Types 1 and 2 diabetes and their complications are on the rise. There is a recognized lack in both approved complications-based therapies and established disease-specific biomarkers in diabetes complications, which significantly hinders clinical trials. This application focuses on the role of the receptor for advanced glycation endproducts (RAGE) and its cytoplasmic domain binding partner, mammalian form of diaphanous1, mDia1, which is essential for RAGE signaling as a fundamental therapeutic target for diabetic complications. To transform our discoveries from the bench to the development of therapies for diabetes complications, we performed a library screen and identified two lead series of small molecules that inhibit RAGE tail-mDia1 interaction with nM affinity and demonstrate efficacy in in vitro and in vivo experimental assays. We have developed novel RAGE and mDia1 floxed mice to probe their cell-specific contributions to diabetes complications. Our approach will involve testing the following specific aims:
AIM 1 will seek to optimize the two lead compound series which block RAGE/mDia1 signaling by maximizing drug-like properties;
Aim 2 will dissect the mechanisms by which RAGE-mDia1 signal transduction contributes to the pathogenesis of diabetic nephropathy;
Aim 3 will dissect the mechanisms by which RAGE-mDia1 signal transduction contributes to the pathogenesis of ischemia-reperfusion (I/R) injury in the diabetic heart;
and Aim 4 will dissect the mechanisms by which RAGE-mDia1 signal transduction contributes to diabetic complications via impaired resolution of inflammation, to serve as a springboard for the development of target engagement biomarkers. We have assembled a multi-disciplinary team with expertise in RAGE/mDia1 signal transduction and diabetes complications;structural biology and NMR spectroscopy;medicinal and computational chemistry;and bioinformatics/biostatistics to tackle the problem of therapies and target engagement biomarkers for diabetic complications.
Diabetes and its complications are on the rise and present a major challenge to quality and duration of life;further, this chronic disease and its consequences pose a major threat to an already burdened health care system. We propose to develop novel therapies and target engagement biomarkers for diabetic complications.
|Schmidt, Ann Marie (2018) Highlighting Diabetes Mellitus: The Epidemic Continues. Arterioscler Thromb Vasc Biol 38:e1-e8|
|Lee, Gloria; Plaksin, Joseph; Ramasamy, Ravichandran et al. (2018) Targeted drug discovery and development, from molecular signaling to the global market: an educational program at New York University, 5-year metrics. J Transl Sci 4:1-9|
|Lee, Gloria; Kranzler, Jay D; Ramasamy, Ravichandran et al. (2018) Training scientists as future industry leaders: teaching translational science from an industry executive's perspective. J Transl Sci 4:|
|Schmidt, Ann Marie (2017) 2016ATVBPlenary Lecture: Receptor for Advanced Glycation Endproducts and Implications for the Pathogenesis an Treatment of Cardiometabolic Disorders: Spotlight on the Macrophage. Arterioscler Thromb Vasc Biol 37:613-621|
|Shekhtman, Alexander; Ramasamy, Ravichandran; Schmidt, Ann Marie (2017) Glycation & the RAGE axis: targeting signal transduction through DIAPH1. Expert Rev Proteomics 14:147-156|
|Xue, Jing; Manigrasso, Michaele; Scalabrin, Matteo et al. (2016) Change in the Molecular Dimension of a RAGE-Ligand Complex Triggers RAGE Signaling. Structure 24:1509-22|
|López-Díez, Raquel; Shekhtman, Alexander; Ramasamy, Ravichandran et al. (2016) Cellular mechanisms and consequences of glycation in atherosclerosis and obesity. Biochim Biophys Acta 1862:2244-2252|
|Manigrasso, Michaele B; Pan, Jinhong; Rai, Vivek et al. (2016) Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction. Sci Rep 6:22450|
|Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie (2016) The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease. Expert Opin Ther Targets 20:431-46|
|Schmidt, Ann Marie (2015) The growing problem of obesity: mechanisms, consequences, and therapeutic approaches. Arterioscler Thromb Vasc Biol 35:e19-23|