CORE--COMPUTATIONAL/BIOINFORMATIC

核心--计算/生物信息学

基本信息

批准号：
7672288
负责人：
RAIMOND Lester WINSLOW
金额：
$ 19.29万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7672288
关键词：
Accounting Acetyl Coenzyme A Action Potentials Address Agreement Architecture Archives Area Behavior Bioinformatics Buffers Cardiac Cardiac Myocytes Cardiovascular system Cataloging Catalogs Cell membrane Citric Acid Cycle Clinical Research Collaborations Communication Communities Complex Computer Simulation Computer software Condition Consumption Coupled Coupling Creatine Kinase Cytoplasm Data Database Management Systems Databases Defect Dependence Dependency Development Discipline Drug Formulations Electron Transport Electron Transport Complex III Electrons Electrophysiology (science)Elements Energy Supply Engineering Enzymes Evaluation Event Experimental Animal Model Experimental Models Fluorescence Fostering Foundations Frequencies Future Gel Glycolysis Guidelines Heart Individual Inner mitochondrial membrane Internet Intervention Ion Channel Ion Transport Ions Ischemia Isometric Exercise Kinetics Language Lead Link Literature Measurable Membrane Transport Proteins Metabolic Metabolic Control Metabolism Methodology Mitochondria Mitochondrial Matrix Mitochondrial Proteins Mitochondrial Proton-Translocating ATPases Modeling Modification Molecular Multienzyme Complexes Muscle Muscle Cells Muscle Contraction Muscle Mitochondria Myocardial Ischemia Myosin ATPase NADH Nature Nonlinear Dynamics Numbers Output Oxidative Phosphorylation Oxidoreductase Oxygen Consumption Participant Pathway interactions Performance Phosphorylation Physiological Physiological reperfusion Play Post-Translational Protein Processing Potassium Channel Principal Investigator Process Production Property Proteins Proteome Proteomics Protocols documentation Psyche structure Range Rate Reaction Relative (related person)Reperfusion Therapy Reporting Research Research Infrastructure Research Personnel Resource Sharing Respiration Role Sarcolemma Services Simulate Site Software Tools Source Code Specific qualifier value Standards of Weights and Measures Technology Time Titrations Translating Transport Process Universities Validation Ventricular Vision Work Workload base cluster computing complex IV computing resources concept cost data modeling design fatty acid oxidation feeding improved in vitro Assay inhibitor/antagonist inorganic phosphate instrument interest member mitochondrial dysfunction model development models and simulation novel oxidation preconditioning programs protein expression research study respiratory response simulation success tool virtual

项目摘要

This is designed to investigate how mitochondrial energetics and integrated cardiac function are remodeled by ischemia and reperfusion in a comprehensive manner, spanning from the molecular level, to the proteome, to global effects on excitation-contraction (EC) coupling and oxygen consumption in intact muscle. However, as a result of complex control interactions within the machinery of oxidative phosphorylation and between mitochondria, the sarcolemma and the cytoplasm, it is difficult to form a complete mental picture of how a particular experimental finding impacts myocyte function as a whole. To help address this challenge, the COMPUTATIONAL/BIOINFORMATICS will develop integrative computational models of the cardiac ventricular myocyte incorporating biophysically detailed descriptions of mitochondrial energetics, which will be used to interpret results from the range of experiments being pursued in this project. Our team has pioneered the development of detailed models of the electrophysiology and Ca2+ handling properties, ion transport processes and mitochondrial energetics, which we are now integrating into comprehensive virtual cardiac ventricular myocyte models. The emphasis has been on using these models as tools for the interpretation of experimental results and for suggesting new experiments that can reveal the fundamental nature of the control of myocyte function under normal or pathophysiological conditions. We will focus the existing collaboration of the leaders on the problem of mitochondrial dysfunction in the post-ischemic heart using a common experimental animal model and a common quantitative mathematical/computational model. It will also foster new collaborative interactions between experts in diverse disciplines. In addition to developing and exploiting the computational model, we will provide expertise and support in the quantitative methodology of metabolic control analysis, for identifying the key controlling factors in oxidative phosphorylation in the post-ischemic heart.

这是为了研究线粒体能量和心脏功能的如何通过缺血和再灌注以全面的方式重塑，从分子水平到蛋白质组，再到完整肌肉中对兴奋 - 收缩（EC）偶联（EC）偶联（EC）偶联的影响。然而，由于复杂的控制相互作用在氧化磷酸化的机械以及线粒体，肌膜和细胞质之间，很难完全心理形象，说明特定的实验发现如何影响整个肌细胞的功能。为了解决这个挑战，计算/生物信息学将开发心室心肌的综合计算模型，该模型结合了线粒体的生物物理详细描述能量学将用于解释该项目中所追求的实验范围的结果。我们的团队开发了电生理学和CA2+处理特性，离子传输过程和线粒体能量的详细模型的开发，我们现在正在整合到综合的虚拟心脏心肌细胞模型中。重点是将这些模型用作解释实验结果的工具，并提出了可以揭示在正常或病理生理条件下控制肌细胞功能的基本性质的新实验。我们将重点关注领导者的现有合作在线粒体问题上使用常见的实验动物模型和一个常见的病后心脏功能障碍定量数学/计算模型。它还将促进各种学科专家之间的新合作互动。除了开发和利用计算模型外，我们还将在代谢控制分析的定量方法中提供专业知识和支持，以识别缺血后心脏中氧化磷酸化的关键控制因子。