Grant: CIHR Clinician Scientist - Phase 1

Heart failure is a major problem in people who have had heart attacks or who suffer from other diseases affecting the heart. People with heart failure cannot pump enough blood forward to meet the metabolic needs of the body. The back pressure from the pump failure also causes fluid to collect in the lungs and the rest of the body, making it difficult to breathe and to move. Understanding heart function at the molecular level is essential to developing new drugs to prevent and treat heart failure. Some drugs reduce the stress on the heart. Others help the heart to pump harder. All drugs work by binding to proteins to change how they function. Proteins are the molecular machines that carry out all biological functions. Two proteins important to heart function are called troponin I and troponin C. Troponin I prevents the muscle cell from contracting when it is not supposed to. (The "I" is for inhibition.) When a muscle cell receives an electrical signal telling it to contract, the signal causes calcium channel proteins to open, flooding the cell with calcium. The calcium binds to troponin C (the "C" is for calcium). This triggers a conformational change in troponin C so that it neutralizes troponin I and allows heart muscle contraction to occur. Nuclear magnetic resonance (NMR) spectroscopy is a powerful technique that allows scientists to "see" proteins at the atomic level. We will use NMR to visualize the complex between troponin I and troponin C. When the body becomes stressed, adrenaline causes the heart to pump harder. One of the ways this happens is troponin I becomes "phosphorylated" - this means that extra phosphate groups are attached to it. We will also use NMR to see how phosphorylation affects the troponin I - troponin C complex and how this changes heart function.