"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: 10066374
• 负责人: JENNY J LINNOILA
• 金额: $ 19.68万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066374
• 关键词: Accounting; Acute Disseminated Encephalomyelitis; Adoptive Transfer; Adult; Animal Model; Antibodies; Antibody Formation; Antigen Presentation; Antigens; Autoantibodies; Autoimmune; 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; autoimmune pathogenesis; 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.

项目总结/摘要： 该指导临床科学家研究职业发展奖（K 08）的目标是A）获得 理论和实践培训：1）啮齿动物磁共振（MR）和正电子发射断层扫描 (PET)分子成像和2）病毒学和免疫学，B）将该训练应用于开发啮齿动物 病毒诱导的自身免疫性脑炎模型，以及C）使用所得数据来创建成功的R 01 在这K 08的最后几年应用。这个奖项将是我实现 发展成为一个独立的自身免疫神经学家，看到病人和研究这些疾病， 实验室，有助于早期诊断和更好地治疗这些致残性疾病。 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。已发表的NMDA受体的啮齿动物模型 （NMDAR）脑炎。然而，它依赖于人抗NMDAR抗体过继转移到细胞中。 老鼠的大脑为了研究这些疾病的发病机制， 开发不依赖外源性抗体的NMDAR脑炎动物模型。已经 最近在人类中认识到，一些NMDAR脑炎病例是由单纯疱疹病毒引发的， (HSV)脑炎建立了啮齿动物HSV脑炎模型。我们实验室的初步工作表明 一些患有HSV脑炎的小鼠产生抗NMDAR抗体。这项研究计划旨在 证明这些抗体的致病性，并使用该模型来更好地了解致病性， NMDAR脑炎的生理学这将通过使用靶向分子成像来了解 机制以及分析参与这种自身免疫性神经系统疾病的免疫反应。 我是一名哈佛毕业的神经科医生，接受过自身免疫性疾病的临床研究培训。 马约诊所的神经科我已经获得了该领域的顶级临床培训。此外，委员会认为， 我在这个课题的基础研究中获得了额外的经验， 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。我带来了一个固体 分子生物学的基础知识，通过我的博士学位问题研究此外，我有一个强大的出版物， 资金记录。本建议书中概述的研究职业发展计划将使我有更好的 了解病毒学和免疫学以及这些领域中可以应用的最新方法 来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MGH，哈佛和麻省理工学院的校园是杰出的，我的导师有相关和必要的 专业知识来指导这个职业发展计划。我是马萨诸塞州的一名全职教师 医院（MGH）神经病学系和哈佛医学院神经病学讲师。我有 我的系主任Cudkowicz博士的全力支持，发展成为一名独立的研究人员。