Grant: Project Grant

Healthier nutrition and lifestyle, along with cholesterol-lowering drugs (statins) have lowered the rates of heart disease in Canada, yet it is still a major health concern and the second leading cause of death. Our research is focused on understanding how the metabolism of cells important for heart disease can control how it starts and worsens. Metabolism and the immune system are tightly linked, and both are critical in heart disease. At the cellular level, there are master regulators of metabolism that can turn on or off cellular programs very quickly. Two important proteins that do this are AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1). In general terms, when there is lots of energy (after a meal), mTORC1 controls several cellular programs that are geared toward using and storing the energy. On the other hand, when energy is low (fasting or during exercise), AMPK is turned on works to preserve and bring in more energy. Both proteins can control dozens of pathways and proteins, they can also signal to block each other in a type of metabolic teeter-totter. During atherosclerosis, which is the buildup of plaque in the arteries, mTORC1 and its activity is high, whereas on the other side of the coin, AMPK and its activity are low. We have genetically engineered mice to be completely normal in every way, except for the specific points of communication that allow AMPK to block mTORC1. Using these mice, we have seen that when AMPK cannot put the break on mTORC1 and the cellular programs it controls, there are differences in key immune cell populations (both in number and how they act), which we think leads to more atherosclerosis. By understanding how these important pathways effect the early and later stages of heart disease, and how this might be different in males and females, we can potentially fine-tune or make new drugs that will further help affected Canadians.