ENERGETIC REGULATION OF CARDIAC ION CHANNELS

心脏离子通道的能量调节

• 批准号: 8518105
• 负责人: Brian O'Rourke
• 金额: $ 36.27万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518105
• 关键词: Adenoviruses; Anions; Antioxidants; Arrhythmia; Award; Benzodiazepine Receptor; Binding; Binding Proteins; Biochemical Pathway; Biological Assay; Biological Preservation; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Line; Cells; Cessation of life; Communication; Complex; Computer Simulation; Coupling; Cultured Cells; Development; Disease; Enzymes; Functional disorder; Gene Expression; Gene Transfer; Genetic Transcription; Giant Cells; Heart; Heart Diseases; Heart failure; Heterogeneity; Image; Instruction; Ion Channel; Ion Transport; Ischemia; Isocitrate Dehydrogenase; Isoquinolines; Kinetics; Knockout Mice; Lasers; Lead; Ligands; Mediating; Membrane; Membrane Potentials; Metabolic; Metabolism; Methods; Mitochondria; Mitochondrial Proteins; Mitochondrial Swelling; Modeling; Molecular; Mus; Myocardial; NAD(P)+ transhydrogenase; NADH; NADP; Natural regeneration; Nuclear; Organ; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Permeability; Plasmids; Post-Translational Protein Processing; Production; Property; Protein Overexpression; Proteins; Proteomics; Reaction; Reactive Oxygen Species; Recovery; Regulation; Relative (related person); Reperfusion Injury; Reperfusion Therapy; Reporter; Role; Signal Pathway; Signal Transduction; Simulate; Source; Subfamily lentivirinae; Suspension Culture; System; Testing; Tissues; Transgenic Mice; Work; base; cell injury; cyclophilin D; heart cell; in vivo; insight; knock-down; mathematical model; mitochondrial dysfunction; model development; prevent; research study; response; screening; small hairpin RNA; stressor; three-dimensional modeling; tool; vector

In order to provide a continuous supply of ATP, heart cells contain thousands of mitochondria, which may be a source of, and subject to damage by, oxidative stress. We have found that cardiac mitochondria are organized as a network of oscillators, whose degree of coupling and synchronization is influenced by reactive oxygen species (ROS). Under pathological conditions, e.g. ischemia-reperfusion, either an increase in ROS production, or a decrease in the capacity to scavenge ROS, results in the collapse or oscillation of mitochondrial inner membrane potential throughout the cell, and in clusters of cells in the myocardial syncytium. In this way, mitochondrial dysfunction scales to produce organ level heterogeneity that significantly alters the electrophysiological and contractile properties ofthe heart Over the prior award period, we have established that stabilization of mitochondrial inner membrane potential by pharmacological agents targeting mitochondrial benzodiazepine receptors can prevent post-ischemic arrhythmias and decrease ischemia-reperfusion injury and we have suggested that a specific inner membrane anion channel (IMAC) was the primary target of ROS, independent of the classical permeability transition pore (PTP). In the present proposal we seek 1) to identify the key proteins implicated in the mechanism of mitochondrial ROS-induced ROS release using molecular methods and experiments in isolated cells and mitochondria, 2) to define the main biochemical pathways responsible for scavenging ROS in cardiac mitochondria and their impact on the approach to mitochondrial criticality, 3) to elucidate the mechanisms of mitochondrial-to-nuclear communication via the redox status ofthe cell, and 4) to continue to develop and expand our integrated computational models of excitation-contraction coupling, mitochondrial energetics, and ROS-induced ROS release to the tissue level to understand the mitochondrial origin of cardiac arrhythmias and contractile dysfunction in heart disease.

为了提供ATP的持续供应，心脏细胞含有数千个线粒体，这可能是一个 氧化应激的来源，并受到氧化应激的损害。我们发现心肌线粒体的组织结构是 振荡器网络，其耦合和同步程度受活性氧物质的影响 （ROS）。在病理条件下，例如缺血-再灌注，ROS产生的增加，或 降低对ROS的抑制能力，导致线粒体内膜的崩溃或振荡 在整个细胞中，以及在心肌合胞体中的细胞簇中的电位。这样，线粒体 功能障碍量表产生器官水平的异质性，显著改变电生理和 心脏的收缩特性在之前的奖励期间，我们已经建立了心脏的稳定性， 通过靶向线粒体苯二氮卓类药物实现线粒体内膜电位 受体可以预防缺血后心律失常，减轻缺血再灌注损伤， 表明，一个特定的内膜阴离子通道（IMAC）是ROS的主要靶点，独立于 典型的渗透率转换孔（PTP）。在本提案中，我们寻求1）鉴定关键蛋白质 使用分子方法，参与线粒体ROS诱导的ROS释放机制， 在分离的细胞和线粒体中进行实验，2）确定负责 清除心肌线粒体中的ROS及其对接近线粒体临界状态的影响，3） 阐明细胞通过氧化还原状态进行细胞核通讯的机制，以及4） 继续发展和扩展我们的兴奋-收缩耦合的综合计算模型， 线粒体能量学和ROS诱导的ROS释放到组织水平，以了解线粒体 心脏病中心律失常和收缩功能障碍的起源。