Project Summary Diabetic retinopathy (DR) is a major cause of blindness worldwide. DR progresses in many patients despite preventable measures such as blood sugar and blood pressure control. Other available treatments require invasive eye injections and are often ineffective—DR remains the leading cause of legal blindness among working-age adults. Current diagnostic tests fail to identify early disease stages or predict disease progression. Consequently, new biomarkers and therapeutic strategies are needed. DR is an established inflammatory disease with leukocyte involvement. Many inflammatory cytokines (products of leukocytes) are consistently elevated in the aqueous and vitreous of patients with advanced DR and diabetic macular edema (DME). Inflammatory mediators are candidates for direct biomarkers that may predict DR progression as well as treatment response. To date the only validated prognostic DR biomarker is the circulating glycemia marker glycated hemoglobin (HbA1C). HbA1C screening, however, reflects glucose control, which indicates disease risk as opposed to DR pathology. Our central hypothesis is that intraocular inflammatory mediators such as PGE2, IL-6, and IL-8 are markers of DR severity and therefore predict risk of disease progression. Equally important, they represent potential novel targets for inhibition. We have recently demonstrated that topically applied ketorolac, a nonsteroidal anti- inflammatory drug, achieves therapeutic vitreous levels and significantly reduces several elevated inflammatory mediators in eyes with DR. These observations and its commercial availability provide rationale to investigate the relationship of inflammatory mediators with DR severity and the long-term effects of chronic topical administration of ketorolac in diabetic patients. Our current goals include confirming inflammation mediators are biomarkers of both systemic diabetes and DR progression in the aqueous. Like the vitreous humor, the aqueous reflects localized ocular inflammation, however, is technically easier to collect with less risk. We will also determine the long-term effects of sustained ketorolac application on intraocular cytokine levels, DR progression, and DME incidence. Our proposal is the first to use a cornea-permeable NSAID for the treatment of DR. We believe local inflammation control in the eye will transform future treatment options for diabetic patients facing blindness. Tracking and inhibiting local inflammatory mediators through all DR stages has the capacity to reduce or prevent disability in millions of patients per year.