Research Overview
Theoretical modeling of excitable systems
Research interests: The last decade has provided a wealth of experimental data in genetics and molecular biology on the structure and function of elementary building blocks of living systems. A challenge of the current research era is to begin integrating these data in order to understand mechanisms of disease and ultimately to facilitate translation of information into development of therapeutic interventions. While one approach to integration is through the use of transgenic animals, the goal of our laboratory is to develop novel complementary theoretical approaches. We have developed models of genetic mutations in cardiac ion channels to determine how molecular defects disrupt the delicate balance of dynamic interactions between the ion channels and the cellular environment, leading to altered cell function. We have developed and utilized virtual transgenic myocytes to elucidate basic mechanisms of arrhythmia and to demonstrate precisely how specific defects disrupt channel-gating kinetics and underlie cardiac arrhythmia. While much of our previous work has been within the realm of cardiac defects and abnormal rhythms, a natural extension is application of the same theoretical techniques to other complex physiological systems. One example is the brain, since very recent studies have shown defects in neuronal channels underlying epilepsy that are remarkably similar to those described in cardiac isoforms related to arrhythmia. Hence, a new direction in the lab is to develop more detailed models of hippocampal neurons to understand basic mechanisms of excitability and inhibition of nerve impulses. These new models will deviate from the traditional Hodgkin-Huxely framework, rather they will derive from a Markovian modeling scheme that is based on channel structure and known conformation states in which channels reside in response to changes in membrane potential. This new approach allows for inclusion of genetic defects that disrupt discrete transitions between conformations. The long-term goal in the laboratory is to improve understanding of the underlying ionic mechanisms of excitable systems and to determine how genetic defects in ion channels may disrupt the balance of membrane ionic currents at the cellular level. The ultimate intent is to then relate these abnormal cellular manifestations to clinically observed disease phenotypes. http://physiology.med.cornell.edu/faculty/clancy/index.html
