Mechano-electric Feedback in the Heart: Mechanisms and Relevance for Normal Cardiac Function

人的一生中心脏跳动30亿到40亿次。在所有脊椎动物中，为了使每次心跳的功能正常，需要严格控制电和机械活动。心脏的电活动和机械活动在正向和反向两个方向上都有联系。电激励通过称为激励-收缩耦合的过程引起机械收缩，并且机械环境通过称为机械-电反馈的过程改变电活动。心脏兴奋-收缩偶联已经被非常详细地研究并且被很好地理解。然而，机械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的定义。我的研究计划的长期目标是确定机械电反馈对心脏正常功能的重要性，并发现这个过程是如何工作的。前五年工作的具体目标是检查心脏中负责启动心跳的区域的机械电反馈，称为窦房结（心脏的天然起搏器）。研究将涉及使用最先进的荧光成像测量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。负责与拉伸发生的电活动的变化的离子电流将通过用特定的药理学试剂阻断它们来确定。这些实验将使用来自多个物种的细胞和组织进行，以测试进化的相似性和差异，并确定最适合未来研究的动物模型。重要的是，拟议的研究将为参与的受训人员提供一个良好的学习环境，向他们介绍一系列先进的实验技术。总的来说，结果将向我们展示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适应性的理解主要基于未控制机械环境的研究。因此，我的研究将解决心脏调节的一个知之甚少的基本方面，这对于完整理解正常心脏功能和整体系统生理学至关重要。

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 normal function of the heart 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.