RAGE-directed imaging in diabetes associated accelerated atherosclerosis

Atherosclerosis in type 1 diabetes takes an accelerated course. Advanced Glycation End Products (AGEs) are formed when glucose in the blood binds to proteins and is a direct consequence of prolonged levels of high blood sugar in diabetes. The molecular structure of RAGE (receptor) is known. Binding of AGEs to receptors induces multiple signaling pathways involved in atherosclerosis progression. Other inflammatory bindings substances identified with atherogenesis have been found to bind to RAGE implicating its role in non-diabetic atherosclerosis as well. With Dr Ann Marie Schmidt and colleagues we have developed a novel antibody in rabbits against RAGE designed to also work in mice, pigs and human. We performed preliminary experiments showing uptake of this antibody against RAGE labeled with a radioactive marker in the atheromatous aortic lesions in mice genetically prone to atherosclerosis and fed a western diet.

The work proposed falls under 3 aims. a. That uptake of radiolabeled antibody fragments in atherosclerotic lesions seen on nuclear imaging scans will be greater in diabetic atherosclerosis prone vs non-diabetic atherosclerosis prone mice, vs control wild type mice. b. That uptake of radiolabeled antibody fragments in atherosclerotic lesions on nuclear imaging scans can identify the accelerated course of atherosclerosis in diabetic atherosclerotic prone mice vs non-diabetic atherosclerosis prone mice. c. That quantitative uptake of the radiolabeled antibody fragments on the nuclear scan images will correlate with histolotical staining for RAGE, with tissue markers of inflammation and cell death, and with serum levels of proteins that bind to RAGE.