Metabolic Oscillations in Heart

心脏的代谢波动

• 批准号: 7633846
• 负责人: ZHILIN QU
• 金额: $ 42.47万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633846
• 关键词: Action Potentials; Acute; Address; Adenine Nucleotides; Adult; Affect; Arrhythmia; Bioprobe; Biosensor; Buffers; Cardiac; Cardiac Myocytes; Cause of Death; Cells; Complement; Computer Simulation; Consumption; Coupling; Creatine Kinase; Cyanides; Development; Dinitrofluorobenzene; Energy Supply; Enzymes; Experimental Models; Feedback; Functional disorder; Generations; Genetic Models; Glycolysis; Goals; Healthcare; Heart; Heart Diseases; Heart Injuries; Hypoxia; Image; Injury; Insulin Signaling Pathway; Ischemia; Knockout Mice; Lead; Mathematical Biology; Metabolic; Metabolic Pathway; Metabolic stress; Minor; Mission; Mitochondria; Modeling; Mus; Muscle; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Neonatal; Nitric Oxide; Nonlinear Dynamics; Oryctolagus cuniculus; Oxidative Phosphorylation; Pancreas; Pathway interactions; Physiological; Physiology; Play; Potassium Channel; Production; Protein Kinase C; Proteins; Public Health; Rattus; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; Signal Pathway; Signal Transduction; Societies; Source; System; Testing; Time; Ventricular; Yeasts; adenylate kinase; anaerobic glycolysis; base; critical period; design; diabetic; fluorescence imaging; heart metabolism; insight; mathematical model; meetings; metabolic abnormality assessment; mitochondrial creatine kinase; monolayer; novel; novel therapeutics; overexpression; patch clamp; prevent; public health relevance

DESCRIPTION (provided by applicant): Efficient coupling of energy production to energy needs is critical for the beating heart, and factors disrupting this relationship are likely to promote injury. Glycolytic oscillations have been characterized extensively in yeast and pancreatic ?-cells, but conditions promoting their occurrence in cardiac myocytes are less established, compared to reactive oxygen species (ROS)-induced metabolic oscillations arising from the mitochondrial network. Our preliminary studies in rabbit ventricular myocytes show that the normally tight buffering of the ATP/ADP ratio by oxidative phosphorylation and the creatine kinase (CK) shuttle prevents glycolysis from oscillating, but under conditions in which this buffering is disrupted, glycolytic oscillations, manifested as large scale action potential duration (APD) oscillations via activation of ATP-sensitive K channels, develop in 90% of cardiac myocytes, as predicted by theoretical predictions. In this multi-PI proposal, our goal is to combine experimental and mathematical biology approaches to address two questions: 1) how are glycolytic oscillations regulated/modulated by physiological factors such as Cai cycling, autonomic tone, insulin, and signaling pathways relevant to cardioprotection? 2) do glycolytic oscillations occur during acute myocardial ischemia, in which the ability of oxidative phosphorylation and the CK shuttle to buffer cellular ATP/ADP ratio is markedly compromised? These questions will be addressed in three Specific Aims which integrate computer simulations and nonlinear dynamics with experimental patch-clamp and imaging studies in isolated myocytes from rabbits, wild-type and genetically-altered mice and neonatal rat ventricular myocyte monolayers subjected to coverslip ischemia/reperfusion. In addition, a novel fluorescent bioprobe designed for subcellular imaging of ATP will be further developed to study metabolism dynamics. These studies will increase our understanding of how cardiac metabolism functions at the systems level during metabolic stress, which may lead to new therapeutic insights towards preventing ischemia/reperfusion injury. PUBLIC HEALTH RELEVANCE: Since heart disease is the major cause of death in industrialized societies, understanding how to protect the heart from injury has major implications for the health care mission of the NIH/NHLBI and for society as a whole. To facilitate this understanding, this interdisciplinary project will integrate experimental physiology and mathematical biology to study the pathophysiology of oscillations in glycolysis, the key metabolic pathway for energy production during ischemia, and how they may contribute to ischemic cardiac injury by uncoupling energy production from energy needs in this critical situation. These insights may suggest novel therapies to protect the heart from injury during metabolic stresses such as heart attacks.

描述（由申请人提供）：能源生产与能量需求的有效耦合对于跳动心脏至关重要，而破坏这种关系的因素可能会促进伤害。糖酵解振荡在酵母和胰腺？ - 细胞中的表征已经广泛，但是与电力定位网络引起的活性氧（ROS）诱导的代谢振荡相比，促进其在心肌细胞中发生的条件的确定性较低。我们在兔心室心肌细胞中的初步研究表明，通过氧化磷酸化和肌酸磷酸化和肌酸激酶（CK）穿梭通常对ATP/ADP比率的紧密缓冲可阻止糖酵解振荡，但在此条件下，这种缓冲的条件被破坏，散热性振动（APD），并且表现为APD的动作（APD）。如理论预测所预测的那样，对ATP敏感的K通道，在90％的心肌细胞中发育。在该多PI提案中，我们的目标是结合实验和数学生物学方法，以解决两个问题：1）如何通过CAI循环，自主态，胰岛素和信号通路等生理因素来调节/调节糖酵解振荡？ 2）在急性心肌缺血期间是否发生糖酵解振荡，其中氧化磷酸化和CK班车对缓冲细胞ATP/ADP比率的能力明显损害？这些问题将以三个特定的目的解决，这些特定目的将计算机模拟和非线性动力学与实验贴片钳和成像研究集成在一起，并在兔，野生型和遗传变化的小鼠和新生儿大鼠心室心肌单层中的孤立的心肌细胞中进行成像研究，并受到了受覆盖层覆盖的层状肌肉和重新化学的等法。此外，设计用于ATP亚细胞成像的新型荧光生物探针将进一步开发以研究代谢动力学。这些研究将提高我们对代谢压力期间心脏代谢如何在系统水平上的功能的理解，这可能会导致预防缺血/再灌注损伤的新治疗见解。公共卫生相关性：由于心脏病是工业社会中死亡的主要原因，因此了解如何保护心脏免受伤害的影响对NIH/NHLBI的医疗保健任务以及整个社会具有重大影响。为了促进这种理解，该跨学科项目将整合实验生理和数学生物学，以研究糖酵解中振荡的病理生理学，缺血期间能源生产的关键代谢途径以及它们如何通过在这种关键情况下从能量产生能源的能源产生能源生产来促进缺血性心脏伤害。这些见解可能建议在心脏病发作等代谢压力期间保护心脏免受伤害的新疗法。