Grant: Doctoral: Vanier Canada Graduate Scholarships

Cardiovascular disease is the second leading cause of death in Canada. Patients with coronary artery disease are treated through percutaneous coronary intervention (PCI) or through bypass surgery. One of the major complications of PCI involves blood clot formation at the site of intervention. To prevent blood clots, two anti-platelet therapies are given in the form of aspirin and a P2Y12 inhibitor (receptor on platelets) after treatment. However, this dual anti-platelet therapy regime appears to function poorly in diabetic patients. Also, diabetic patients are known to have hyperactive platelets and increased chance of blood clot formation. Currently, the reason why diabetic patients have higher platelet reactivity than their non-diabetic peers is poorly understood. One protein of interest is plasminogen activator inhibitor 1 (PAI-1 or SERPINE1), which is responsible for inhibiting the breakdown of blood clots in the body. Resistance to existing anti-platelet therapy could be due to high levels of PAI-1 in diabetic patients. As a result, this proposal seeks to identify the reason for the elevated level of PAI-1 expression in diabetics. It is of utmost importance to understand why diabetic platelets express more PAI-1 than non-diabetic platelets as this protein may contribute to resistance to current medicine. The goals of this project involves understanding the molecular basis of PAI-1 expression and to develop new potential therapies to specifically target PAI-1. In addition, novel therapies could be developed and tested in diabetic animal models. The knowledge gained from understanding the regulation of PAI-1 expression is important to the research community, as it may serve as a blueprint to develop novel inhibitors. In the future, these inhibitors may be developed into new drugs to decrease hyperactive platelets in diabetic patients undergoing PCI to reduce adverse events after the procedure to reduce mortality.