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

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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.