Mechanisms of Abdominal Aortic Aneurysm Formation

This amended PPG application is designed to provide mechanistic insight into the mechanisms involved in the initiation and propagation of abdominal aortic aneurysms (AAAs). Projects will use a model of AAA in which angiotensin II will be infused into hyperlipidemic mice. This was described originally by faculty who are Project Leaders in this application. This model has now been adopted widely in both academic and pharmaceutical research programs. Many characteristics of the model reproduce features of the human disease, including the strong gender specific prevalence in males. Studies on the cellular sequence of events in the development of AAAs demonstrate the involvement of inflammation cells at all stages of development. Four projects and 5 core facilities are proposed. This brings together a group of faculty who has interacted for several years. The synergy of their interactions is demonstrated by the multiple joint publications and co-investigator status on grants. These projects and cores have been designed to provide mechanistic insight into the development of AAAs in the following areas: Project 1 (Lisa A. Cassis) will study the role of androgens and androgen receptors in defining the gender specific effects. Project 2 (Alan Daugherty) will determine the role of smooth muscle cells specific AT1a receptors in the mechanisms of AAA initiation. Project 3 (Fred C. de Beer) will determine the role of serum amyloid A and its interaction with selected matrix metalloproteinases. Project 4 (Nancy R. Webb) will determine the role of specific isoenzymes of secretory phospholipases. These projects will be supported by Cores of: A. Administration. B. Human studies. C. Quantitative pathology. C. Mouse maintenance.