Stephanie Thuy Duong Pham - PhD Scholarship 2022

Project summary:
Does kallistatin polymers and the contact activation system cause abdominal aortic aneurysm progression?

Abdominal aortic aneurysm (AAA) is a life-threatening and often asymptomatic disease with challenges of early diagnosis. Hence, identifying therapeutic targets and molecular mechanisms, underlying the pathogenesis of AAA, are needed. Previous studies show that the contact activation system (CAS) is linked to AAA. This project focuses on the CAS-inhibitor kallistatin, which belongs to a protein group known to polymerize in certain diseases. Our aim is to examine the effect of kallistatin polymers on CAS and AAA progression.

Project title

The role of kallistatin and the contact activation system in abdominal aortic aneurysms

Background

Abdominal aorta aneurysm (AAA) is a permanent and specifically localized dilation of the abdominal aorta. Rupture of AAA is associated with life-threatening internal bleeding, causing mortality in up to 85% of the cases. Currently, there is no medical treatment for AAA. This clearly emphasizes the need of identifying new therapeutic targets. Our pre-liminary experiments suggest a novel link between AAA and the contact activation system (CAS). Growing evidence has shown that especially serpins are a target for protein polymerization, often associated with disease, due to their involvement in important biological regulatory processes. This project focuses on the serpin and CAS-regulator kallistatin as a target of protein polymerization and its role in the disease AAA.

Aim and methods

The overall aim of this project is to identify molecular mechanisms that underlie the pathogenesis of AAA, with focus on the role of CAS and polymerized kallistatin. The project combines both advanced in vitro molecular and cellular studies with translational studies where unique human blood and tissue samples from patients with AAA are analyzed, aiming to evaluate CAS-proteins as potential biomarkers for disease progression.