Bicuspid aortic valves (BAVs) are the most prevalent congenital heart defect in adults, affecting around 2% of the global population and causing more fatalities and complications than all other congenital heart abnormalities combined. Patients with a BAV are more prone to have ascending aortic dilatation (AAD) which increases their risk of dissection or rupture. It is still uncertain whether bicuspid aortopathy is caused by hereditary factors or aberrant hemodynamics, though both structural integrity impairment and shear stress overload on the aortic wall are likely involved. My project aims to investigate these two factors in order to acquire a better understanding of the disease progression of BAV-AAD. By measuring proteomic perturbations in previously established in vivo models, I hope to confirm that C-type natriuretic peptide (CNP) serves in a protective role, and identify novel targets involved in flow regulated AAD development. In vitro experiments will also be performed to investigate how disturbances in shear stress due to a BAV affect aortic endothelial cell function. By combining these approaches, and obtaining expert clinical perspectives to ensure translational relevance of my work, I hope to ultimately identify biomarkers for risk-stratification and discover new therapeutic targets for improved medical management of the millions of at-risk BAV patients.