non-enzymatic glycation; protein modification; advanced glycation end products; diabetic complications; pyridoxamine
In diabetes, the elevated levels of glucose and its degradation products cause the increase in specific chemical modifications of proteins called advanced glycation end products or AGEs. Our research focuses on uncovering the mechanisms by which such protein modifications could cause diabetic complications, in particular diabetic nephropathy. Studies include (i) biochemical characterization of AGE modifications and their effects on protein structure and function; (ii) effects of AGE-modified proteins on cell signaling and cell behavior; (iii) determination of global changes in cellular proteome caused by AGE-modified proteins. We also focus on development of novel strategies to inhibit AGE modifications and preserve protein functionality in diabetes. In particular, we investigate mechanisms of action of pyridoxamine, a prospective drug for treatment of diabetic nephropathy. In our laboratory and through multiple collaborations we employ such experimental methods as nuclear magnetic resonance, X-ray crystallography, mass-spectrometry, analysis of protein conformation by absorbance and fluorescence techniques, high performance liquid chromatography, cell culture and animal models.