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

心脏是一个电控机械泵，有点像电动机。类似于“发电机模式”下的电动机，心脏能够将机械干预转化为电信号。这种机械-电反馈（MEF）可以在心脏的所有结构和功能整合水平上观察到，从分子水平到整个器官和生物体。在患者中，MEF效应可能引起和终止心律紊乱，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，即使是在正常组织中也是如此。大多数现实生活中的情况构成了更大的挑战，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潜在机制，也不知道MEF用于心律管理的潜力和局限性。这在很大程度上是由于缺乏合适的实验和理论模型，我希望解决这个不足，在目前的proposal.My目标，因此，是开发和整合一套先进的“湿”实验和“干”计算研究技术，研究心肌缺血对心脏机械电串扰的影响。这将涉及技术的发展，涉及在正常和缺血条件下保存的离体心脏组织，（微电极）和非接触（光学技术）电活动的映射、区域组织变形的高速视频宏观检查、靶向SAC的药理学干预以及心肌的高级计算模型的应用，这将使我能够重新整合记录的各种数据，以帮助分析，解释和预测。因此，该方法将结合联合收割机先进的工程，生物实验和计算工具的系统应用，以达到心脏MEF和缺血的复杂相互关系的综合系统观点。除了开发先进的实验技术来研究迄今为止尚无法解决的生命科学问题外，还提供了对基本心脏功能的临床相关方面的新见解，以及开发计算资源来进行理论实验并确定有希望的研究目标，以便进行实验随访（这将有助于减少、改进和部分取代“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，这个项目也是我职业发展的重要一步。我希望获得新的技能，以帮助我更深入地研究心脏的机械和电气特性之间的相互作用机制。我相信，结合实验和数学建模是理解复杂的生物系统和正常行为恶化为疾病的过程的关键。我在牛津大学的接待团队提供了这些技能的独特组合，并且是我所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最好的当今研究人员学习（这是本奖学金计划的一个独特且非常重要的方面）。

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).