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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).
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