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

Aortic aneurysm is a common age-related disease caused by progressive weakening of the vessel wall and is frequently observed as a severe complication of atherosclerosis. Incidence has been reported to be as high as 9% of the population over 65. 80% of aortic aneurysms occur in the abdominal region of the aorta and are often asymptomatic until rupture occurs. Although rupture carries a 90% rate of mortality, there are currently no therapeutic options available to prevent the development of aneurysms apart from surgical procedures that also entail significant risk of death. The exact mechanism for aneurysm development is as yet unclear; however, we believe we have identified a novel enzyme involved in the development of abdominal aortic aneurysms (AAA). Previous work in our laboratory has demonstrated that granzyme B (GrB) deficiency can reduce the incidence of AAA from 86.7% to 33.8% in mice. GrB is an enzyme more commonly recognized for its role in the immune process of programmed cell death but is also becoming known for its ability to degrade targets outside the cellular environment. Both mechanisms can potentially result in considerable loss of structural integrity, predisposing the vessel to dilation under stress and subsequent rupture. The current proposal aims to determine the mechanism by which GrB contributes to the development of AAA as well as to test the efficacy of GrB inhibition as a means of preventing aneurysm growth and rupture. The results of these studies will help us establish the role of GrB in AAA and whether GrB inhibitors could be employed as a therapeutic strategy for patients identified to be at high risk for developing aneurysms or aortic rupture. As aneurysms are primarily an age-related disease, the incidence of AAA will only continue to grow with the aging populations of the developed world, highlighting the need for better understanding of this disease and the necessity of a therapeutic strategy to reduce the burden of AAA on society.