Grant: Doctoral Research Award: Canada Graduate Scholarships

Healthy, normal human hearts rely on extremely regulated relaxation and contraction cycles. A healthy heart has steady and even heartbeats, i.e., normal cardiac rhythm. These beats are tightly controlled by passages, called ion channels, which regulate certain molecules such as sodium ions and potassium ions. Sometimes, heartbeats and ion channels are unbalanced, from drugs or mutations, triggering irregular cardiac rhythms. Irregular cardiac rhythms may cause serious disorders such as stroke and sudden death. Longer than normal beats result in arrhythmias - long QT syndrome (LQTS). Shorter than normal beats result in atrial fibrillation or short QT syndrome (SQTS). These heart diseases kill between 25% and 33% of all men and women, respectively, between 30 and 70 years of age in the developed world. We need more knowledge on how ion channels properly operate, how to correct abnormalities, and thus treat these serious heart disorders. I hypothesize that certain drugs activate and can fix abnormal channels and that the structure and function of these channel changes can explain healthy and diseased hearts. Recently, our group was the first to fully describe how one specific drug is bound in these channels. I will use modern molecular and biophysical techniques to investigate the effects of select drugs on both frog oocytes and relevant human cardiac cells. Notably, I will use the state-of-the-art cryo-electron microscopy technique to characterize the structure of ion channel channels in detail. The genes for these channels will be expressed and particular structural features will be changed to mimic the effect of LQTS and SQTS diseases and the gold standard patch clamp technique to examine their function. The results will allow us to construct models of both healthy and diseased heart function. Our experiments will contribute to the knowledge base of how the heart works in health and disease and will help to define optimal treatment strategies.