INTEGRATED EXPERIMENTAL AND COMPUTATIONAL RESEARCH TOOLS FOR THE STUDY OF ACUTE ISCHAEMIC EFFECTS ON CARDIAC MECHANO-ELECTRICAL INTERACTIONS

用于研究心脏机电相互作用的急性缺血效应的综合实验和计算研究工具

• 批准号: EP/F042868/2
• 负责人: Thomas Quinn
• 金额: $ 12.7万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FF042868%2F2
• 关键词: INTEGRATED; EXPERIMENTAL; COMPUTATIONAL; RESEARCH; TOOLS

The heart is an electrically controlled mechanical pump, a bit like an electric motor. Similar to an electric motor in 'dynamo mode', the heart is able to translate mechanical interventions into electrical signals.This mechano-electric feedback (MEF) can be observed at all levels of structural and functional integration of the heart, from the molecular level, to whole organ and organism. In patients, MEF effects may both cause and terminate heart rhythm disturbances, which make MEF an important research target for the Life Sciences. However, MEF involves a complex range of interdependent regulatory pathways, which make it difficult to study MEF, even in normal tissue. Most real-life scenarios pose an even greater challenge, as in most patients, MEF effects occur on the background of myocardial ischaemia (where the heart is starved of oxygen / the most common cause of heart rhythm disturbances). Currently, we know neither the mechanisms underlying MEF effects on heart rhythm in ischaemic heart disease, nor the potential and limitations of MEF for heart rhythm management. This is largely caused by a lack in suitable experimental and theoretical models, and I wish to tackle this shortfall in the present proposal.My goal, therefore, is to develop and integrate a suite of advanced 'wet' experimental and 'dry' computational research techniques to study the effects of myocardial ischaemia on cardiac mechano-electrical cross-talk. This will involve technological developments involving isolated heart tissue kept in normal and ischaemic conditions, direct (microelectrodes) and non-contact (optical techniques) mapping of electrical activity, high-speed video-macroscopy of regional tissue deformation, pharmacological interventions that target SAC, and the application of advanced computational models of heart muscle, which will allow me to re-integrate the diverse range of recorded data to aid analysis, interpretation, and prediction.Thus, the approach will combine advanced engineering, biological experimentation, and systematic application of computational tools, to arrive at an integrated systems view of the complex interrelation of cardiac MEF and ischaemia. Tangible outcomes include, in addition to the development of an advanced experimental technique to study hitherto inaccessible life science questions, the provision of novel insight into a clinically relevant aspect of basic cardiac functionality, and the development of computational resources to conduct theoretical experiments and identify promising research targets for experimental follow-up (which will help to Reduce, Refine, and partially Replace 'wet' experimentation). These tools will be applicable to a wider range of research questions, such as more severe stages of ischaemic heart disease, or pathological changes in heart structure, and provide a way to test new devices or pharmacological treatments.This project is also an important step in my career development. I wish to gain new skills to help me study mechanisms of interaction between the mechanical and electrical properties of the heart in more depth. I believe that combining experimental and mathematical modelling is the key to understanding complex biological systems and the processes by which normal behaviour deteriorates into disease. My host teams at the University of Oxford offer a unique combination of these skills and are experts in my chosen field of study. In addition, the opportunity to work with world-leading experts at other universities during this EPSRC Fellowship will give me the chance to learn from some of the best current-day researchers in my field (which is a unique and very important aspect of the present fellowship programme).

心脏是一个电控机械泵，有点像电动机。与“发电机模式”下的电动机类似，心脏能够将机械干预转化为电信号。这种机电反馈 (MEF) 可以从分子水平在心脏结构和功能整合的各个层面观察到，到整个器官和生物体。在患者中，MEF 效应可能引起或终止心律紊乱，这使得 MEF 成为生命科学的重要研究目标。然而，MEF 涉及一系列复杂的相互依赖的调节途径，这使得研究 MEF 变得困难，即使在正常组织中也是如此。大多数现实生活场景提出了更大的挑战，因为在大多数患者中，MEF 效应发生在心肌缺血的背景下（心脏缺氧/心律紊乱的最常见原因）。目前，我们既不知道 MEF 对缺血性心脏病心律影响的机制，也不知道 MEF 在心律管理方面的潜力和局限性。这很大程度上是由于缺乏合适的实验和理论模型造成的，我希望在当前的提案中解决这一不足。因此，我的目标是开发和整合一套先进的“湿”实验和“干”计算研究研究心肌缺血对心脏机电串扰影响的技术。这将涉及技术开发，包括保持正常和缺血条件下的离体心脏组织、直接（微电极）和非接触（光学技术）电活动测绘、区域组织变形的高速视频宏观检查、针对 SAC 的药物干预、以及先进的心肌计算模型的应用，这将使我能够重新整合各种记录的数据，以帮助分析、解释和预测。因此，该方法将结合先进的工程、生物实验和系统应用计算工具，获得心脏 MEF 和缺血之间复杂相互关系的综合系统视图。切实成果除了开发先进的实验技术来研究迄今为止无法解决的生命科学问题外，还包括对基本心脏功能的临床相关方面提供新颖的见解，以及开发计算资源来进行理论实验并识别有前途的后续实验的研究目标（这将有助于减少、细化和部分取代“湿”实验）。这些工具将适用于更广泛的研究问题，例如缺血性心脏病的更严重阶段，或心脏结构的病理变化，并提供测试新设备或药物治疗的方法。该项目也是我的职业发展。我希望获得新技能来帮助我更深入地研究心脏机械和电气特性之间的相互作用机制。我相信，将实验和数学模型结合起来是理解复杂生物系统以及正常行为恶化为疾病的过程的关键。我在牛津大学的主办团队提供了这些技能的独特组合，并且是我选择的研究领域的专家。此外，在 EPSRC 奖学金期间与其他大学的世界领先专家合作的机会将使我有机会向我所在领域的一些当今最优秀的研究人员学习（这是当前的一个独特且非常重要的方面）研究金计划）。

项目成果

Electrophysiological properties of computational human ventricular cell action potential models under acute ischemic conditions.

急性缺血条件下计算人心室细胞动作电位模型的电生理学特性。

• DOI: http://dx.10.1016/j.pbiomolbio.2017.02.007
• 发表时间: 2017
• 期刊: Progress in biophysics and molecular biology
• 影响因子: 3.8
• 作者: Dutta S

Concurrent optical mapping of voltage and calcium in rat isolated hearts using one camera

使用一台相机同时光学测绘大鼠离体心脏的电压和钙

• 发表时间: 2011
• 期刊: Proc Physiol Soc
• 作者: Bollensdorff C

Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve.

早期后除极促进缺血性人心室的透壁折返，复极储备减少。

• DOI: http://dx.10.1016/j.pbiomolbio.2016.01.008
• 发表时间: 2016
• 期刊: Progress in biophysics and molecular biology
• 影响因子: 3.8
• 作者: Dutta S

Rabbit-specific computational modelling of ventricular cell electrophysiology: Using populations of models to explore variability in the response to ischemia.

兔特异性心室细胞电生理学计算模型：使用模型群体探索缺血反应的变异性。

• DOI: http://dx.10.1016/j.pbiomolbio.2016.06.003
• 发表时间: 2016
• 期刊: Progress in biophysics and molecular biology
• 影响因子: 3.8
• 作者: Gemmell P

Recent human ventricular cell action potential models under varied ischemic conditions

最近不同缺血条件下的人心室细胞动作电位模型

• 发表时间: 2013
• 期刊: Computing in Cardiology
• 作者: Dutta S