Sunday, May 5, 2024
5/5/2024
PROJECT SUMMARY / ABSTRACT Chronic autoimmune uveitis is often a treatment-resistant disease, leading to irreversible vision loss in a significant number of patients, particularly in the working-age population, and thus adds a substantial socio- economic burden due to consequent healthcare costs and productivity loss. The preponderance of previous studies investigating autoimmune uveitis have focused on the acute stage of the disease using the popular murine models of acute uveitis, which in fact uncommonly leads to severe vision loss in humans in contrast to chronic uveitis. Thus, there is a major deficiency in our current understanding of the precise pathogenic mechanisms in chronic uveitis. Our laboratory has recently developed and validated a mouse model of chronic autoimmune uveitis (CAU) in wild-type animals, which replicates the clinical features of chronic sight-threatening uveitis observed in humans. Using this unique CAU model, we have demonstrated distinct long-lived memory CD4+ T cells in chronic disease, in contrast to the short-lived effector CD4+ T cells in acute disease. These memory T cells are antigen-specific, autoreactive effectors (`effector-memory' T cells) responsible for the chronic persistence of intraocular inflammation in CAU. Furthermore, our preliminary work reveals a local hypoxic microenvironment within the inflamed retina in CAU, which is associated with prominent up-regulation of hypoxia-inducible factor-1a (HIF-1a), glycolytic metabolism, and Wnt/ß-catenin transcriptional activity selectively in the retinal infiltrating memory T cells but not in other retinal cells. We thus hypothesize that HIF-1a promotes chronic autoimmune uveitis via maintaining the pathogenic memory CD4+ T cell pool through regulating metabolic and transcriptional reprogramming of T cells that facilitates their function and long-term survival. The principal objectives of this project are to (i) determine individual contribution of HIF-1a, glycolysis, and Wnt/ß-catenin activation to uveitogenicity of memory CD4+ T cells; and further (ii) determine whether HIF-1a modulates memory CD4+ T cells and chronic uveitis through activating glycolytic metabolism and Wnt/ß-catenin transcriptional pathway. To achieve these objectives, three specific aims have been developed: Aim 1: Is HIF-1a expression by memory T cells required for their function and long-term survival and maintaining disease chronicity? Aim 2: Is enhanced glycolysis in memory T cells required for their pathogenic function and driven by HIF-1a? And Aim 3: Is activated Wnt/ß- catenin transcriptional pathway in memory T cells required for their longevity and driven by HIF-1a? Successful completion of this project will substantially advance our knowledge of molecular mechanisms in modulating pathobiology of uveitogenic memory T cells and provide potentially novel therapeutic approaches precisely targeting the underlying cause of chronic autoimmune uveitis.
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