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

Heart disease is one of the leading causes of death in North America. The major clinical features of heart disease have been well documented but there is a great need for understanding the molecular determinants of heart failure. In 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 which causes muscle contraction. For muscle relaxation to occur, calcium is transported back to the SR. The major protein responsible for muscle relaxation in the heart is the sarcoplasmic reticulum calcium pump (SERCA) that is reversibly inhibited by two small membrane proteins called phospholamban (PLB) and sarcolipin (SLN). In a healthy heart, PLB and SLN are regulated in a process that causes them to dissociate from SERCA. This dissociation is acheived by an increase in the amount of calcium in the SR, which in turn increases the rate of beating and force of contraction in the heart. In a failing heart, this process is greatly impaired, causing a decreased pumping force in patients. Recent studies have shown abnormal SERCA activity and regulation in early stages of heart disease. Several genetic mutations in PLB have already been found to cause lethal dilated cardiomyopathy, and it is likely that mutations will be found in SLN that similarly cause heart failure. My research will focus on studying the mechanism of interactions between SERCA and SLN. First, I will systematically study the different mutants of SLN in hopes to identify possible heart disease causing mutations. Second, I hope to use electron microscopy to obtain structural information on the complex formed by SERCA and SLN. If the interaction between SERCA and its endogenous peptide regulators is better understood at a molecular level then it will open the door to a new understanding and treatment of heart failure.