Regulation of Glucose Transport in the Ischemic Heart

描述（由申请人提供）：本研究的总体目标是确定心肌缺血时调节葡萄糖转运的细胞和分子机制。葡萄糖代谢在维持缺血心脏的功能和活力中起关键作用，并由葡萄糖转运蛋白GLUT4和GLUT1介导。amp活化蛋白激酶（AMPK）是一种丝氨酸-苏氨酸蛋白激酶，可被能量应激激活，是心脏和许多组织中重要的细胞内信号通路，调节主要代谢途径、基因转录和线粒体生物发生。本研究将进一步证实AMPK在介导缺血葡萄糖摄取中起关键作用，AMPK缺乏导致缺血再灌注过程中心肌损伤和凋亡增加的假设。本研究的目的是：1)确定在缺血心脏中介导GLUT4易位到细胞表面的新机制；2)确定在缺血心脏中AMPK激活的分子机制；3)确定AMPK通路在心脏缺血/再灌注过程中是否具有心脏保护作用。在当前的建议中概述的实验利用新的细胞，分子和遗传方法，试图更好地理解葡萄糖转运在缺血心脏中的调节。与冠状动脉疾病相关的心肌缺血是美国人口发病率和死亡率的主要原因。提出的研究的最终目标是开发新的方法来保护心脏免受缺血性损伤，这将补充现有的治疗和程序。这种新疗法可以改善生活质量，防止心脏死亡，对美国人的健康有显著的好处。

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.