Matrix Metalloproteinases in Thoracic Aortic Dissection

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DESCRIPTION (provided by applicant): My major goal is to develop research skills through a mentored training program that will lead to independent translational and clinical research focusing on the treatment of thoracic aortic dissection. Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins, such as elastin and collagen, and play a key role in cardiovascular disease. Accumulating data demonstrates that MMPs are involved in the pathogenesis of aneurysms of the abdominal aorta, intracranial vessels, and coronary arteries. More importantly, both animal experiments and clinical trials have shown that MMPs are promising targets in the prevention of abdominal aortic expression. In contrast, little is known about the role of MMPs in thoracic aortic dissection. Based on preliminary data from our laboratory, our central hypothesis is that MMP-9 plays an important role in aortic degeneration after dissection and represents a potential target for therapeutic intervention. The data gathered from the proposed study will represent the first step in developing clinical trials for pharmacologic prevention of aortic expansion and rupture in patients with thoracic aortic dissection. The specific aims of this project are: 1) to determine if overexpression of MMP-9 within aortic wall tissue coincides with the progression of thoracic aortic degeneration and aneurysm formation in patients with aortic dissection; 2) to explore the hypothesis that functional genetic variants within the MMP-9 gene contribute to MMP-9 overexpression, which in turn causes thoracic aortic degeneration and aneurysm formation in patients with aortic dissection; and 3) to investigate our hypothesis that MMP-9 overexpression is a key step in thoracic aortic aneurysm formation and rupture in a mouse model of aortic dissection. Support of this application for the K08 award at this stage of my career will be invaluable, as it will allow for the development of a solid foundation for future independent translational research in the treatment of thoracic aortic dissection.