Drug Testing Initiative: Targeting the Ligand-RAGE Axis

AGE interaction with RAGE activates pathways inside the cell that upregulate molecules that initiate and amplify perturbation of the vasculature, especially in endothelial cells (EC), the cells that line the vessel wall. Our JDRF Center for Diabetic Complications is focused on elucidating the mechanisms by which RAGE is intimately linked to the pathogenesis of vascular and inflammatory cell complications in diabetes. In each of the areas of study, cardiovascular complications, nephropathy and retinopathy, endothelial cell perturbation is a critical contributor to the pathogenesis of complications. We will test the hypothesis that pharmacological agents that block ligand-RAGE interaction on murine aortic endothelial cells will be the foundation for the development of novel agents for therapeutic intervention in type 1 diabetes. We will screen a library of compounds for their ability to block signal transduction and upregulation of proinflammatory genes in primary cultures of murine aortic EC. Leads identified by this approach will then be screened in primary cultures of human aortic EC