RAGE-directed imaging in diabetes-induced accelerated atherosclerosis

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We propose to develop an approach to imaging accelerated atherosclerosis in diabetes by targeting Receptors Advanced Glycated Endproducts (RAGE). Advanced Glycation End Products (AGEs) formed by the nonenzymatic linkage of glucose to proteins induce the expression of RAGE on cells. RAGE is a member of the immunoglobulin superfamily, comprised of an extracellular region and one V-type domain followed by two C-type domains. Binding of AGEs to RAGE induces multiple signaling pathways involved in plaque progression. Other inflammatory ligands identified with atherogenesis bind to RAGE implicating its role in non- diabetic atherosclerosis. With our collaborators we have developed a novel antibody against the V-domain of RAGE designed to display immunoreactivity in mice, pigs and human. Using hybridoma technology murine monoclonal antibodies were produced, fragmented, and labeled with 99mTc, and show uptake in aortic lesions of diabetic apoE -/- mice. In the proposed work we plan to explore novel RAGE directed quantitative SPECT imaging to detect differences in RAGE expression in diabetic compared to non-diabetic atherosclerosis and in apoE -/- mice with genetically modified RAGE expression. We propose to explore RAGE imaging to detect therapeutic reduction in RAGE expression. Finally we propose to investigate RAGE directed imaging in diabetic atherosclerotic swine as a translational step. The results of these experiments should establish RAGE directed imaging as a potentially useful tool in the management of diabetes.