
$ 19.13万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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

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.

这是一项专注于人类抗体研究的五年研究职业发展计划的提案与自身免疫性脑炎中的神经元细胞表面蛋白结合。目标是获得对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点。这首席研究员 David R. Benavides，医学博士、哲学博士，是纽约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转化领域的独立研究者研究重点是神经系统疾病中神经功能的免疫调节。为了实现这个目标，我提出蛋白质组学、先进活细胞显微镜和活体微型显微镜方面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一部分。研究项目建设关于我之前在信号转导和分子神经科学方面的研究以及临床经验神经免疫学，并整合了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。我提出了一个综合的发展计划，结合教学由我的导师监督的指导、正式课程、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能够一套独特的技能将使我能够作为转化领域的医师科学家过渡到独立神经科学研究。脑炎是一种具有显着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部分受到控制，通过一类称为 NMDAR 的谷氨酸神经递质受体。 NMDAR 功能障碍可导致精神病、记忆力受损、烦躁、运动障碍、癫痫发作和昏迷，可能是由许多原因引起的条件，例如药物使用、遗传倾向和抗体靶向（例如抗 NMDAR 脑炎）。 NMDAR 抗体对自身免疫性脑炎脑功能的影响仍未完全确定。我的初步数据显示 NMDAR 抗体改变原代啮齿动物的神经元信号传导和神经元活动分离的神经元培养物。 NMDAR 抗体究竟如何在抗 NMDAR 脑炎中发挥作用仍是一个问题本提案开始解决这一问题。具体来说，该提案的目标是：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，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类 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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anti-NMDAR Encephalitis: A Multidisciplinary Approach to Identification of the Disorder and Management of Psychiatric Symptoms.

DOI：
10.1016/j.psym.2020.04.017
发表时间：
2020-09
期刊：
Psychosomatics
影响因子：
3.4
作者：
Forrester A;Latorre S;O'Dea PK;Robinson C;Goldwaser EL;Trenton A;Tobia A;Aziz R;Dhawan S;Brennan A;Kurukumbi M;Dong Y;Benavides DR;Offurum AI
通讯作者：
Offurum AI

Role of responsive neurostimulation and immunotherapy in refractory epilepsy due to autoimmune encephalitis: A case report.