The Role of the Intracardiac Nervous System in Cardiac Autoregulation

人的一生中心脏会跳动30亿到40亿次。为了完成这一惊人的壮举，数百万个细胞必须以良好的协调方式工作，同时迅速调整它们的活动以适应生理变化。这种协调和适应在很大程度上是由完全发生在心脏本身的调节驱动的。我的研究计划的长期目标是探索心脏功能的这种“内在”调节。调节心脏功能的一个关键因素是心脏内复杂的神经网络，称为心内神经系统（IcNS）。然而，人们对IcNS的整体功能知之甚少，因为它嵌入心脏组织中，因此很难用现有技术进行研究。我们目前项目的目标是了解IcNS在维持正常心脏活动中的作用。目前认为ICNS只是一个从中枢神经系统到心脏的信号的“中继站”。最近的证据表明，它实际上参与了神经信号的局部处理和反馈，从而充当了心脏中的“小大脑”。在这个项目中，我们将采用一种创新的方法来确定ICNS是否对心脏活动的局部控制很重要，独立于中枢神经系统。我们的方法将涉及使用：（i）斑马鱼作为动物模型，其使得能够在整个心脏中接近IcNS。(ii)先进的3D荧光成像技术，能够测量整个 IcNS。(iii)数学建模来回答问题不可能只通过实验。我们的开创性研究将由具有心脏和神经生理学，工程学，物理学和数学背景的国际专家团队推动。这些研究的结果将揭示：（i）ICNS的功能及其与整个心脏的心脏细胞的通讯。(ii)不同细胞类型在IcNS中对其整体功能的作用和重要性。(iii)ICNS对生理刺激的反应。(iv)在心脏发育和衰老过程中发生的IcNS变化。总的来说，我们的项目将“推动边界”的实验和数学调查的ICNS，以克服以前的局限性，其综合研究。我们将提供直接证据证明ICNS是否处理神经元输入并将信息直接反馈到心脏，而不依赖于中枢神经系统。这些新的信息将揭示IcNS在发育和年龄中局部控制心脏功能的作用，这对于理解心脏功能调节的基本性质至关重要。与此同时，该项目开发的创新实验数学建模方法将对其他研究人员研究局部神经系统控制在身体其他器官中的重要性非常有用。

The heart beats an incredible 3-4 billion times over a lifetime. To accomplish this amazing feat, millions of cells must work in a well-coordinated fashion, while rapidly adjusting their activity to physiological changes. This coordination and adaptation are driven largely by regulation that occurs entirely within the heart itself. The long-term objective of my research program is to explore this `intrinsic' regulation of heart function. One critical factor for the regulation of heart function is a complex network of nerves within the heart, known as the intracardiac nervous system (IcNS). Yet, little is known about the overall function of the IcNS, as it is embedded within the tissue of the heart, so difficult to study with current technologies. The goal of our current project is to understand the role of the IcNS in the maintenance of normal heart activity. It is currently thought that the IcNS is simply a `relay station' for signals from the central nervous system to the heart. Recent evidence suggests that it is in fact involved in the local processing and feedback of nerve signals, thus acting as a `little brain' in the heart. In this project, we will apply an innovative approach to determine whether the IcNS is important for local control of heart activity, independent of the central nervous system. Our approach will involve the use of: (i) Zebrafish as an animal model that enables access to the IcNS in the whole heart. (ii) Advanced 3D fluorescence imaging techniques that enable measurement of activity across the entire        IcNS. (iii) Mathematical modelling to answer questions not possible with experimentation alone. Our pioneering studies will be driven by an international team of experts with backgrounds in cardiac and neuronal physiology, engineering, physics, and mathematics. The results of these studies will reveal the: (i) Function of the IcNS and its communication with heart cells across the whole heart. (ii) Role and importance of different cell types in the IcNS for its overall function. (iii) Response of the IcNS to physiological stimuli. (iv) Changes in the IcNS that occur during heart development and with ageing. Overall, our project will `push the boundaries' of experimental and mathematical investigation of the IcNS to overcome previous limitations for its integrative study. We will provide direct evidence demonstrating whether the IcNS processes neuronal inputs and feeds back information directly to the heart, independent of the central nervous system. This new information will reveal the role of the IcNS in local control of heart function in development and with age, which is critical for understanding the fundamental nature of the regulation of heart function. At the same time, the innovative experimental-mathematical modelling approach developed in this project will be highly useful for other researchers studying the importance of local nervous system control in other organs across the body.