Nonlinear dynamics of coupled oscillator networks underlying control of gut motility

肠道的运动以促进营养的吸收和沿消化道的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，特别是在肠道和结肠。我的实验室在肠道起搏细胞，卡哈尔间质细胞(ICC)方面拥有独特的专业知识，正是这些细胞主导了对运动模式生成的控制。 在20世纪90年代，我的实验室发现ICC具有启动肠道肌肉细胞收缩的电振荡，导致在高影响力的科学期刊(自然和自然医学)上发表文章。这就解释了为什么收缩模式通常是有节奏的(ICC振荡)，但很少有其他的。为了解释这些模式本身，我们需要了解ICC如何在空间和时间上相互作用，这是我们研究提案的主题。ICC排列整个肠道，并通过肠壁在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的邻居的振荡，也可以感知其他ICC网络的振荡。2014年，我们在《自然通讯》上发表了这项提议的一些基础工作。我们认为，正是这些网络内部和网络间的相互作用，才能产生复杂的收缩模式。只有借助数学模型和理论，才能全面了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。这一理论已经建立得很好，处于正确的描述水平，在我们手中已经显示出解释模式的前景。我们将发现ICC如何发挥网络的作用，协调对生命至关重要的复杂的肠道收缩模式。加拿大的炎症性和功能性胃肠道疾病的发病率是世界上最高的，动力障碍是一个主要或压倒一切的问题。我们建议的优势在于我们在建模、生理学和临床研究方面的整体专业知识，即本建议仅侧重于数学建模和直接相关的生理学实验来获得模型参数。 我们建议的研究将通过一项培训计划进行，该计划涉及受训者在数学建模、生理学和临床研究方面的密切合作，所有这些都在Farncombe家庭消化健康研究所内进行，在那里学生可以找到一个蓬勃发展的研究-培训环境。此外，还与麦克马斯特大学和多伦多大学的工程系进行了合作。培训计划还得到了我担任荣誉生物学药理合作项目主任和我的生物医学工程协会会员的推动。我们将培训学生、博士后和研究人员进行跨学科翻译研究。

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.