Cardiac electrophysiological homeostasis

心脏电生理稳态

• 批准号: BB/F023863/1
• 负责人: James Fraser
• 金额: $ 110.87万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF023863%2F1
• 关键词: Cardiac; electrophysiological; homeostasis

The membrane potential, cell volume, and intracellular ion concentrations are fundamental cellular parameters that exert profound influences upon cellular, tissue and organ physiology. Electrophysiological homeostasis is the process of controlling these parameters, despite significant changes in the demands that are placed on the heart during normal activity. Much previous experimental and theoretical work has focused on the control of each parameter individually, yet their values are strongly interdependent. These complex interdependencies must be fully characterized in order to understand the relationship between cardiac electrical activity and the underlying properties of ion channels and pumps. The aim of this proposal is to create a model that will permit a thorough investigation of cardiac electrophysiological homeostasis. Predictions of the model will be tested in focused experiments in normal mice and mice with strategic mutations of ion channel functions. I have introduced and tested a novel modelling technique based on strict physical conservation principles, termed charge-difference modelling. I have shown in a recent review article that this method of modelling has significant advantages over existing cardiac models in that it accurately predicts the determinants of intracellular ion concentrations, cell volume and the membrane potential, whereas existing models do not (Fraser & Huang, 2007; Prog. Biophys. Mol. Biol. 94, 336-372). In addition, it allows the simulation of volume changes, electroneutral fluxes, multiple interacting electrically-charged compartments and non-isoelectric compartments, allowing accurate organelle as well as cytosolic simulation. My previous work has involved modelling skeletal muscle using this method. This lead to the development and successful experimental testing of a unifying theory for determination, regulation and maintenance of the membrane potential, cell volume and intracellular ion concentrations in skeletal muscle. I will now: (1) extend these novel modelling techniques to investigate ionic homeostasis in cardiac muscle cells and thereby provide the first formulation amongst available cardiac myocyte models that attains true steady states that are independent of initial intracellular ion concentrations. In turn, this will permit: (2) Use of the model to generate experimentally-testable hypotheses regarding the determinants of electrophysiological homeostasis in cardiac myocytes; and (3) Use of the model to investigate the influence of variations in electrophysiological homeostatic steady-state upon the cell-to-cell spread of electrical activity that is required for the normal pattern of cardiac excitation

膜电位、细胞体积和细胞内离子浓度是对细胞、组织和器官生理学产生深远影响的基本细胞参数。尽管正常活动期间心脏的需求发生了显着变化，但电生理稳态是控制这些参数的过程。以前的许多实验和理论工作都集中于单独控制每个参数，但它们的值是强烈相互依赖的。必须充分表征这些复杂的相互依赖性，以便了解心电活动与离子通道和泵的基本特性之间的关系。该提案的目的是创建一个模型，允许对心脏电生理稳态进行彻底研究。该模型的预测将在正常小鼠和具有离子通道功能战略突变的小鼠的集中实验中进行测试。我介绍并测试了一种基于严格物理守恒原理的新颖建模技术，称为电荷差建模。我在最近的一篇评论文章中表明，这种建模方法比现有心脏模型具有显着优势，因为它可以准确预测细胞内离子浓度、细胞体积和膜电位的决定因素，而现有模型则不能（Fraser & Huang, 2007; Prog. Biophys. Mol. Biol. 94, 336-372）。此外，它还可以模拟体积变化、电中性通量、多个相互作用的带电隔室和非等电隔室，从而实现准确的细胞器和细胞溶质模拟。我之前的工作涉及使用这种方法对骨骼肌进行建模。这导致了确定、调节和维持骨骼肌膜电位、细胞体积和细胞内离子浓度的统一理论的发展和成功的实验测试。我现在将：（1）扩展这些新颖的建模技术来研究心肌细胞中的离子稳态，从而提供可用的心肌细胞模型中的第一个配方，该模型能够达到独立于初始细胞内离子浓度的真正稳态。反过来，这将允许：（2）使用该模型生成关于心肌细胞电生理稳态决定因素的可实验检验的假设； (3) 使用该模型研究电生理稳态变化对正常心脏兴奋模式所需的电活动在细胞间传播的影响

项目成果

Conduction velocity changes contribute to arrhythmogenicity in a murine model of catecholaminergic polymorphic ventricular tachycardia, RyR2-P2328S

传导速度的变化导致儿茶酚胺能多形性室性心动过速鼠模型 RyR2-P2328S 的致心律失常

• 作者: James Fraser (Co-Author)

Relationships between resting conductances, excitability, and t-system ionic homeostasis in skeletal muscle.

骨骼肌静息电导、兴奋性和 t 系统离子稳态之间的关系。

• DOI: 10.17863/cam.37287
• 发表时间: 2011
• 作者: Fraser J

Mkk4 is a negative regulator of the transforming growth factor beta 1 signaling associated with atrial remodeling and arrhythmogenesis with age.

Mkk4 是转化生长因子 β 1 信号传导的负调节因子，与年龄相关的心房重塑和心律失常发生相关。

• DOI: 10.17863/cam.58773
• 发表时间: 2014
• 作者: Davies L

Assessment of magnitude and dispersion of epicardial conduction velocity in Langendorff perfused murine hearts

Langendorff 灌注小鼠心脏心外膜传导速度大小和离散度的评估

• 作者: James Fraser (Co-Author)

The determinants of t-system volume in resting skeletal muscle

静息骨骼肌 T 系统体积的决定因素

• 作者: James Fraser (Author)