ENERGETIC REGULATION OF CARDIAC ION CHANNELS

心脏离子通道的能量调节

基本信息

批准号：
8300141
负责人：
Brian O'Rourke
金额：
$ 38.1万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/8300141
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 Screening procedure 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 small hairpin RNA stressor three-dimensional modeling tool vector

项目摘要

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.

为了提供持续的 ATP 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。我们发现心脏线粒体的组织方式为振荡器网络，其耦合和同步程度受活性氧的影响（ROS）。在病理条件下，例如缺血再灌注，ROS 产生增加，或清除ROS的能力下降，导致线粒体内膜崩溃或振荡整个细胞以及心肌合胞体细胞簇中的电位。这样，线粒体功能障碍会产生器官水平的异质性，从而显着改变电生理和心脏的收缩特性在之前的奖励期内，我们已经确定了心脏的稳定性靶向线粒体苯二氮卓类药物的线粒体内膜电位受体可以预防缺血后心律失常并减少缺血再灌注损伤，我们有表明特定的内膜阴离子通道（IMAC）是 ROS 的主要目标，与经典渗透率转变孔（PTP）。在本提案中，我们寻求 1) 识别关键蛋白质使用分子方法参与线粒体 ROS 诱导 ROS 释放的机制在分离的细胞和线粒体中进行实验，2）确定负责的主要生化途径清除心脏线粒体中的 ROS 及其对线粒体临界性的影响，3) 通过细胞的氧化还原状态阐明线粒体与核通讯的机制，4) 继续开发和扩展我们的兴奋-收缩耦合的集成计算模型，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。