Mechano-Electric Coupling in the Heart: Mechanisms and Relevance for Cardiac Autoregulation

人的一生中心脏跳动30到40亿次。在所有脊椎动物中，为了保证每一次心跳的正常功能，都需要对电和机械活动进行严格的控制。心脏的电和机械活动在正向和反向上都有联系。电激励通过一个称为激励-收缩耦合的过程引起机械收缩，机械环境通过一个称为机电反馈的过程改变电活动。心脏兴奋-收缩耦合已被详细研究，并得到了很好的理解。然而，机电反馈在心脏中的重要性通常被忽视，其工作方式也没有很好地定义。我的研究计划的长期目标是确定机电反馈对心脏功能调节的重要性，并发现这一过程是如何工作的。前五年工作的具体目标是检查负责启动心跳的心脏区域的机电反馈，称为窦房结（心脏的自然起搏器）。研究将包括使用最先进的荧光成像技术测量来自窦房结的单个细胞和完整组织的电活动，同时它们受到生理拉伸。在拉伸过程中引起电活动变化的离子电流将通过用特定的药理学药物阻断它们来确定。这些实验将使用来自多个物种的细胞和组织来测试进化的相似性和差异性，并为未来的研究确定最合适的动物模型。重要的是，拟议的研究将通过向学员介绍一系列先进的实验技术，为他们提供一个良好的学习环境。总的来说，结果将告诉我们心脏起搏器如何适应生理需求的变化。目前，我们对窦房结以及心脏其他部分的适应性的理解，主要是基于机械环境不受控制的研究。因此，我的研究将解决心脏调节的一个鲜为人知的基本方面，这对于完全理解正常心脏功能和整体系统生理学是必不可少的。

The heart beats 3 to 4 billion times in a human lifetime. In all vertebrates, for normal function of each heartbeat, tight control of electrical and mechanical activity is needed. Electrical and mechanical activity in the heart are linked in both the forward and reverse direction. Electrical excitation causes mechanical contraction through a process called excitation-contraction coupling and the mechanical environment changes electrical activity through a process called mechano-electric feedback. Cardiac excitation-contraction coupling has been studied in great detail and is well understood. However, the importance of mechano-electric feedback in the heart is generally ignored and the way in which it works is not well defined. The long-term goal of my research program is to determine the importance of mechano-electric feedback for regulation of heart function and to discover how this process works. The specific objectives of the first five years of work are to examine mechano-electric feedback in the region of the heart responsible for initiating the heartbeat, called the sinoatrial node (the heart's natural pacemaker). Studies will involve measuring the electrical activity of individual cells and intact tissue from the sinoatrial node using state-of-the-art fluorescence imaging, while they are being subjected to physiological stretch. The ionic currents responsible for changes in electrical activity that occur with stretch will be determined by blocking them with specific pharmacological agents. These experiments will be carried out using cells and tissue from multiple species to test for evolutionary similarities and differences, as well as to determine the most appropriate animal model for future research. Importantly, the proposed studies will provide an excellent learning environment for the trainees involved by introducing them to a range of advanced experimental techniques. Overall, results will show us how the heart's pacemaker adapts to changes in physiological demand. Currently, our understanding of the adaptation of the sinoatrial node, as well as the rest of the heart, is based mostly on studies in which the mechanical environment was not controlled. Thus, my research will address a poorly understood fundamental aspect of heart regulation that is essential for a complete understanding of normal heart function and overall systems physiology.