In silico Investigation of the Mechanisms of Abnormal Spontaneous Excitation from Cell to Organ - Insights on the Development of Atrial Fibrillation

房颤是最常见的心脏疾病，导致发病率和死亡率在发达国家增加，但有效的临床治疗仍然存在问题。心房颤动是一种与年龄相关的疾病，由心房（心脏的上部腔室）快速和不规则的电活动确定，超过正常的起搏并中断正常的心律。这种脑电活动可能导致进一步的并发症，包括心脏病发作和中风。最近的研究在了解房颤的进展方面取得了一些进展，但其根本原因在很大程度上是未知的。为了有效地诊断和治疗这种疾病，迫切需要了解这些原因。异常的自发电活动（“异位活动”）可以中断正常的心律，并被认为是心房颤动起始的一种机制。细胞内钙离子循环的缺陷被认为是异位活性的可能原因，但对钙循环和异位活性之间的联系的了解尚不完整。钙循环本身依赖于复杂的细胞结构和微观尺度上的随机过程，但心房颤动主要是一种器官尺度的现象。因此，考虑跨多个尺度的行为的方法对于异位活动的详细调查是必不可少的。计算模型提供了一种跨多个尺度研究生物功能的强大方法。然而，最先进的心脏模型还不能解释整个器官模型的微观细节。这个项目的目的是发展新的方法来克服这一限制，并解决下列问题：异位活动是如何发生的？疾病状态如何促进异位活性？异位活动在房颤的发展中起什么作用？这将通过开发多尺度的计算模型来实现，其中在最详细的模型中观察到的行为将在简化模型中得到解释。首先，详细的心房单细胞模型，这说明了复杂的结构和疾病状态，将开发研究如何异位活动发生。其次，数学技术将应用于简化模型，同时保留微观尺度上的行为。这些模型将用于模拟多个耦合细胞，以研究异位活动如何同步。最后，将应用技术进一步简化模型，以便在整个心房模型中解释同步行为，以研究源自单个细胞的过程对组织行为的影响。该项目将在曼彻斯特大学复杂系统和统计物理小组进行，项目发起人是Alan McKane教授。该小组目前使用的数学方法将用于实现概述项目所需的简化。已选定多个实验合作者，以促进项目和提供模型开发和验证所需的实验数据；Mark Cannell教授（布里斯托尔大学）将提供细胞内心房结构重建；安东尼·沃克曼博士（格拉斯哥大学）将提供有关健康和疾病单细胞的数据集；Jonathan Jarvis教授（利物浦约翰摩尔斯大学）和Halina Dobryznski博士（曼彻斯特大学）将提供高分辨率的心房解剖重建。该项目的结果将是：(i)更深入地了解异位活动和心房颤动的原因和行为，这将有助于有效地诊断和治疗这种疾病；（ii）多尺度建模工具，可用于进一步研究心脏疾病，并推广到其他系统的细胞和器官行为。

Atrial fibrillation is the most common cardiac disease leading to increased morbidity and mortality in the developed world, yet effective clinical treatment remains problematic. Atrial fibrillation is an age-related disorder identified by rapid and irregular electrical activity in the atria, the upper chambers of the heart, overriding normal pacemaking and interrupting normal heart rhythm. Such electrical activity can lead to further complications including heart attack and stroke. Recent studies have made some progress in understanding the progression of atrial fibrillation, but the underlying causes are largely unknown. There is a pressing need to understand these causes for effective diagnosis and treatment of the disorder.Abnormal spontaneous electrical activity ('ectopic activity') can interrupt normal heart rhythm and has been suggested as a mechanism of atrial fibrillation initiation. Flaws in the cycling of calcium ions within the cell have been suggested as a possible cause of ectopic activity, but understanding of the link between calcium cycling and ectopic activity is incomplete. Calcium cycling itself depends on complex cellular structure and random processes at the microscopic scale, but atrial fibrillation is primarily an organ scale phenomenon. Therefore, approaches which account for behaviour across multiple scales are essential for detailed investigation of ectopic activity.Computational modelling provides a powerful method of investigating biological function across multiple scales. However, state-of-the-art cardiac models do not yet account for microscopic detail in whole organ models. The aim of this project is to develop new approaches to overcome this limitation and address the following questions:1. How does ectopic activity occur?2. How do disease states promote ectopic activity?3. What role does ectopic activity play in the development of atrial fibrillation?This will be achieved through the development of computational models at multiple scales, wherein behaviour observed in the most detailed models will be accounted for in simplified models. Firstly, detailed models of the atrial single cell, which account for complex structure and disease states, will be developed to investigate how ectopic activity occurs. Secondly, mathematical techniques will be applied to simplify the models while preserving behaviour originating at the microscopic scale. These models will be used to simulate multiple coupled cells to investigate how ectopic activity synchronises. Finally, techniques will be applied to further simplify the models, such that the synchronised behaviour can be accounted for in models of the entire atria, to investigate the effect of processes originating within single cells on the tissue behaviour. The project will be based in the Complex Systems and Statistical Physics Group (University of Manchester) with project sponsor Prof. Alan McKane. The mathematical approaches currently used within this group will be applied to achieve the simplifications necessary for the outlined project. Multiple experimental collaborators have been selected to facilitate the project and supply experimental data necessary for model development and validation; Prof. Mark Cannell (University of Bristol) will supply reconstructions of intracellular atrial structure; Dr. Antony Workman (University of Glasgow) will supply datasets concerning healthy and disease single cells; Prof. Jonathan Jarvis (Liverpool John Moores University) and Dr. Halina Dobryznski (University of Manchester) will supply high-resolution reconstructions of atrial anatomy. The outcome of the project will be (i) a deeper understanding of the causes and behaviour of ectopic activity and atrial fibrillation, which will assist in effective diagnosis and treatment of the disorder, and (ii) a multi-scale modelling tool which can be used to investigate further cardiac disorders and generalised to cellular and organ behaviour in other systems.