of Candidates Immediate and Long-term Goals. My immediate goals are to continue my postdoctoral training under the mentorship of Dr. Nigel Mackman, an expert in the field of coagulation and thrombosis. I still have much to learn from Dr. Mackman regarding the function of tissue factor in vascular disease. I would also like to advance my skills as a research scientist in the academic field and publish my remaining projects from my current F32 NRSA grant and, if awarded, the K99 studies proposed in my grant. My long-term and ultimate career goal is to become a respected academic scientist whose research is focused on understanding the initiation and progression of cardiovascular disease with a focus on abdominal aortic aneurysm. Like every other scientist, I hope to one day find an effective treatment to alleviate the suffering of multitudes of patients afflicted with diseases and prolong the quality and duration of life. In addition, I look forward to teaching and mentoring young scientists to instill the techniques, knowledge, and skills that have been taught to me and propagate the continued cycle of academic mentorship. Summary of Key Elements of Research Career Development Plan. During the duration of this training program, I will attend regular lab meetings to discuss pertinent data and literature with my group. In addition, I will be expected to present my research to the division at least once a year for criticism and feedback. In order to increase my knowledge in the field of vascular biology and pathology in cardiovascular disease, I will audit several courses at the UNC-CH. I will also attend several seminars both on and off campus to strengthen both my writing and leadership skills. UNC-CH has several weekly and monthly seminars by experts in the field, which I will attend. I will continue to travel to scientific conferences to present my data and interact with the scientific community. Finally, I will meet with my mentor, during the K99 phase, on a weekly basis to discuss my results and the future direction of my research. Project Abstract. Abdominal aortic aneurysm (AAA) affects 5-10% of the male and females over the age of 65 and is the 13th leading cause of death in the United States. AAA, defined as a permanent localized dilation in the arterial wall with a diameter greater than 50% of normal, is an inflammatory disease of the aorta that can result in dissection of the wall, formation of an intramural clot, and rupture of th aorta resulting in almost immediate death in the majority of cases. Importantly, the role of the intramural clot in the etiology of AAA remains poorly explored. We will test the general hypothesis that formation of an intramural clot stabilizes AAAs. Specifically, I will investigate te roles of tissue factor (TF), thrombin, platelets, and protease activated receptors (PARs) in the formation and progression of AAAs. We will utilize the angiotensin II (AngII) LDLr-/- mouse model of AAA. We will use both genetic and pharmacologic approaches to modulate the expression and activity of different proteins and determine the effect on AAA. My proposal is divided into three aims, the first being mentored and the last two being independent.
Aim 1 will determine the role of TF in AngII-induced AAA progression and rupture. We hypothesize that decreased TF coagulant activity will reduce clot formation that promotes AAA rupture, and reduced TF and PAR-2 expression by vascular smooth muscle cells (VSMCs) will result in expansion of AAAs due to reduced VSMC migration.
Aim 2 will determine the role of thrombin and the downstream effectors fibrinogen and PAR-1 in AAA. We hypothesize that fibrinogen deficiency and anticoagulant therapy will decrease clot formation and lead to an increase in AAA rupture and, that PAR-1 deficiency will increase AAA due to decreased VSMC migration.
Aim 3 will examine the role of platelets and the thrombin receptor on platelets (PAR-4) in AAA. We hypothesize that decreased PAR-4-dependent activation on platelets or anti- platelet therapy will reduce clot formation and increase AAA rupture. Together, these studies will increase our understanding of the role of the coagulation cascade, platelets, and PARs in the initiation, progression, and rupture of AAAs. The clinical significance of this work is that use of anti-thrombotic drugs may increase the risk of AAA rupture in patients.
Owens III, Albert, Phillip Project Narrative Abdominal aortic aneurysm is a dilation of the aorta which may result in catastrophic rupture and death. This cardiovascular disease is estimated to affect almost 10% of people over the age of 50 with an estimated 1 out of every 250 people affected. As such, between 15,000 and 30,000 Americans die every year due to this disease. Despite decades of research, there are no clinically approved drug regimens for this disease. Since this affects elderly populations, these patients are commonly on antithrombotic therapies for other cardiovascular diseases. Our preliminary data indicate that the activation of coagulation may be beneficial to prevent catastrophic rupture of the aorta resulting in death in these patients. A better understanding of the role of the coagulation system and platelets in AAA may prevent an increased risk of rupture for AAA patients by prohibiting the use of antithrombotic drug therapies in these patients. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page