The Systems Biology of Sudden Cardiac Death

心脏性猝死的系统生物学

基本信息

批准号：
7487458
负责人：
RAIMOND Lester WINSLOW
金额：
$ 31.85万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7487458
关键词：
Action Potentials Adult Affect Age Anatomy Anions Antibodies Appendix Architecture Arrhythmia Award Bioenergetics Bioinformatics Biological Sciences Canis familiaris Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone Cardiac Cardiovascular system Cause of Death Cavia Cell Count Cell Nucleus Cell model Cells Chemicals Collaborations Collection Committee Members Computer Simulation Computer software Condition Connexins Consensus Coronary Coronary Arteriosclerosis Count Coupling Cross-Linking Reagents Cyclosporine Cytoplasm Data Data Collection Databases Decision Making Depth Development Diamide Diazepam Dilated Cardiomyopathy Dimensions Electron Transport Exhibits Exposure to Failure Felis catus Fiber Figs - dietary Fluorescence Frequencies Funding Future Gene Expression Generations Genetic Genetic Medicine Genetics and Medicine Glyburide Government Guidelines Healthcare Heart Heart Diseases Heart Ventricle Heart failure Human Resources Image Imaging Techniques Implantable Defibrillators Injection of therapeutic agent Inner mitochondrial membrane Institutes Institution Intellectual Property Ion Channel Ischemia Island Isometric Exercise Label Laboratories Lasers Lead Localized Location Maps Measurement Measures Mediator of activation protein Medicine Membrane Membrane Potentials Metabolic Metabolic Control Metabolic stress Metabolism Methods Microtome - medical device Mitochondria Mitochondrial Matrix Mitochondrial Proteins Modeling Modification Molecular Monitor Muscle Cells Myocardial Ischemia Myocardium Nature Normal tissue morphology Operative Surgical Procedures Optics Participant Patients Pattern Permeability Photons Physiological reperfusion Play Population Positioning Attribute Predisposition Preparation Principal Investigator Process Production Program Research Project Grants Property Proteins Proteome Proteomics Protons Purpose Range Reactive Oxygen Species Recommendation Regional Perfusion Relative (related person)Reperfusion Therapy Reporting Research Research Personnel Research Project Grants Resolution Risk Role Series Source Code Staging Staining method Stains Standards of Weights and Measures Stress Structure Sulfhydryl Compounds Surface Systems Biology Techniques Testing Time TimeLine Tissues Transcript Universities Update Variant Ventricular Ventricular Arrhythmia Week Western World Work authority base behavior influence carbonylcyanide 4-trifluoromethoxyphenylhydrazone cellular imaging clinically relevant commercialization data modeling day density experience innovation interest member middle age mitochondrial membrane model development models and simulation mortality novel open source patch clamp programs protein expression reconstruction research study response sample fixation second harmonic simulation sudden cardiac death therapy design tissue fixing two-photon

项目摘要

DESCRIPTION (provided by applicant): Sudden Cardiac Death (SCD) remains a leading cause of death in the western world. Estimates suggest that roughly 10-20% of all annual mortality in the U.S. results from SCD and that approximately 5% of the middle-aged U.S. population has a significant predisposition to SCD. The major causes of SCD in adults age 35 and older are coronary artery disease (CAD; ~ 80%) and dilated cardiomyopathy (~10-15%), with risk increasing dramatically with age. While implantable cardioverter defibrillators (ICDs) are proving to be effective in reducing the occurrence of SCD, wholesale deployment of ICDs in large patient populations is impractical economically and ignores the facts that the majority of patients with ICDs are likely never to require them and that there are as yet no effective means for identifying patients at highest risk for SCD. Working both from the top-down (whole heart optical mapping, anatomical reconstruction and simulation) and from the bottom up (mitochondrial and cellular imaging and modeling), our aim is to achieve an unprecedented level of integration of structure and function in order to understand and model the ways in which coupling between metabolic and electrophysiological processes in the myocyte contribute to risk of cardiac arrhythmias under conditions of metabolic stress. We refer to this as the metabolic sink hypothesis. Cluster Project 1 will test the hypothesis that metabolic sinks may be formed by producing local regions of IKATP activation in the intact-perfused guinea pig (GP) heart and will assess their impact on ventricular conduction and arrhythmia generation. Cluster Project 2 will test the hypothesis that metabolically stressed myocardium is particularly susceptible to formation of metabolic sinks leading to arrhythmia in the setting of heart failure. Cluster Project 3 will develop novel biophysically, metabolically and anatomically detailed computational models of electrical conduction and, in conjunction with Cluster Projects 1 & 2, test hypotheses regarding the ways in which the interplay between metabolic and electrophysiological function contributes to generation of arrhythmias under conditions of metabolic stress. The metabolic sink hypothesis has never been tested directly by producing metabolic uncoupling of mitochondria in local regions of myocardium and measuring effects on electrical conduction and generation of arrhythmias. Whether or not failing myocytes are susceptible to metabolic oscillations, whether or not failing tissue is more or less susceptible to formation of metabolic sinks than is normal tissue, and whether or not metabolic sinks form a substrate for reentry in failing myocardium is unknown. This project will test these hypotheses and the results will have major importance for our understanding of the mechanisms and treatment of arrhythmias.

描述（由申请人提供）：心脏性猝死（SCD）仍然是西方世界的一个主要原因。据估计，美国每年约有 10-20% 的死亡率是由 SCD 造成的，并且大约 5% 的美国中年人口有明显的 SCD 倾向。 35 岁及以上成年人发生 SCD 的主要原因是冠状动脉疾病 (CAD；约 80%) 和扩张型心肌病 (约 10-15%)，风险随着年龄的增长而急剧增加。虽然植入式心律转复除颤器 (ICD) 已被证明可有效减少 SCD 的发生，但在大量患者群体中大规模部署 ICD 在经济上是不切实际的，并且忽视了这样一个事实：大多数佩戴 ICD 的患者可能永远不需要它们，而且目前还没有有效的方法来识别 SCD 风险最高的患者。我们的目标是从自上而下（全心脏光学测绘、解剖重建和模拟）和自下而上（线粒体和细胞成像和建模）工作，实现结构和功能前所未有的集成水平，以便了解并模拟肌细胞代谢和电生理过程之间的耦合在代谢应激条件下导致心律失常风险的方式。我们将此称为代谢汇假说。集群项目 1 将测试以下假设：代谢库可能是通过在完整灌注的豚鼠 (GP) 心脏中产生局部 IKATP 激活区域而形成的，并将评估其对心室传导和心律失常产生的影响。集群项目 2 将检验以下假设：代谢应激的心肌特别容易形成代谢汇，从而在心力衰竭的情况下导致心律失常。集群项目 3 将开发新颖的生物物理、代谢和解剖学详细的电传导计算模型，并与集群项目 1 和 2 结合，测试关于代谢和电生理功能之间的相互作用在以下条件下导致心律失常产生的方式的假设：代谢压力。代谢汇假说从未通过在心肌局部区域产生线粒体代谢解偶联并测量对电传导和心律失常产生的影响来直接测试。衰竭的心肌细胞是否容易受到代谢振荡的影响，衰竭的组织是否比正常组织更容易或不太容易形成代谢汇，以及代谢汇是否形成衰竭心肌再进入的基质尚不清楚。该项目将测试这些假设，结果对于我们理解心律失常的机制和治疗具有重要意义。