Lisa Ang

2008 Research Trainee Award, Junior Graduate Studentship

The extracellular role of Granzyme B in abdominal aortic aneurysm

An aortic aneurysm is a swelling of the aorta, the body’s largest blood vessel, caused by progressive weakening of the vessel wall. Aortic aneurysms are frequently observed as a severe complication of atherosclerosis (narrowing and hardening of the arteries). Incidence of these aneurysms has been reported to be as high as 8% in men over 60 and 1.5% in women in the same age category. 80% of aortic aneurysms occur in the abdominal region of the aorta and are often asymptomatic until rupture occurs. Although rupture carries a 90% mortality rate, there is currently no therapeutic strategy available to prevent the development of aneurysms or to halt the growth of aneurysms following diagnosis. The only treatment options currently offered, apart from intensive monitoring, involve surgical procedures that also entail significant risk of death.

The exact mechanism for aneurysm development is unclear, but a novel protease (enzyme) involved in the pathogenesis of abdominal aortic aneurysms (AAA) has been identified. Previous research has demonstrated that a deficiency of Granzyme B (GrB) in hyperlipidemic mice (with elevated lipid levels) reduces the incidence of AAA from 86.7% to 33.8%. GrB is an enzyme more commonly recognized for its role in initiating programmed cell death during development as well as in viral-infected cells, tumours and other instances of severe cell damage. GrB is also becoming known for its ability to degrade targets outside the cellular environment that can lead to increased inflammation and scarring of the vascular wall. Both mechanisms can potentially result in considerable loss of structural integrity, predisposing the vessel to dilation under stress, leading to aneurysm and subsequent rupture.

Lisa Ang is researching the mechanism by which GrB contributes to the development of AAA. She is also testing the effectiveness of inhibiting GrB as a means of preventing aneurysm development, growth and rupture in a mouse model. Results of these studies will help establish the role of GrB in AAA and determine whether GrB inhibitors can be employed as pre-emptive treatment for patients identified to be at high risk for developing aneurysms.

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