Cardiac electrophysiology through 3-Photon Optical technology

数以百万计的人受到心跳异常或心律失常的影响，心律失常是一组心脏跳动不规律，太快或太慢的情况。发生在心脏大腔室（心室）的心律失常可能导致危及生命的心室颤动，一种不受控制的颤振，而不是协调的泵送或心脏骤停。了解促进心律失常形成的确切条件的进展对于开发针对高危患者的新治疗策略至关重要。心功能的一个关键概念是心肌细胞（心脏可兴奋的肌肉细胞）通过称为动作电位的电信号脉冲进行交流。心肌细胞需要对初始脉冲同步反应，以协调的方式扩散，使血液在每次跳动时有效地泵入全身。相反，当心肌细胞之间的电传导不正常时，心肌细胞就会停止协同工作，整个心脏以健康的速度相应的泵送就会中断。因此，为了理解心律失常的形成，我们需要了解心脏细胞在其原生周围结构环境中的细胞电生理。由于心脏功能和结构复杂相关，光学方法非常适合这些研究，因为它们是非侵入性的。利用荧光染料，根据心肌细胞的电状态改变其发光，光学显微镜技术使我们能够用光来研究心脏的电传导。在这个研究项目中，我建议开发基于3光子显微镜的新型光学技术，以研究脑室壁深处的电活动，这超出了目前技术水平的范围。

Millions of people are affected by the appearance of abnormal heartbeats, or arrhythmias- a group of conditions in which the heart beats irregularly, too fast or too slow. Arrhythmias arising in the large chambers of the heart, the ventricles, may lead to life-threatening ventricular fibrillation, an uncontrolled flutter rather than coordinated pumping or cardiac arrest. Advances in understanding the precise conditions which promote the formation of arrhythmias will be vital to the development of novel treatment strategies for at-risk patients. A key concept of cardiac function is the communication of cardiomyocytes, the excitable muscle cells of the heart, via electrical signalling impulses called action potentials. Cardiac muscle cells need to act synchronously to an initiating impulse spreading in a coordinated manner to allow blood to be efficiently pumped around the body with each beat. Conversely, when the electrical conduction between cardiomyocytes is not working properly, cardiomyocytes stop working together in a coordinated way and corresponding pumping of the entire heart at a healthy rate breaks down. Therefore, to understand the formation of arrhythmias we need understanding of the cellular electrophysiology of heart cells within their native surrounding structural environment. Since cardiac function and structure are intricately related, optical approaches are well-suited for these investigations because they are non-invasive. Using fluorescent dyes which change their light emission depending on the electrical state of the cardiomyocyte, optical microscopy techniques allow us to investigate cardiac electrical conduction with light. In this research programme, I propose to develop novel optical techniques based on 3-photon microscopy to investigate electrical activity deep within the ventricle wall beyond the reach of what is feasible with the current state of the art.