Uveitis is an important cause of vision loss ranking fifth among causes of blindness in the United States. The inflammation that occurs in uveitis leads to ocular damage including glaucoma, macular edema, cataract, epiretinal membranes, and persistent media opacity. Treatments for uveitis are suboptimal; most uveitis is treated with corticosteroids, which are potent, non-specific agents that have high rates of serious ocular and systemic complications. This work aims to understand the mechanisms of autoinflammatory uveitis in the AIFU mouse model. My goal is to gain insights into the roles the innate immune system plays in ocular inflammation in order to develop novel therapeutic approaches that could prevent vision loss and blindness in patients with uveitis. Our core hypothesis is that the AIFU model serves as an animal model of autoinflammatory human uveitis with mixed innate and adaptive immune features. I propose to port the AIFU model from rats to mice to access the genetic tools available in this animal model, and to develop a novel real time reporter system to detect and monitor ocular inflammation in vivo. Using mouse genetic and immunologic assays, I will identify the contribution of the innate and adaptive immune systems to this model of autoinflammatory uveitis, and determine the role of the Mller glia in the ocular inflammatory response.
Three specific aims are proposed to address the central hypothesis: 1) Generate the AIFU mouse model including a real time ocular inflammation reporter system. 2) Determine the role of the Mller glia in AIFU inflammation. 3) Determine the contribution of the innate and adaptive immune response to AIFU. As an academic ophthalmologist practicing in the field of uveitis, I have both a clinical and research interest in understanding the mechanisms of ocular inflammation. As a fellow and then faculty member at the University of Washington, my clinical specialty will be treating patients with uveitis and my research program will study ocular inflammation with a focus on the innate immune system. The Department of Ophthalmology and the University of Washington Eye Institute has a world-class faculty and facilities that will help me to fully develop as a clinician-scientist. As my career develops, I will benefit from close mentoring by experienced scientists and clinicians who are deeply committed to my success.
This project seeks to understand the roles of the innate and adaptive immune system in a new mouse model of autoinflammatory uveitis (AIFU). Uncontrolled inflammation in patients with uveitis leads to severe visual loss and blindness. As uveitis is the second leading cause of blindness in the working age population, this represents an important public health concern. Current treatments including corticosteroids and immunomodulators are non-specific, and have high rates of complications, which can sometimes be life- threatening. This mouse model will help develop a better understanding of the role of the innate immune system in ocular inflammation and allow for testing of new treatments targeting both the innate and adaptive immune system in the eye. Due to their molecular specificity, such treatments may provide safer and more effective therapies for uveitis than steroids or currently available immunomodulators.
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