A synthetic biosensor of immunologic synapse formation allowing multiplexed T cell antigen discovery for autoimmune neurologic disorders

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Summary/Abstract Candidate: I am a neurologist-scientist at UCSF with a long-term goal to lead an independent laboratory- based research program focused on T cell autoantigen targets in autoimmune neurologic diseases. The K08 application is key for my career development, providing me with (1) mentorship from an accomplished team of scientists and physician-scientists, (2) dedicated teaching to expand my knowledge in basic and clinical immunology and synthetic biology (3) extensive hands-on training in biosensor engineering and T cell Ag detection, and (4) data collection for an R01 application. Research: T cells are important contributors to autoimmune neurological disorders including MS, MOGAD, and autoimmune encephalitis. Deeper understanding of pathogenesis is needed to develop more precise therapeutics that promise both improved efficacy and better safety profiles relative to broad-based immunosuppressant medications currently used. While high throughput methods for antibody discovery have transformed the field of autoimmune neurology by producing crucial diagnostic biomarkers, T cell Ags remain largely undefined given the lack of high throughput T cell Ag discovery platforms. This knowledge gap is significant given that T cells play important roles in disease pathogenesis. The current proposal introduces a novel technology to address the challenge of simultaneously evaluating many candidate Ags against a diverse T cell repertoire, which is based on an engineered biosensor that detects immune synapse formation at the single cell level, allowing multiplexed analysis. This proposal outlines the first experiments to further develop immune synapse sensing technology for the purposes of Ag discovery in autoimmune T cells. Mentorship and Training: My training will be accomplished through formal coursework and under direct mentorship of world leaders including Wendell Lim, PhD, who has extensive expertise in synthetic biology and cell engineering technologies. Professor Lim has over his 20 years at UCSF mentored ~50 postdoctoral fellows as well as 5 clinical fellows. I will be co-mentored by Scott Zamvil, MD/PhD and Michael Wilson MD, MAS, both physician-scientists with extensive experience in Neuroimmunology and autoimmune antigen biology. Environment: The University of California, San Francisco is an exceptional research environment with state- of-the-art facilities and world-renowned faculty. As a member of the UCSF Neurology Division of Neuroimmunology and Glial Biology and the UCSF Cell Design Institute, my work and training will bridge synthetic cell engineering and autoimmune Ag discovery. I will benefit from existing clinical autoantigen discovery infrastructure including the UCSF Center for Encephalitis & Meningitis led by Dr Wilson.