Regulation of Glucose Transport in the Ischemic Heart

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DESCRIPTION (provided by applicant): The overall goal of this research is to determine the cellular and molecular mechanisms regulating glucose transport during myocardial ischemia. Glucose metabolism has a key role in maintaining the function and viability in the ischemic heart and is mediated by the glucose transport proteins GLUT4 and GLUT1. The AMP-activated protein kinase (AMPK) is a serine-threonine protein kinase which is activated by energetic stress and is emerging as an important intracellular signaling pathway in the heart and many tissues, modulating the major metabolic pathways, gene transcription, and mitochondrial biogenesis. This research will further address the hypothesis that AMPK has a critical role in mediating ischemic glucose uptake and that AMPK deficiency leads to increased myocardial injury and apoptosis during ischemia and reperfusion. The aims of the proposed research will be i) to determine novel mechanisms mediating GLUT4 translocation to the cell surface in the ischemic heart, ii) to determine the molecular mechanisms responsible for AMPK activation in the ischemic heart and iii) to determine whether the AMPK pathway has a cardioprotective action during ischemia/reperfusion in the heart. The experiments outlined in the current proposal utilize novel cellular, molecular and genetic approaches in an attempt to better understand the regulation of glucose transport in the ischemic heart. Myocardial ischemia associated with coronary artery disease is the major cause of morbidity and mortality in the U.S. population. The ultimate goal of the proposed research is to develop novel approaches to protecting the heart against ischemic injury which will complement existing therapies and procedures. Such novel therapies may improve the quality of life and prevent cardiac death and have significant health benefit for the U.S. population.