Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

In Canada, one in three deaths is caused by stroke or heart disease. The major clinical features of heart disease are well documented but little is known about the molecular changes that occur at the onset of disease. Inside the cells of the heart, there is a calcium storage compartment called the sarcoplasmic reticulum (SR). During a single beat of the heart, calcium is released from the SR to trigger muscle contraction and calcium is restored to the SR for muscle relaxation. One of the major proteins in the heart that is involved in muscle relaxation is the sarcoplasmic reticulum calcium pump (SERCA). A small membrane protein called phospholamban (PLB) interacts with SERCA and inhibits calcium pumping. When we experience a "rush of adrenaline", PLB is regulated in a process that causes it to dissociate from SERCA. This is followed by an increase in the amount of calcium available in the SR, which in turn increases the rate of beating and force of contraction in the heart. In heart disease, this process is significantly impaired, causing the decreased pumping force normally observed in patients. Inherited mutations in PLB that cause heart disease have been identified and initial research has suggested mechanisms by which they act, but a comprehensive study is needed. To address this issue, my research will have two main lines of investigation. First, I will study the residues that are important in the phosphorylation and dephosphorylation of PLB. By studying a series of mutations of PLB, I hope to better understand the disease-causing mutations. Second, since PLB is phosphorylated when it is bound to SERCA, a supramolecular complex must be formed, which I hope to solve using electron microscopy. The inherited forms of heart disease can provide insight into potential events that distinguish normal from impaired cardiomyocyte performance, and if we understand heart disease at a molecular level we have a better chance of halting the progression of the disease.