Prof. dr. Ann Marie Schmidt

RAGE/DIAPH1: Implications for the Mechanisms and Treatment of Cardiometabolic Disease 

 

My laboratory discovered the multi-ligand receptor for advanced glycation end products (RAGE). Our discovery that RAGE was a multi-ligand receptor, and our findings that RAGE bound non-AGE ligands, such as S100/calgranulins, high mobility group box-1 and amyloid-b peptide, transformed our understanding of the ligand-receptor axis in mechanisms of sterile inflammation and opened up novel areas for research in diabetes, obesity, aging, neurodegeneration, and inflammation. My laboratory has led studies using cellular and animal models to reveal that blockade of RAGE or genetic deletion of the receptor exerts protective effects in murine models of obesity, diabetes macro- and microvascular complications, neurodegeneration and inflammation. In 2008, my laboratory reported that the cytoplasmic domain of RAGE bound to its intracellular interacting molecule, Diaphanous1 (DIAPH1), a member of the formin family, which is important for RAGE signal transduction. In the context of translational science, my laboratory has developed small molecule inhibitors of the interaction of the RAGE cytoplasmic domain with DIAPH1 that are now undergoing intensive development to reach clinical trials in RAGE-related chronic disease. In in vitro and early in vivo studies in animals, representatives of these chemical probes suppress RAGE ligand-mediated inflammation and oxidative stress. Collectively, this research holds promise for the treatment of RAGE/DIAPH1-related chronic diseases.

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