Diabetic retinopathy is the leading cause of visual loss, and recent evidence suggests that inflammatory-like processes and capillary cell death play important roles in the pathogenesis of the retinopathy. Metabolites of arachidonic acid via the cyclooxygenase and lipoxygenase pathways, collectively known as eicosanoids, are known mediators of inflammation. This grant examines the role of eicosanoids in the pathogenesis of diabetic retinopathy. The candidate's preliminary data suggest that both lipoxygenase and cyclooxygenase inhibitors can ameliorate the high glucose-induced cell death seen in cultured retinal endothelial cells. This proposal dissects the significance of three major enzymes in the eicosanoid pathway, lipoxygenase (Specific Aim 1), cyclooxygenase (Specific Aim 2), and phospholipase A2 (Specific Aim 3), in the pathogenesis of hyperglycemia-induced death of capillary cells and other lesions of retinopathy. In vitro and in vivo techniques will be used. Experiments will compare diabetic and nondiabetic knockout mice (i.e., 5- and 12-lipoxygenase, cyclooxygenase-2 or cytosolic phospholipase A2 knockouts) to wild-type mice for alterations in development of retinopathy and mechanism-based biochemical parameters (e.g., eicosanoids;oxidative stress;cytokines;and cell death enzymes). Dr. Timothy Kern, an internationally-recognized investigator of diabetic retinopathy and director of the Center for Diabetes Research, will mentor the candidate and provide expert training in retinal pathology and animal models. The Center will provide exposure to leading investigators in diabetes with the necessary skills to assist the candidate in this project. Collaborations with Dr. Jerry Nadler and Dr. Joseph Bonventre, both leaders in the field of eicosanoid research, will provide additional expertise. This stimulating environment, along with the candidate's dedication to research, and the support of the Department of Pediatrics form a foundation for the candidate to achieve her goal of research independence as a pediatric endocrinologist.