Integrative 3D modelling of ion and proton transport in a heart cell

心脏由数百万个细胞组成，这些细胞共同发挥作用，将血液输送到身体各处，每个细胞几乎同步地收缩，以响应一波电激活。心脏细胞的结构非常复杂：外膜表面包含许多错综复杂的内折和裂隙，而细胞内部则存在大量复杂的亚细胞室和维持正常细胞功能所需的细胞机械。此外，重要的调节分子在每个细胞内分布不均匀。心脏细胞内部组织的缺陷可能导致心律失常，这是一个临床术语，指的是异常的电活动，可能会产生潜在的致命后果。因此，该项目的主要科学目标是创建一个几何上准确的单个心脏细胞的3D模型，以回答一些重要的悬而未决的问题，如细胞结构和内部安排如何在心脏的正常功能中发挥作用，以及心律失常的发生机制是什么？虽然这个模型适用于许多研究，但我们将重点放在当供氧和排泄废物的血管突然受阻时，正常的细胞功能是如何改变的。不仅堵塞下游区域的细胞会缺氧，乳酸的积聚也会损害这些细胞的收缩和电功能，并似乎使它们容易发生心律失常。我们将专门研究细胞如何对这种所谓的酸中毒做出反应，以及心律失常发生的机制。为了建立这个模型，我们将使用复杂的图像处理技术，从高分辨率数据集中建立细胞结构的精确3D几何表示。先进的数值方法将被用来建立重要分子在细胞内扩散的数学方程，这些方程将使用高性能计算机求解。尖端的实验程序将提供有关含酸蛋白质位置的关键信息，使该模型能够预测细胞内的酸运输，更重要的是，酸中毒可能损害细胞功能的哪些方面，以及正常的电活动如何退化为心律失常。数学建模技术和实验研究的这种结合对于阐明心脏病病因和进展的潜在机制至关重要，并最终可能导致改进治疗和预防。

The heart is composed of millions of cells that function together to pump blood around the body, each cell contracting in near synchrony in response to a wave of electrical activation. The structure of heart cells is highly complex: the outer membrane surface contains many convoluted infoldings and clefts, whereas inside the cell resides a plethora of elaborate subcellular compartments and cellular machinery required to maintain normal cell function. Furthermore, important regulatory molecules are distributed nonuniformly inside each cell. Defects to the internal organization of heart cells can lead to arrhythmia, a clinical term for abnormal electrical activity that can have potentially fatal consequences. Thus, the main scientific goal of this project is to create a geometrically accurate 3D model of a single heart cell to answer important unresolved questions such as, how does the cell structure and internal arrangement play a role in normal functioning of the heart, and what mechanisms underlie the development of arrhythmias? Although this model is suitable for a number of investigations, we will focus on how normal cellular function is altered when blood vessels, supplying oxygen and removing wastes, suddenly become blocked. Not only do cells in regions downstream from the blockage become starved of oxygen, but buildup of lactic acid impairs the contractile and electrical function of these cells and appears to predispose them to arrhythmias. We will specifically investigate how the cell responds to this so-called acidosis, and the mechanisms by which arrhythmia occurs. In order to build this model, we will use sophisticated image processing techniques to build an accurate 3D geometrical representation of cell structure from high resolution datasets. Advanced numerical methods will be used to formulate mathematical equations for the diffusion of important molecules within the cell, and these equations will be solved using high performance computers. Cutting edge experimental procedures will provide key information on locations of acid-bearing proteins, allowing the model to predict acid transport within the cell and, more importantly, what aspects of cellular function may be impaired by acidosis, and how normal electrical activity degenerates to arrhythmia. Such combinations of mathematical modeling techniques and experimental investigations are vital for elucidating the mechanisms underlying the causes and progression of cardiac diseases and may ultimately lead to improved treatment and prevention.