Vascular Injury in Type 1 Diabetes - A Failure of Repair: Probing the Liga

Our laboratory established the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathogenesis of T1D complications. The critical discovery that firmly altered our view of this receptor was the observation that RAGE was not solely a receptor for AGEs, but a receptor for molecules that mediate inflammation a critical component of the complications of T1D. Pharmacological blockade of RAGE in rodents, and/or its genetic modulation in mice leads to suppression of macro- and microvascular complications. Propelled by these observations, our biotechnology collaborator, TransTech Pharma, developed antagonists of RAGE. These agents, now in Phase I and II clinical trials in diabetic subjects, are rapidly proceeding toward clinical development. In parallel, basic science experimentation continues to aggressively probe the question does RAGE possess innate and adaptive functions in vascular repair. We will employ RAGE antagonists to dissect the contribution of RAGE in macrophages, cells of bone marrow origin and the local vessel wall in the response to peripheral artery ischemic stress in T1D. We will probe the possibility that at distinct sites and times, RAGE in one or more of these compartments, may contribute to tissue repair.