Nonlinear dynamics of coupled oscillator networks underlying control of gut motility

耦合振荡器网络的非线性动力学是肠道运动控制的基础

• 批准号: RGPIN-2017-06243
• 负责人: Huizinga, Jan
• 金额: $ 2.91万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711567
• 关键词: Nonlinear; dynamics; coupled; oscillator; networks

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.

肠道的蠕动促进营养物质的吸收和沿着消化道的运输对于生命至关重要。然而，我们对运动的控制机制仍然知之甚少，特别是在肠道和结肠中。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，从而在高影响力的科学期刊（《自然》和《自然医学》）上发表了论文。这解释了为什么收缩模式通常是有节奏的（ICC 振荡），但除此之外几乎没有其他原因。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，这就是我们研究计划的主题。 ICC 排列在肠道的整个长度上，并在穿过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 ICC 可以感知同一网络中其邻居的振荡以及其他 ICC 网络的振荡。我们于 2014 年在《自然通讯》上发表了该提案的一些基础工作。我们相信正是这些网络内和网络间的相互作用使得复杂的收缩模式得以生成。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。我们相信这些理论中最好的是非线性动力学。该理论已经很成熟，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 如何作为网络来协调对生命至关重要的肠道收缩的复杂模式。加拿大是世界上炎症性和功能性胃肠道疾病发病率最高的国家，其中运动功能障碍是一个主要或首要问题。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整体专业知识，因此该提案仅关注数学建模和直接相关的生理实验以获得模型参数。 我们提出的研究将通过一项培训计划来完成，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，所有这些都在法恩科姆家庭消化健康研究所内进行，学生在那里找到了一个蓬勃发展的研究培训环境。与麦克马斯特大学和多伦多大学工程系的合作对此进行了补充。我担任荣誉生物药理学合作项目主任和生物医学工程副会员也促进了该培训计划。我们将为学生、博士后和研究人员提供跨学科转化研究方面的培训。