Grant: Project Grant

Aortic aneurysm (focal dilation of the aorta) is a serious vascular disease and a great health concern with fatal or devastating outcomes. Aorta is the largest artery in the body which carries the blood from the heart to the rest of the body. In aortic aneurysm, an area of the aorta becomes enlarged (bulges out). The wall of the aorta loses its elastic property (like an old rubber band) and unable to squeeze the blood along (forward) to different body parts/organs. When an old rubber band is subjected to high pressure (blood pumped from the heart), it can snap (i.e. aortic rupture) which results in a large amount of blood loss which can often result in death (if in the chest), or lower body paralysis (if in abdominal area). So far, there have been no treatment for this devastating disease. ADAM17 is a an enzyme located in the cells withing the aortic wall. It can clip membrane-bound molecules and release them initiating (or inhibiting) their activity. ADAM17 is increased in the aortic wall during aneurysm formation, but it is unknown whether it contributes to disease progression, or if it is simply a by-stander. In addition, it could have different functions in the thoracic versus the abdominal aorta. Our lab is among the few labs (world-wide) that has developed models of aortic aneurysm (in thoracic and in abdominal aorta, independent from atherosclerosis). We will use genetically modified mice that with cell-specific ADAM17-deficiency (in smooth muscle cell or endothelial cells) and models of thoracic and abdominal aortic aneurysm to determine the role of ADAM17 (in different cell types in the aorta) in aortic aneurysm formation and progression. We will use aorta specimens from patients with aortic aneurysm to confirm our findings from our mouse models. The findings from this study will reveal novel function of ADAM17 in aortic aneurysm which can also be beneficial for patients with other aneurysms (e.g. brain aneurysm & stroke).