Abdominal Aortic Aneurysm (AAA) results in significant morbidity and mortality in upwards to 15,000 patients in the United States. No effective pharmaceutical intervention exists and treatment is limited to surgical intervention at the point of maximal expansion. The pathogenesis of this disease is poorly understood, making development of pharmaceutical intervention difficult. The protein fibrinogen, an important participant in hemostatic, inflammatory and wound-healing processes, is known to be elevated in AAA patients. However, this observation has not been adequately investigated, and no mechanism to explain this elevation has been experimentally identified. Work performed in our lab has demonstrated that depletion of fibrinogen in a mouse model successfully attenuates an accepted animal model of AAA, and decreases inflammatory cytokines. However, the molecular mechanism(s) responsible for fibrinogen mediated AAA pathogenesis remains unclear. As such, understanding the molecular mechanism(s) responsible for fibrinogen depletion attenuating AAA could lead to novel therapeutic strategies in AAA. The primary goal of this proposal is investigate the mechanisms by which fibrinogen contributes to AAA pathogenesis. Specifically, we will study how macrophage binding with fibrinogen contributes to AAA pathogenesis, and how fibrin clot structure and accompanying fibrinolytic resistance contributes to AAA pathogenesis. We hypothesize that fibrinogen deposition into AAA accelerates aneurysmal growth by increasing the activation of coagulation and inflammation. This hypothesis will be addressed with two specific aims and several unique mouse models. In these aims, we will assess the influence of fibrinogen on AAA through hemostatic action via analysis of fibrin clot structure and factor XIII (FXIII;
aim 1) and inflammatory action via deletion of the macrophage binding site in the fibrinogen gamma chain (aim 2). The long term objective of this work is to identify a role for fibrinogen in this disease process. If successfully completed, identified a mechanism to explain fibrinogen elevation in AAA patients. The outcomes from the proposed studies are expected to have also significantly advanced our current knowledge of AAA pathogenesis, and have a positive impact on our ability to identify possible targets for AAA therapy. This fellowship grant will also train the principle investigator in molecular biology and functional genomics in order to establish a research career in the field.
RELEVANCE TO PUBLIC HEALTH Abdominal Aortic Aneurysm (AAA) is an often fatal cardiovascular disease which leads to mortality in approximately 15,000 Americans per year. Unfortunately, no effective pharmaceutical treatments for AAA currently exist and the only available treatment is surgical intervention. This study seeks to understand the contribution of the clotting protein fibrinogen to AAA pathogenesis, and determine if targeting fibrinogen is a viable target for AAA therapy.
