DESCRIPTION (provided by applicant): Currently, 30 million people have been diagnosed with diabetes, with an additional 86 million being treated for pre-diabetes, and this epidemic continues to rise annually in the US. Beyond this, one in every four Veterans receiving care from the VA is being treated for diabetes and its many physical complications, with almost half suffering from diabetic retinopathy, which is the leading cause of blindness in the US. With such a significant impact on both the US and the Veteran community, new therapeutics is required to stay abreast of the financial and physical threat posed by this visual disease. One of the most promising sources of such a therapeutic target lies within the immune system. The alteration of the immune system mediates much of the pathogenesis in diabetic complications through protein cytokine production, with IL-17 being the most prevalent cytokine in inflammatory disorders and diabetes. This research project will focus on the role of IL-17 in diabetic retinopathy, and will be the first study to characterize IL-7 producing neutrophils in diabetes. IL-17 producing neutrophils will be a major focus in this study because they are the only cell in the immune system that has an autocrine IL- 17 function that increases production of pro-inflammatory chemokines, proteinases, and reactive oxygen species, which likely play a role in diabetic retinopathy. Murine models of diabetic retinopathy will be used to test the hypothesis that diabetes alters the immune system, promoting IL-17 production by neutrophils and lymphocytes, which lead to chronic inflammation, oxidative stress, and development of clinical retinopathy. Further, through these studies potential therapeutic targets will be identified to immunomodulate IL-17 production and delay the onset of retinal pathology.