Mechanosensitive adaptor proteins in vascular pathology

The flow of blood through an artery exerts the frictional force of fluid shear stress on the underlying endothelial cells (ECs). Depending on vessel geometry, shear stress can be laminar (LSS) or oscillatory (OSS). While the former is protective, the latter results in upregulation of inflammatory markers and triggers atherosclerosis. Our current understanding of how ECs sense and respond to flow is rather rudimentary. I hypothesize that the ability of ECs to respond to flow relies on mechanosensitive adaptor proteins. In this application, I propose to study the effects of over-expressing mechanosensitive adaptor protein mutants in the mouse aorta, and examining effects on inflammation and atherosclerosis. I propose to do this using a novel AAV-based gene delivery system that specifically targets the endothelium, and upon development, will be a valuable new tool available for investigators within the Oxford BHF-CRE.