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

“HSV1 诱导的 NMDA 受体脑炎：自身免疫性脑炎的新生小鼠模型”

• 批准号: 9295591
• 负责人: JENNY J LINNOILA
• 金额: $ 20.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295591
• 关键词: Accounting; Acute Disseminated Encephalomyelitis; Adoptive Transfer; Adult; Animal Model; Antibodies; Antibody Formation; Antigen Presentation; Antigens; Autoantibodies; Autoimmune Process; Autoimmune encephalitis; Autoimmunity; Award; Back; Basic Science; Behavioral; Brain; Cervical lymph node group; Cessation of life; Clinic; Clinical; Clinical Trials; Data; Development; Development Plans; Diagnosis; Disease; Doctor of Philosophy; Early Diagnosis; Early treatment; Encephalitis; Environment; Etiology; Faculty; Fc Receptor; Fellowship; Functional disorder; Funding; General Hospitals; Goals; Harvest; Herpesviridae Infections; Herpesvirus 1; Hippocampus (Brain); Hospital Departments; Human; Imaging Device; Immune response; Immune system; Immunologics; Immunology; Immunotherapy; Intervention; K-Series Research Career Programs; Laboratories; Lead; Left; Magnetic Resonance; Magnetic Resonance Imaging; Massachusetts; Matrix Metalloproteinase Inhibitor; Mediating; Memory; Mentors; Methodology; Modeling; Molecular; Molecular Biology; Molecular Target; Mus; N-Methyl-D-Aspartate Receptors; Neurologist; Neurology; Neurons; Pathogenesis; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Peroxidases; Positron-Emission Tomography; Proteins; Publications; Publishing; Reporting; Research; Research Personnel; Research Proposals; Risk; Rodent; Rodent Model; Scientist; Simplexvirus; Site; Solid; Surface Antigens; Teratoma; Testing; Time; Tissues; Training; Transverse Myelitis; Viral; Work; career development; cytokine; disability; experience; experimental study; imaging agent; imaging probe; improved; in vivo imaging; instructor; medical schools; member; molecular imaging; mouse model; nervous system disorder; neuroinflammation; novel; receptor density; relating to nervous system; targeted biomarker; targeted imaging; targeted treatment; tumor; virology

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.

项目摘要/摘要： 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) 将这种培训应用于开发啮齿动物 病毒诱发的自身免疫性脑炎模型，以及 C) 使用所得数据创建成功的 R01 在 K08 的最后几年申请。这个奖项将成为我实现总体目标的重要垫脚石 发展成为一名独立的自身免疫神经科医生，在现场观察患者并研究这些疾病 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致命，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。有已发表的 NMDA 受体啮齿动物模型 (NMDAR) 脑炎。然而，它依赖于将人类抗 NMDAR 抗体过继转移到体内 老鼠的大脑。为了研究这些疾病的发病机制，特别重要的是 开发不依赖外源抗体的 NMDAR 脑炎动物模型。它一直 最近在人类中发现一些 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HSV脑炎啮齿动物模型。我们实验室的初步工作表明 一些患有 HSV 脑炎的小鼠会产生抗 NMDAR 抗体。本研究计划旨在 证明这些抗体的致病性并使用该模型更好地了解致病性 NMDAR 脑炎的生理学。这将通过使用靶向分子成像来了解 机制以及分析与这种自身免疫性神经系统疾病有关的免疫反应。 我是一名经过董事会认证、经过哈佛大学培训的神经科医生，接受过自身免疫方面的特定临床研究员培训 梅奥诊所的神经病学。我已经获得了该领域的顶级临床培训。此外， 通过在实验室的工作，我获得了该主题基础研究的额外经验 著名的自身免疫神经学家 Josep Dalmau 博士是我在这个项目上的合作导师之一。我带来了固体 通过我的博士学位获得了分子生物学的基础。研究。此外，我还有强大的出版物和 资金记录。本提案中概述的研究职业发展计划将使我拥有更好的能力 了解病毒学和免疫学以及这些领域内可以应用的最新方法 揭示副感染性自身免疫性神经系统疾病的病理生理学。研究环境 在麻省总医院、哈佛大学和麻省理工学院校园中的表现都很出色，我的导师拥有相关且必要的知识 指导该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 医院 (MGH) 神经内科和哈佛医学院神经内科讲师。我有 在我系主任 Cudkowicz 博士的全力支持下，我成长为一名独立研究员。