Project summary: The overarching goal of this project is to develop the principal investigator (PI) into an independent clinician- scientist contributing to the field of ocular autoimmunity. The PI has obtained his PhD in neuroscience, exploring the roles of the adaptive immune system in axonal injury models. He has additional clinical training in ophthalmology and subspecialty training in uveitis and ocular immunology, which forms the basis for his medical practice in the Department of Ophthalmology and Visual Sciences at Washington University in St. Louis. The five-year career development plan outlined here will utilize a combination of didactic courses, individualized training from expert collaborators, and mentorship from established investigators to enhance his knowledge base, to learn new experimental models he can continue to use in his career, and to define the research questions on which he will base the start of his independent research program. By the end of this program, he will have acquired the skills necessary to become an independent investigator. His primary mentor is Rajendra Apte, MD PhD, an R01-funded investigator who has a longitudinal track record of training early-stage investigators that have gone on to productive independent careers. He is a preeminent scholar in the field of choroidal immunity and has a strong background as a clinician scientist that will be vital for helping the PI navigate the challenges involved in transitioning to an independent lab. Dr. Apte will be supported by Rachel Caspi, PhD, the world-leading expert in experimental autoimmune uveitis, Jonathan Kipnis, PhD, the foremost expert in the adaptive immune system in border tissues, and Gregory Wu, MD PhD, a recent K08 awardee and expert on CNS autoimmunity. The PI will take advantage of his mentorship committee and the vibrant scientific environment of Washington University, one of the world’s premiere medical research institutions, to develop the unexplored topic of the adaptive immune response in the choroid. Uveitis is one of the leading causes of preventable blindness, and while much work has gone in to evaluating the effects of T cell-derived cytokines, there is a significant gap in understanding of the anatomy of the immune response including where the adaptive immune system interfaces with ocular antigens. This deficit has led to toxic and often ineffective systemic therapies as the mainstay of treatment. We show that intraocular antigens are taken up in the choroid, a tissue that has a rich adaptive immune presence. In autoimmune uveitis there is an increase of CD4+ T cells in the choroid, indicating that the choroid plays a vital role as the immune interface between the intraocular space and adaptive immune system. In this proposal, we will test the hypothesis that the adaptive immune system is activated by retinal antigens in the choroid and that this interaction plays a central role in uveitis. We will further elucidate the mechanisms contr...