This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This project is a collaborative project with Dr. Henriquez' group at Duke University. This project aims at using discrete multi-domain models at a the cellular level in order to study the effect of tissue structure on the electrophysiology of cardiac tissue. The most commonly used models for this type of study employ continuous bidomain models, an approach which averages out the intra- and extracellular spaces to form continuous interleaved volumes separated by a membrane. This type of model, however, does not take into account the shape and location of the actual membrane nor does it deal with the fact that cells are discrete entities. In order to further analyze the effect of averaging, and more specifically to tie the averaged properties to the underlying tissue pathology, the project aims at using discrete geometric and computational models at a cellular scale to perform simulations of the propagation of the depolarization front in cardiac tissue.The original goal of this collaboration was to apply this simulation and modeling system to the study of electroporation and to determine the parameters required for successful application of electroporation to inject DNA into cells as part of a gene therapy approach. The application focus has changed over the past year to one directed at the study of the spread of excitation at the cellular level, still with the same emphasis on the parameters that determine the speed and effectiveness of activation under a variety of conditions. The relevance of this goal lies in the fact that propagation clearly changes under a host of pathophysiological changes from, for example, ischemia or reperfusion, because of changes in the geometry of the cells and the intersticial space, or local alterations in electrolyte concrentrations or gap junctional conductivity. These factors are linked to both benign fluctuations in propagation of the action potential but also to life threatening arrhythmias. Our modeling approach is uniquely suited to parameter studies in this domain simply because of its small physical scale and the level of control over relevant parameters. We are able to study a tissue preparation at the same scale typically emplyed for models of single cells and this can observe contributions from both the cells and cell membrane as well as the cell matrix and intersticial spaces to the spread of excitation. The response of an isolated cell in this context (and probably many other contexts) will be quite different from the response of that same cell when it is part of a syncytium. It is the local electrical behavior near the plasma membrane that dictates the number of channel that open or the extracellular currents that flow. Creating models with such detail is a change compare to the approach of Dr. Henriquez and his group to date; they have used the local tissue structure and cell membrane dynamics to predict averaged properties of tissue and used this information in macroscopic models. In this project, they begin with realistic models of 10-30 myocytes, decimate this space into millions of finite elements to which we can assign indivdual properties, and then simulate the resulting response to electrical stimulation.
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