"HSV1-Induced NMDA Receptor Encephalitis: a De Novo Murine Model of Autoimmune Encephalitis"

项目摘要/摘要： 本指导临床科学家研究职业发展奖(K08)的目标是A)获得 1)啮齿动物磁共振(MR)和正电子发射断层扫描的理论和实践培训 (PET)分子成像和2)病毒学和免疫学，B)将这种训练应用于发育啮齿动物 病毒诱导的自身免疫性脑炎的模型，以及C)使用结果数据创建成功的R01 在这个K08的最后几年申请。这一奖项将是我实现以下总目标的重要踏脚石 发展成为一家独立的自身免疫性神经科医生，在医院看病和研究这些疾病 实验室，有助于这些致残性疾病的早期诊断和更好的治疗。 自身免疫性脑炎可能是致命的，并可能导致严重残疾。很难收集到足够的 自身免疫性脑炎患者进行临床试验。有一种已发表的NMDA受体啮齿动物模型 (NMDAR)脑炎。然而，它依赖于人抗NMDAR抗体的过继转移到 老鼠的大脑。为了研究这些疾病的发病机制，尤其重要的是 建立一种不依赖外源性抗体的NMDAR脑炎动物模型。一直以来 最近在人类中发现的一些NMDAR脑炎病例是由单纯疱疹病毒引发的 (单纯疱疹病毒)脑炎。建立单纯疱疹病毒性脑炎啮齿动物模型。我们实验室的初步工作显示 一些单纯疱疹病毒脑炎小鼠会产生抗NMDAR抗体。这项研究提案旨在 证明这些抗体的致病性，并使用这个模型来更好地理解 NMDAR脑炎的生理学。这将通过使用靶向分子成像来理解 对这种自身免疫性神经紊乱的机制以及免疫反应进行分析。 我是哈佛大学毕业的神经科医生，在自身免疫方面接受过专门的临床研究。 通过梅奥诊所的神经学。我已经接受了这一领域最好的临床培训。此外， 我在这个主题的基础研究方面获得了更多的经验，通过在 著名的自身免疫神经学家Josep Dalmau博士，我在这个项目上的共同导师之一。我带了一个固体的 以分子生物学为基础，通过我的博士学习获得的。此外，我有一本很有影响力的出版物和 资金记录。这份提案中概述的研究职业发展计划将使我拥有更好的 了解病毒学和免疫学，以及在这些领域中可以应用的最新方法 目的：揭示副传染性自身免疫性神经疾病的病理生理学。研究环境 在麻省理工学院、哈佛大学和麻省理工学院的校园里都很出色，我的导师们拥有相关和必要的 指导这项职业发展计划的专业知识。我是马萨诸塞州综合医院的全职教员 曾任哈佛大学医学院神经病学讲师。我有过 在我的系主任库德科维奇博士的全力支持下，我发展成为一名独立的研究员。

PROJECT SUMMARY / ABSTRACT: The goals of this Mentored Clinical Scientist Research Career Development Award (K08) are to A) obtain theoretical and hands-on training in 1) rodent magnetic resonance (MR) and positron emission tomography (PET) molecular imaging and 2) virology and immunology, B) apply this training towards developing a rodent model of viral-induced autoimmune encephalitis, and C) to use the resulting data to create a successful R01 application in the final years of this K08. This award will be a crucial stepping-stone towards my overall goal of developing into an independent autoimmune neurologist that sees patients and studies these diseases in the laboratory, contributing to earlier diagnoses and better treatments for these disabling disorders. Autoimmune encephalitis can be fatal and can lead to significant disability. It is difficult to gather enough patients with autoimmune encephalitis for clinical trials. There is a published rodent model of NMDA receptor (NMDAR) encephalitis. However, it relies on the adoptive transfer of human anti-NMDAR antibodies into the brains of mice. In order to study the pathogenesis of these disorders, it would be particularly important to develop an animal model of NMDAR encephalitis which does not rely on exogenous antibodies. It has been recently recognized in humans that some cases of NMDAR encephalitis are triggered by herpes simplex virus (HSV) encephalitis. Rodent models of HSV encephalitis are established. Preliminary work by our lab showed that some mice with HSV encephalitis make anti-NMDAR antibodies. This research proposal aims to demonstrate the pathogenicity of these antibodies and to use this model to better understand the patho- physiology of NMDAR encephalitis. This will be done by using targeted molecular imaging to understand the mechanisms as well as profiling the immune responses involved in this autoimmune neurologic disorder. I am a board-certified Harvard-trained neurologist with specific clinical fellowship training in autoimmune neurology through the Mayo Clinic. I have obtained the top clinical training available in this field. Furthermore, I have gained additional experience in basic research within this topic by spending time in the laboratory of the renowned autoimmune neurologist Dr. Josep Dalmau, one of my co-mentors on this project. I bring a solid grounding in molecular biology, gained through my Ph.D. studies. In addition, I have a strong publication and funding record. The research career development plan outlined within this proposal will equip me with a better understanding of virology and immunology and the latest methodologies within these fields that can be applied to uncover the pathophysiology of parainfectious autoimmune neurologic disorders. The research environment across the MGH, Harvard, and MIT campuses is outstanding and my mentors have the relevant and necessary expertise to guide this career development plan. I am a full time faculty member in the Massachusetts General Hospital (MGH) Department of Neurology and an Instructor in Neurology at Harvard Medical School. I have the full backing of the chair of my department, Dr. Cudkowicz, to develop into an independent researcher.