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期间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性心脏的功能和活力方面具有关键作用，并且由葡萄糖转运蛋白GLUT 4和GLUT 1介导。AMP激活蛋白激酶（AMPK）是一种丝氨酸-苏氨酸蛋白激酶，在能量应激时被激活，是心脏和许多组织中重要的细胞内信号通路，调节主要的代谢途径、基因转录和线粒体生物合成。本研究将进一步阐明AMPK在介导缺血性葡萄糖摄取中具有关键作用以及AMPK缺乏导致缺血和再灌注期间心肌损伤和细胞凋亡增加的假设。拟议研究的目的是：i）确定缺血心脏中介导GLUT 4易位至细胞表面的新机制，ii）确定缺血心脏中AMPK激活的分子机制，iii）确定AMPK通路在心脏缺血/再灌注期间是否具有心脏保护作用。在目前的建议中概述的实验利用新的细胞，分子和遗传方法，试图更好地了解缺血性心脏中葡萄糖转运的调节。与冠状动脉疾病相关的心肌缺血是美国人群发病率和死亡率的主要原因。拟议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。这些新疗法可以改善生活质量，预防心脏性死亡，并对美国人口具有显着的健康益处。

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.