"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： 这个指导的临床科学家研究职业发展奖（K08）的目标是a） 1）啮齿动物磁共振（MR）和正电子发射断层扫描中的理论和动手训练 （PET）分子成像和2）病毒学和免疫学，b）将此训练用于开发啮齿动物 病毒引起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 在此K08的最后几年的应用。该奖项将是我的整体目标的至关重要的垫脚石 发展成独立的自身免疫性神经科医生，发现患者并研究这些疾病 实验室，有助于早期诊断，并为这些残疾疾病提供更好的治疗方法。 自身免疫性脑炎可能是致命的，可能导致严重的残疾。很难收集足够的 患有自身免疫性脑炎的患者进行临床试验。有一个已发表的NMDA受体的啮齿动物模型 （NMDAR）脑炎。但是，它依赖于人类抗-NMDAR抗体的收养转移 小鼠的大脑。为了研究这些疾病的发病机理，对于 开发不依赖外源抗体的NMDAR脑炎的动物模型。它一直 最近在人类中认识到某些NMDAR脑炎是由单纯疱疹病毒触发的 （HSV）脑炎。建立了HSV脑炎的啮齿动物模型。我们的实验室的初步工作显示 一些患有HSV脑炎的小鼠会产生抗NMDAR抗体。该研究建议旨在 证明这些抗体的致病性，并使用此模型更好地了解病原 NMDAR脑炎的生理学。这将通过使用靶向分子成像来理解 机制以及这种自身免疫性神经系统疾病所涉及的免疫反应。 我是经过董事会认证的哈佛神经科医生，并在自身免疫中进行了特定的临床奖学金培训 神经学通过梅奥诊所。我已经获得了该领域的最佳临床培训。此外， 我通过在实验室中花费时间来获得该主题的基础研究的额外经验 著名的自身免疫性神经科医生Josep Dalmau博士是我在这个项目上的副主管之一。我带来坚固的 通过我的博士学位获得的分子生物学基础。研究。此外，我有很强的出版物， 资金记录。该提案中概述的研究职业发展计划将使我能够更好 了解病毒学和免疫学以及这些领域内的最新方法论可以应用 揭示了自身免疫性神经系统疾病的病理生理。研究环境 在整个MGH，哈佛和麻省理工学院校园非常出色，我的导师具有相关和必要的 指导这一职业发展计划的专业知识。我是马萨诸塞州将军的全职教师 医院（MGH）神经病学系和哈佛医学院神经病学讲师。我有 我部门主席库德科维奇（Cudkowicz）博士的全部支持，以发展成为一名独立的研究人员。