Recent investigations demonstrate the importance of receptor for advanced glycation end products (RAGE) mediated signal transduction in promoting pathogenic inflammation, renal failure and diabetic complications. Animal studies indicate that the extracellular domain of RAGE (soluble Rage, sRAGE) can inhibit RAGE function and ameliorate these pathologies, however, this form of the protein has unfavorable pharmacokinetics. Thus, the overall goal of the present proposal is to create and test an immunoglobulin Fc fusion protein of sRAGE as a novel inhibitor. The Fc domain is expected to extend the serum half-life of sRAGE which will greatly facilitate its use for chronic disease. In phase I, a series of recombinant, soluble RAGE-Fc fusion molecules will be created and evaluated using an in vitro assay. If subsequent in vivo proof-of-principle animal studies are positive, Phase II will focus on preclinical animal efficacy and toxicology studies in preparation for an IND to evaluate the RAGE-Fc molecule as a novel inhibitor of the inflammation found in type II diabetes and rheumatoid arthritis. In addition, we expect RAGE-Fc will be evaluated to control the clinically important complications of advanced diabetes: atherosclerosis, nephropathy, neuropathy, retinopathy, and reduced chronic wound healing. Project Narrative: Currently there are no clinically approved drugs to prevent inflammatory pathology induced by advanced glycation end products. This proposal will develop a novel therapeutic for complications of diabetes, including atherosclerosis, nephropathy, neuropathy, and retinopathy, as well as rheumatoid arthritis. ? ?
