Grid Based Modeling of Electrical Propagation in Excitable Tissue

描述（由申请人提供）：我们提出开发、构建和改进数学和计算多尺度模型，其将心脏中的宏观电脉冲传播与基础的基于膜的亚细胞离子电流和其他细胞间和细胞内代谢过程联系起来，以保持心脏的解剖结构。这样的模型将包含更真实的生理学和解剖学，同时避免当前双域模型的许多空间平均问题。单个亚细胞和膜参数不能在繁殖过程中测量。通过创建包括这些参数的传播模型，我们试图对心脏和其他可兴奋组织（如神经和肌肉）中的电脉冲传播产生新的理解。此外，类似的技术也可以用于模拟大脑中的异常电活动，这有助于癫痫，以及胃肠道中的异常电活动，胃肠道运动障碍的主要原因。这种类型的大多数以前的大规模模型已经纳入了各种简化的细胞结构的计算效率的利益。这种假设产生的结果并不总是经得起实验的仔细检查。为了让根本上重要的组织架构的复杂性，我们将继续发展新的建模技术，跨越规模的桥梁，并采用高阶显式时间积分器，使他们可以有效地运行使用并行计算的分布式内存集群的多处理器。这将允许对整个心室或整个心脏的有效模拟，而不会平均心脏的离散细胞性质的影响。由于这些研究的亚细胞和宏观方面可以处理不同程度的复杂性，我们将纳入模块化库，从使用cellML（一种XML衍生的建模语言）开发的库开始，在IUPS Physiome项目下。这些模块化库可以用来在复杂性和执行速度之间进行权衡，这适合于给定的模型。我们已经取得了实质性的成功，采用新的显式数值积分技术在物理和生物问题。为了进一步利用这些新技术在生物环境中的方式是有效的和可扩展的，新的大学合作已经形成之间的生物医学工程系，位于健康科学中心在孟菲斯，和数学系，位于主校区在诺克斯维尔。我们将在每个性能站点创建一个适度规模的并行计算机集群，并能够通过具有非常高性能的通信通道的网络将它们链接起来。在这种更粗链接的集群环境中开发的软件将有助于构建更大规模的模型，以便在数百到数千个处理器和相关分布式内存的计算网格环境中运行。 公共卫生相关性经过50年的实验和建模，仍然不知道致命的心律失常是否通常由单一的“易激”病灶（增强的自律性）引起，然后传播到心脏的其余部分，或者，原发性异常是传播本身的障碍（折返）。类似地，在神经科学中，人们并不真正知道癫痫有多常见是由于大脑中的一个单一的“易激”病灶，以及原发性疾病有多常见是通过大脑本身的连接纤维传播冲动。我们寻求支持，以开发基于新的数学技术和解剖学和生理学的新知识的建模工具，试图回答这些问题。

DESCRIPTION (provided by applicant): We propose to develop, construct, and refine mathematical and computational multi-scale models which will link macroscopic electrical impulse propagation in the heart to underlying membrane-based sub-cellular ionic currents and other intercellular and intracellular metabolic processes, in ways which preserve anatomical architecture of the heart. Such a model will incorporate more realistic physiology and anatomy while avoiding many of the spatial averaging problems of current bi-domain models. Individual sub-cellular and membrane parameters cannot be measured during propagation. By creating propagating models which include these parameters, we seek to create a new understanding of electrical impulse propagation in the heart and in other excitable tissue, such as nerve and muscle. Moreover similar techniques can also be used to model abnormal electrical activity in the brain, which contributes to epilepsy, and abnormal electrical activity in the gastrointestinal tract, a major cause of GI motility disorders. Most previous large scale models of this type have incorporated various simplifications of the cellular architecture in the interest of computational efficiency. Such assumptions have produced results which have not always withstood close experimental scrutiny. In order to allow for fundamentally important tissue architectural complexities, we will continue the development of new modeling techniques which bridge across scales and which employ high order explicit time-integrators so that they can run efficiently using parallel computation on distributed memory clusters of multiprocessors. This will allow for efficient simulations of an entire ventricle or whole heart without averaging out the effects of the discrete cellular nature of the heart. Since both the sub-cellular and macro aspects of these studies can be treated with varying degrees of complexity, we will incorporate modular libraries, starting with the library developed using cellML, an XML derived modeling language, under the IUPS Physiome project. These modular libraries can be used to make trade-offs between complexity and speed of execution which are appropriate for a given model. We have already had substantial success at employing newer explicit numerical integration techniques in both physical and biological problems. In order to further exploit these newer techniques in a biological environment in a way which is efficient and scalable, new university collaborations have been formed between the Biomedical Engineering Department, located at the Health-Science Center in Memphis, and the Mathematics Department, located on the main campus in Knoxville. We will create a modest sized cluster of parallel computers at each of the performance sites with the ability to link them across the network with very high performance communications channels. Software developed in this more coarsely linked, clustered environment will be useful for constructing even larger scale models to run in computational grid environments of hundreds to thousands of processors and associated distributed memory. PUBLIC HEALTH RELEVANCE After 50 years of experimentation and modeling, it is still not known whether lethal cardiac arrhythmias usually arise from a single "irritable" focus (enhanced automaticity) and are then propagated to the rest of the heart or, alternatively, that the primary abnormality is a disorder of propagation itself (reentry). Similarly, in the neurosciences, it is not really known how often epilepsy is due to a single "irritable" focus in the brain and how often the primary disorder is in the propagation of impulses through connecting fibers of the brain itself. We seek support to develop modeling tools based on newer mathematical techniques and newer knowledge of anatomy and physiology to try to answer these questions.