Cardiac modeling of arrhythmias

Cardiac arrhythmia is the number one killer in the developed world. Recently, a genetic component of arrhythmia has been realized, as physicians and experimental scientists have identified genetic mutations linked to arrhythmia.  A number of these mutations have been found in genes encoding specialized ion channel proteins.  Mutations cause abnormal ion channel behavior and disrupt the precisely timed synchronization of cardiac ion channels that normally underlies the spread of cardiac electrical activity and drives rhythmic contraction of the heart.  Mutations in cardiac ion channels have been shown to underlie the development of several distinct clinical syndromes, including Long QT Syndrome, Brugada Syndrome and Cardiac conduction disorders.

The discovery of the link between genes and disease has led to a large number of genetic, basic science and clinical science studies that have focused on improved understanding of the mechanistic basis of these diseases.  These studies typically concentrate on an individual component of a disease at a single scale.  For example, arrhythmia predisposition has been studied at the level of the DNA, where the location of a mutation or polymorphism in a gene has been anticipated to provide information about the ensuing alteration and protein structure, and by extension, protein function.   Proteins are also the objects of study, almost exclusively in isolation, away from their natural environment where engagement in complex nonlinear interactions with other cellular components may be required for normal physiological function.   At the next scale, isolated cells have been used for experimentation in an attempt to recreate a physiologically relevant environment where disease mechanisms can be elucidated.  Tissue level studies have also been undertaken, but the collected data are often so complex that they preclude reasonable analysis of underlying components.  These investigations have led to novel insights into the functioning of many subcellular systems in both physiological and pathophysiological conditions.   However, more often than not, these single scale investigations fail to generate the widely sought information that is predictive of disease states.

The Clancy Lab aims to employ a "systems biology" approach and develop theoretical methodologies in order to try to understand the emergent disease properties that develop over multiple scales: how mutations in cardiac ion channels alter protein, cell and tissue level function to cause arrhythmia.  Ultimately we aim to implement theoretical modeling techniques to reveal the widely sought and elusive connection between perturbation in a gene and the cellular and tissue properties that are altered to result in the development of excitable disease.


Research

Cardiac modeling of arrhythmias

Models of hippocampal neurons