Explore small conductance calcium activated (SK) channel pharmacology in cardiomyocytes and cardiac tissue
Propagation of the electrical signal through the heart is mediated by ion channels. The different types of ion channels form a complex and sensitive sequence of events ultimately resulting in a heart beat. In atrial fibrillation (AF), the healthy heart rhythm is overruled by arrhythmic, disorganized electrical impulses from the atria which decrease cardiac function and increase risk of stroke. With increasing prevalence of AF in the general, but especially in older population, there is an unmet need for safe and efficient treatment options.
The small conductance calcium-activated potassium (SK) channel contributes to atrial repolarization and has an implicated role in onset and progression of AF.This suggests SK channels as a promising target in AF treatment. However, the effect of SK modulation on human electrophysiology is complex and knowledge is limited. Physiological experiments are limited by technical and ethical boundaries, and are therefore insufficient in bridging the gap across scales and translation to humans. Instead, an integrated approach of patch clamp experiments and biophysical modeling is required to unravel the complexity and potential of SK channel pharmacology in AF treatment.
Computer models can help understand the mechanisms and specific conditions to be met for maximum efficacy of compounds targeting SK channels. A recently developed Markov model of SK channel gating (based on detailed experimental data) will provide the basis for implementation of the SK channel in cell and tissue models of the heart. This project will combine the new Markov model of the SK channel with existing ordinary differential equation (ODE) models of the cardiomyocyte membrane. The effect of SK channels in the onset and progression of AF will be assessed with arrhythmic biomarkers and extended with simulating pharmacological profiles of compounds targeting SK channels.
The goal of this thesis is to unravel the effect of SK channel and pharmacological block on human heart models in healthy and atrial fibrillation affected heart.
- Gain understanding of cardiac electrophysiology and pharmacology
- Gain experience with modelling cardiac cells and tissues using ordinary differential equations (ODE)
- Work in an interdisciplinary field, gaining experience with physiology, pharmacology and computational modelling
The master’s student will ideally have:
- Completed a bachelor’s degree in informatics or a related discipline
- General programming skills, preferably python
- Familiarity with version control system such as Github
- Exposure or interest in interdisciplinary work in biophysics, human physiology and/or pharmacology
- Main supervisor: Ilse van Herck