Grant: Banting Postdoctoral Fellowship Program

Cardiac arrhythmias are electrical disturbances in the heart which can cause a wide variety of potentially life threatening conditions. Antiarrhythmic drugs that target a particular type of protein called an ion channel are useful in converting these irregular heart rhythms back to a normal beating, substantially enhancing the quality of life of patients. Unfortunately, many available anti-arrhythmic drugs have serious side effects. Nor do we know what chemical characteristics make a good/safe anti-arrhythmic drug, making it difficult to engineer the next generation of life saving cardiac drugs. We therefore aim to better understand the basic mechanisms of action of anti-arrhythmic drugs. This is highly relevant because cardiac arrhythmias are on the rise in our aging population and can lead to either increased chance of stroke or, in the case of heart failure, sudden death. The proposed experiments aim at filling crucial gaps in our understanding of how anti-arrhythmic drugs regulate heart function. We have recently made significant progress by combining cutting edge chemical methods with computer modeling to define the essential characteristics of what makes a "good" anti-arrhythmic drug. Our next goal is even more important, as it aims at defining the precise nature of their receptor in the heart through which they modulate electric excitability. For this purpose, we will employ novel fluorescent probes to give us insights into the atomic level movements of the receptor during drug binding. All of the technologies used here have been tested in other relevant systems but never for this purpose, thus placing us in a unique place to make substantial contributions to the field of cardiovascular pharmacology. Previous technical shortcomings have served slow progress in this clinically relevant area of research and it is our goal to break past these limitations and enhance our comprehension of these electric disturbances in the heart.