Kit Parker

Associate Professor of Biomedical Engineering

My research team’s focus is on understanding cellular mechanotransduction in the heart. Specifically, we are interested in how extracellular matrix and cytoskeletal architecture potentiate and modulate the activation of mechanochemical and mechanoelectrical signaling pathways and genetic programs in cardiac cells and tissues. In order to study these mechanisms at different spatial scales, we use cellular and tissue engineering techniques that allow us to build custom-designed cardiac myocytes and ventricular tissue constructs as experimental preparations.

Why are we interested in this problem of biological scaling in the heart?
The Cardiac Arrhythmia Suppression Trial (CAST) of the late 1980’s was a clinical trial designed to test the hypothesis that suppression of premature ventricular contractions (PVC) with Class I antiarrhythmics (blockers of excitatory sodium currents) would reduce arrhythmic death risk. The trial was ended prematurely by the FDA when the mortality rate of those patients on encainide and flecainide, the Class I drugs studied, nearly quadrupled the mortality rates of those patients on placebo. Subsequent studies of antiarrhythmic drugs indicate that drugs that alter ion channel kinetics often show little or no benefit in the suppression of ventricular tachycardia and ventricular fibrillation. To date, there is no clinically reliable means of treating cardiac arrhythmias medicinally.

How are we approaching this problem?
We hypothesize that single channel blockade antiarrhythmic strategies were inherently flawed because they target a single scale (molecular level) without considering the fact that the pathogenesis of arrhythmias transcends multiple levels of integration, i.e., it is a multiscale problem. We propose that increasing the spatial scale of the drug target search, from single proteins to protein networks, will result in the development of more effective antiarrhythmic medicinal therapies. Thus, we take a multiscale approach, by targeting several spatial magnitudes simultaneously. At the length scale of a single cell, we study the cytoskeletal networks that span the entirety of the cardiac myocyte and modulate the kinetics of many of the more than half dozen ion channels that contribute to the cardiac action potential. More specifically, we investigate 1) how the cardiac myocyte cytoskeleton self-assembles; and, 2) the role of cytoskeletal architecture modulating action potential morphology and calcium metabolism. In tissue-scale studies, we investigate cell ensembles and correlate their behavior to larger tissue and whole heart function. Cell-cell mechanocoupling, via cell adhesion proteins and extracellular matrix, undoubtedly contributes to the electrical synchrony amongst cardiac myocytes. Here, more specific studies are directed towards investigating how the mechanical continuity amongst cardiac myocytes modulates electrical excitability and may contribute to the wavebreaks that mark the transition from ventricular tachycardia to ventricular fibrillation.

See Also: Personal Link
See Also: Parker Lab: Disease Biophysics Group