• March 2006 - Current, Postdoctoral training, Biomedical Sciences,  Cornell University, Ithaca, NY
• May 2006 , Ph.D., Mathematics,  University of Utah, Salt Lake City, UT
• August 1990, M.S., Mathematics,  Korea University, Seoul, South Korea
• February 1988, B.Sc., Mathematics,  Korea University, Seoul, South Korea

CV
Publication

Research Area: Ca²⁺ signaling in cardiac cells

Cardiac cell image (Lee 2007)

1.  Ca²⁺signaling in cardiac Purkinje cells
The Purkinje network is believed to contribute importantly to the genesis of ventricular arrhythmias through a variety of mechanisms, including the generation of period-doubling bifurcations (Gilmour et al.,1997). Despite of  its important role in cardiac arrhythmogenesis, not much information is known about EC coupling in Purkinje cells. Therefore I study how electrical stimulation activates Ca²⁺ release, how Ca²⁺ wave propagates in Ca²⁺ overload, and how Ca²⁺ alternans arises.  

2.  Ca²⁺ wave propagation
Calcium (Ca²⁺) waves in cardiac cells are usually found under Ca²⁺ overload conditions and might cause cardiac arrhythmias. Ca²⁺ waves are initiated at local discrete Ca²⁺ channels on the sarcoplasmic reticulum and spread to neighboring channels mediated by the regenerative process of Ca²⁺-induced Ca²⁺ release. To understand the roles of Ca²⁺ waves, we simulated one-dimensional reaction-diffusion model of Ca²⁺-induced Ca²⁺ release. This model showed that alternating patterns of Ca²⁺ wave propagation can occur with periodic Ca²⁺ stimulation under condition of Ca²⁺ load above a threshold level. The follwoing figure shows an alternating pattern of Ca²⁺ wave propagation.

Simulation result of CICR model (Lee and keener)

3. Mechanism of  alternans Ca²⁺
With periodic stimulations cardiac cell shows the corresponding electrical (action potential), chemical (Ca²⁺ concentration), mechanical (contraction) rhythms. Low-frequency stimulation leads to a uniform patterns of these three rhythms, but high-rate stimulation can induce an alternating shape of each rhythm. This is called cardiac alternans, which was first introduced by Trube in 1872. Since then, cardiac alternans have become an important problem because these phenomena are often observed in heart diseases before these are tranferred to cardiac arrhythmias. Despite its importance of the problem, the underlying mechanism of cardiac alternans is not well understood.To understand the underlying mechanism of alternans, we constructed a mathematical model by an assumption that fractional SR Ca²⁺ release is a steeply increasing function of SR Ca²⁺ content, based on the data of Shannon et al 2004. This model shows that a reduced SR Ca²⁺ release increases the SR content unitl it reaches the threshold level, and then Ca²⁺ cycling becomes unstable. The following figure illustrates that period-doubling (alternans) becomes chaotic as the slope of the steepness of SR Ca²⁺ release increases.

Period-doubling bifurcation of discrete model (Lee and keener)

4. Regulation of RyR channel
We developed a kinetic model of RyR which has three binding sites two cytosolic sites for Ca²⁺ activation and inactivation, and one SR luminal site for CSQ binding. The RyR kinetic model was incorporated into a local CICR model that has both a diadic space and junctional SR (jSR). This model suggests that CSQ plays an inhibitory role of RyR gating at low jSR load through more CSQs binding to RyR. In addition, this local CICR model produces a nonlinear fractional relation of jSR Ca²⁺ release on jSR load. The following figure describes local CICR model based on the idea of Rice et al 1999.

Local control CICR model adapted from Rice et al 1999