Identification of Immunomodulators for Diabetic Retinopathy Therapeutics

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ABSTRACT More than 9% of the US population has diabetes, with an additional 25% being treated for pre-diabetes, and this epidemic continues to rise annually. As diabetes progresses, >60% of Type II and >95% of Type I diabetics develop diabetic retinopathy; one of the leading causes of blindness in the working-age population worldwide. Currently, there are no preventative therapies to inhibit the asymptomatic chronic inflammation that slowly destroys retinal cells, which leads to vascular lesions and the onset of diabetic retinopathy. With such a significant impact on human health, new therapies are required to stay abreast of this diabetes complication. One of the most promising therapeutic targets lie within the inflammatory response, because inflammation can mediate much of the pathogenesis in diabetes complications. In a murine model of Streptozotocin (STZ)- induced-diabetes, we determined that diabetes mediated the production of Interleukin-17A (IL-17), one of the most prevalent cytokines associated with autoimmune and inflammatory pathogenesis. We also found that IL- 17 induced vascular permeability and capillary degeneration in the retina, which are hallmarks of non- proliferative diabetic retinopathy. Finally, we identified IL-17 receptor and the CIKS (Connection to IB Kinase and Stress activated protein) adaptor molecule constitutively expressed on multiple retina cells, which elicits retinal inflammation, oxidative stress, and the vascular lesions. The goal of this proposal is to unravel the IL-17 receptor/CIKS signaling events involved in retinal pathogenesis to reveal novel therapeutic targets for the early onset of diabetic retinopathy. We postulate that diabetes mediates a cascade of CIKS-TRAF (TNF Receptor Associated Factor) signaling events that initiate oxidative stress and retinal inflammation, which lead to vascular permeability and capillary degeneration in the retina. This is a precursor to the onset of proliferative diabetic retinopathy and vision loss. By using murine models of STZ-induced diabetes and ex vivo retina assays, we will identify the mechanism within the CIKS-TRAF signaling cascade that initiates retinal inflammation and pathogenesis. Through these studies therapeutic targets will be identified, which we postulate will delay the onset of diabetic retinopathy and inhibit vision loss.