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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL063811-05
Application #
6921822
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
1999-12-01
Project End
2009-03-31
Budget Start
2005-04-15
Budget End
2006-03-31
Support Year
5
Fiscal Year
2005
Total Cost
$367,875
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Kim, Grace E; Ross, Jenna L; Xie, Chaoqin et al. (2015) LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation. Cardiovasc Res 108:197-208
Qi, Dake; Atsina, Kwame; Qu, Lintao et al. (2014) The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury. J Clin Invest 124:3540-50
Wang, Jingying; Tong, Chao; Yan, Xiaoyan et al. (2013) Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction. Circulation 128:225-36
Zaha, Vlad G; Young, Lawrence H (2012) AMP-activated protein kinase regulation and biological actions in the heart. Circ Res 111:800-14
Shugrue, Christina A; Alexandre, Martine; Diaz de Villalvilla, Alexander et al. (2012) Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation. Am J Physiol Gastrointest Liver Physiol 303:G723-32
Kim, Agnes S; Miller, Edward J; Wright, Tracy M et al. (2011) A small molecule AMPK activator protects the heart against ischemia-reperfusion injury. J Mol Cell Cardiol 51:24-32
Qi, Dake; Hu, Xiaoyue; Wu, Xiaohong et al. (2009) Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion. J Clin Invest 119:3807-16
Kim, A S; Miller, E J; Young, L H (2009) AMP-activated protein kinase: a core signalling pathway in the heart. Acta Physiol (Oxf) 196:37-53
Young, Lawrence H (2008) AMP-activated protein kinase conducts the ischemic stress response orchestra. Circulation 117:832-40

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