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

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.