The Role of the Intracardiac Nervous System in Cardiac Autoregulation

心内神经系统在心脏自动调节中的作用

• 批准号: RGPIN-2022-03150
• 负责人: Quinn, TAlexander
• 金额: $ 2.84万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763313
• 关键词: Role; Intracardiac; Nervous; System; Cardiac

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.

心脏在一生中跳动30-40亿次，令人难以置信。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内部的调节驱动的。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。心脏功能调节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，因为它嵌入在心脏组织中，因此很难用目前的技术进行研究。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。目前人们认为ICNS仅仅是一个从中枢神经系统向心脏传递信号的‘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，因此在心脏中扮演着一个“小大脑”的角色。在这个项目中，我们将应用一种创新的方法来确定独立于中枢神经系统的ICNS对于心脏活动的局部控制是否重要。我们的方法将涉及使用：(I)斑马鱼作为动物模型，使其能够接触到整个心脏的冰核。(2)先进的3D荧光成像技术，能够测量整个国家的活动。(3)用数学模型来回答仅靠实验不可能解决的问题。我们的开创性研究将由一个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。(2)ICNS中不同细胞类型对其整体功能的作用和重要性。(Iii)ICNS对生理刺激的反应。(4)在心脏发育期间和随着年龄增长而发生的ICN的变化。总体而言，我们的项目将“突破”IcNS的实验和数学调查的界限，以克服以前对其综合研究的限制。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。这一新信息将揭示IcNS在发育和随年龄变化的心脏功能局部控制中的作用，这对于理解心脏功能调节的基本性质至关重要。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非常有用，这些研究人员将研究全身其他器官局部神经系统控制的重要性。