Nonlinear dynamics of coupled oscillator networks underlying control of gut motility

肠道的运动促进营养物质的吸收和沿着消化道运输是生命所必需的。然而，我们仍然对运动的控制机制知之甚少，特别是在肠和结肠中。我的实验室在肠道起搏器细胞、Cajal间质细胞（ICC）方面有独特的专长，正是这些细胞主导着运动模式的产生。***在20世纪90年代，我的实验室发现ICC具有引发肠道肌肉细胞收缩的电振荡，从而在高影响力的科学期刊（自然和自然医学）上发表了文章。这解释了为什么收缩模式通常是有节奏的（ICC振荡），而不是其他的。为了解释这些模式本身，我们需要了解ICC在空间和时间上是如何相互作用的，这是我们研究计划的主题。ICC排列在肠道的整个长度上，并在肠壁的不同深度形成许多独立的网状细胞层（网络）。我们的想法是，振荡的ICC既可以感知同一网络中邻居的振荡，也可以感知其他ICC网络的振荡。2014年，我们在《自然通讯》上发表了这一提议的一些基础工作。我们认为，正是这些网络内部和网络之间的相互作用使得复杂的收缩模式得以产生。只有借助数学模型和理论，才能全面理解这些相互作用的复杂现实。我们认为这些理论中最好的是非线性动力学。这个理论已经建立起来，处于正确的描述水平，并且在我们手中已经显示出解释模式的希望。我们将发现ICC作为网络如何协调肠道收缩的复杂模式，这对生命至关重要。加拿大是世界上炎症性和功能性胃肠疾病发病率最高的国家，其中运动功能障碍是一个主要或最重要的问题。我们提案的优势在于我们在建模，生理学和临床研究方面的综合专业知识，因此我们的提案只关注数学建模和直接相关的生理学实验来获得模型参数。***我们提出的研究将通过一个培训计划来完成，该计划涉及学员在数学建模、生理学和临床研究方面的密切合作，所有这些都在Farncombe家族消化健康研究所进行，在那里学生可以找到一个蓬勃发展的研究培训环境。这是与麦克马斯特大学工程系和多伦多大学合作的补充。我是荣誉生物学药理学合作项目的主任，也是生物医学工程的准会员，这也为培训计划提供了便利。培养跨学科转化研究的学生、博士后和科研人员。

Motility of the gut to facilitate absorption of nutrients and transport along the alimentary canal is essential for life. Yet we still know little about control mechanisms of motility, in particular in the intestine and colon. My laboratory has unique expertise in pacemaker cells of the gut, the interstitial cells of Cajal (ICC), and it is these cells that dominate control over pattern generation of motility.*** In the 1990s my laboratory discovered that ICC have electrical oscillations that initiate contraction of gut muscle cells, resulting in publications in high impact scientific journals (Nature and Nature Medicine). This explained why contraction patterns are usually rhythmic (the ICC oscillate), but little else. To explain the patterns themselves we need to understand how ICC interact with each other in space and time, and this is the subject of our research proposal. ICC line the whole length of the gut and form a number of separate, net-like layers of cells (networks) at different depths through the gut wall. Our idea is that an oscillating ICC can sense both the oscillations of its neighbours in the same network and the oscillations of other ICC networks. We published some groundwork for this proposal in Nature Communication in 2014. It is these intra- and inter- network interactions that we believe allow complex contractile patterns to be generated. The complex reality of these interactions can only be understood comprehensively with the help of mathematical models and theories. We believe that the best of these theories is nonlinear dynamics. The theory is well established, is at the right level of description and in our hands has already shown promise in explaining patterns. We will discover how ICC behave as networks to orchestrate the complex patterns of gut contraction that are so vital to life. Canada has the highest rates of inflammatory and functional gastrointestinal disorders in the world, with motility dysfunction as a major or the overriding problem. The strength of our proposal lies in our overall expertise in modeling, physiology, and clinical studies, whereby this proposal focuses only on the mathematical modeling and directly relevant physiological experiments to obtain the model parameters. ***Our proposed research will be done through a training plan that involves close collaboration between trainees in mathematical modeling, physiology and clinical studies, all within the Farncombe Family Digestive Health Research Institute, where students find a thriving research-training environment. This is supplemented with collaborations with the Departments of Engineering at McMaster and the University of Toronto. The training plan is also facilitated by my directorship of the Honours Biology Pharmacology Coop Program and my associate membership of Biomedical Engineering. We will train students, postdocs and research staff in interdisciplinary translational research.