ROLE OF POSTTRANSLATIONAL PROTEIN MODIFICATIONS IN DIABETIC CARDIOMYOPATHY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Six percent of the USA population suffers from diabetes mellitus, with the greatest mortalities caused by cardiovascular complications. Diabetic cardiomyopathy is a chronic condition and is characterized by impaired function and alterations in the morphological structure of the heart muscle. The molecular mechanisms underlying this pathology are not well understood, however hyperglycemia is thought to be the main etiological factor in its development. Many proteins in the diabetic heart show profoundly altered function, due to changes in their expression level and/or structure. Changes in posttranslational modifications of proteins have been linked to a variety of disease states; however, this area is poorly explored in the malfunctioning diabetic heart. The objective of this research project is to identify the molecular mechanisms responsible for cardiac protein modification that may contribute to development of diabetic cardiomyopathy. The autoimmune diabetic rat model, the closest animal counterpart of human type 1 diabetes, will be used in this study, and left ventricular tissue will be analyzed as diabetic heart dysfunction initially develops in the left ventricle. We will perform diabetic heart protein fractionation, separation using 2D-PAGE, in-gel digestion, and identification of posttranslationally modified proteins and localization of the modified sites using MALDI-TOF mass spectrometry. In addition we will uncover possible mechanisms of such modifications in cardiac proteins in diabetes. At the completion of the study we will have better understanding of the molecular pathways involved in the development of diabetic cardiomyopathy that will allow to identify candidate proteins for therapeutic targeting. This project will contribute to our long-term research goal which is to elucidate the mechanisms responsible for the detrimental effects of diabetes in the heart, and to identify effective interventions to halt this pathological condition.