Aortic Aneurysm Formation

Background

Aortic aneurysms comprise the 10th leading cause of death accounting for more than 16,000 deaths yearly. To date, there have been no medical therapies proven to prevent or treat aortic aneurysms. Thus, understanding molecular mechanisms for this disease are critical to developing novel treatment strategies. The majority of laboratories investigating aortic aneurysms have focused on leukocyte infiltration and MMP production, while little is known about the role of smooth muscle cells (SMCs). Early in the course of aneurysm formation, SMCs undergo proliferation; however, in maturing aneurysms, smooth muscle cells (SMCs) undergo apoptosis, thereby eliminating cells that are the primary source for the extracellular matrix. There is significant data to suggest SMCs are plastic and have the ability to undergo phenotypic switching in response to environmental cues. One of our goals is to identify SMC phenotype during aneurysm formation. Of major significance, studies in our lab are determining the role of IL-1 induced changes in SMC gene expression as well as direct assessment of the role of IL-1 signaling in SMC phenotypic switching in vivo during aneurysm formation using a variety of unique transgenic and knockout mice developed in the mentor's laboratory. Further experiments include the use of a conditional KLF4 KO mouse, a downstream effector of IL-1 developed by the mentor to determine the mechanisms by which IL-1 exerts its effects. With expanded knowledge of the regulators of SMC phenotype in aneurysm formation, these experiments may lead to novel therapies to alter SMC phenotype, cease degradation of the aortic wall, and remodel the aortic wall matrix.

Basic Science Model

We utilize a murine model of elastase perfusion of the abdominal aorta to develop aneurysms. Several unique transgenic and conditional knockout mice are being studied through close collaboration with Dr. Gilbert Upchurch and Dr. Gary Owens, Chair of the Cardiovascular Research Center at the University of Virginia and also a mentor on our program.

More information on our aortic aneurysm research can be found on our Aortic Aneurysm Formation website.