Grant: Project Grant

Apart from the thousands of people who die suddenly of disordered heart rhythms every year, there are genetic diseases that cause serious heart rhythm disturbances, which affect the everyday lives of 1:2000 of the population, so about 20,000 Canadians. This research will help us understand the underlying properties of an ion-conducting protein in the heart that is responsible for some of the most common forms of inherited arrhythmias, and some cases of atrial fibrillation. By better understanding how the ion channel protein works normally and in disease, in the future we expect to design drugs to treat these chronic disease states, acute disorders of rhythm, and causes of sudden death. Many people need to wear implantable defibrillators, or take drugs to suppress their arrhythmias. This work is the first step towards developing more specific therapies to treat these heart conditions. We identified an important set of clinical cases where mutations in a specific region of one of the ion channels responsible for normal heart rhythm, called IKs, cause clinical arrhythmia syndromes. We will understand how and why these mutations cause disease by finding out at the molecular level what makes the channels less effective than they should be, or more effective than they should be. Both circumstances can have deleterious effects on stable heart rhythms. The genes for the channels will be expressed and particular structural features will be changed to mimic the effect of the arrhythmia disease. The modified channels will be studied electrically using micro-electrodes and advanced microscopy to determine exactly how different parts of the channels interact in the normal situation and in the presence of the arrhythmia-causing mutations. Advanced computer modeling will be used to understand results and gain insight into how the channel complexes normally work, and how this is modified in the disease-causing mutants.