The cardiac myocyte is a highly organized structure of membrane networks, contractile proteins, ion channels and buffering systems. The heartbeat is the result of tightly regulated electrical, chemical and mechanical processes that repeatedly occur at the subcellular scale across the millions of cells that make up the heart. The sensitivity of whole-organ function to the spatial organization of its subcellular components is especially highlighted when studying cardiac cell structure/function relationships. We have several projects underway to build computational models of cardiac cell ultrastructure and to quantify the role that spatial organization plays in cell function.
Measuring and Modelling Cardiac Cell Structure
Although many basic aspects of cardiac cell structure have been identified and investigated, the spatial organisation and “design” is far from complete. We are performing detailed measurements of structural organisation in cardiac cells using high resolution data from electron microscopy and immunofluorescence techniques. We are developing novel computer algorithms to use these measurements to build structurally detailed and accurate models of the cardiac cell. The movie below shows a computationally derived realistic distributions of clusters of ryanodine receptors around experimentally imaged z-discs in the cardiac cell.
Exploring Hypertrophic Calcium Signaling in Structurally Detailed Models
Latest high-resolution imaging methods like super-resolution microscopy and electron tomography are opening up new questions about how cardiac cells function. Our detailed structural models are excellent test beds to explore questions regarding calcium signalling. We are exploring the spatio-temporal dynamics of calcium during each heart-beat (known as excitation-contraction coupling, or ECC) and also asking questions about how these dynamics are different from long-term hypertrophic calcium signalling for cell growth.
Quantifying the Effects of Structural Change on Function and Vice Versa
An over-arching theme of our research is to work on one of the biggest challenges with cell biology – remodelling. We are developing methods to quantify changes in cell structure in conditions such as diabetic cardiomyopathy. Our structurally detailed computational models allow us to deconstruct the chicken and egg question in cardiac cell biology – the feedback and feedforward loops between cell structure and cell function.