Funded Projects

Diabetic retinopathy (DR) is a major complication of diabetes mellitus and the leading cause of vision loss worldwide in adults aged 20-74 years. Early pathological events in DR include retinal inflammation and endothelial dysfunction that lead to disruption of endothelial barrier and vascular leakage resulting in diabetic macular edema (DME). Glycosylation plays a crucial role in many cellular processes including inflammatory response and endothelial barrier formation. Disturbance in the glycolytic process directly affects the function of cell surface proteins and changes in glycans have been associated with a broad range of pathologies in human diseases. Clinically, genetic mutations of glycoenzymes have been identified as risk factors in type 2 diabetes and obesity. However, their pathogenic implications in DR have not been studied. In this pilot project, we will combine the expertise from three experienced investigators in vascular biology, glycobiology, and genetics, and seek to understand the role of a key enzyme that catalyzes the terminal step of N-glycan biosynthesis in the regulation of protein expression and function of endothelial adhesion molecules and tight junction proteins. We will examine if downregulation of this enzyme will have a direct impact on endothelial inflammation and barrier dysfunction using an in vitro model of DR. Finally, we will determine if epigenetic changes mediated by DNA methylation contribute to the altered expression of regulatory genes involved in N-glycosylation in DR. Completion of this pilot project will generate valuable information for understanding how dysregulation of glycosylation contributes to vascular damage in DR pathogenesis.