This proposal is a five-year training program for the development of Alan Dardik's academic career in Vascular Surgery. Dr. Dardik completed surgical training at the Johns Hopkins Hospital and is currently Assistant Professor of Surgery at Yale University School of Medicine. This training program will allow him to develop, coordinate, and translate laboratory findings into practical clinical applications for the diagnosis and treatment of patients with atherosclerotic carotid disease, and allow him to develop into an independent investigator including preparation and submission of an R-01 proposal. William Sessa, PhD, Professor of Pharmacology and Director of the Vascular Cell Signaling and Therapeutics Program, and Co-Director of the Yale/NHLBI Proteomics Center, and Bauer Sumpio, MD, PhD, Professor of Surgery at Yale, will serve as comentors, and guide Dr. Dardik's research and career development, including instruction in the Responsible Conduct of Research. Dr. Dardik will closely interact with senior faculty in Yale's Interdepartmental Vascular Biology and Transplant Program such as Jordan S Pober, MD, PhD. Stroke affects 2% of Americans, with an annual incidence of 700,000 strokes, and cost of over $50 billion;women and minorities are disproportionally affected. Carotid angioplasty (CA) is a rapidly evolving endovascular treatment for carotid stenosis, preventing stroke. However, the hemodynamic responses following CA are not well defined and may influence the outcome and long-term durability of CA. The applicant hypothesizes that plaque fracture and endothelial denudation after CA directly expose smooth muscle cells (SMC) to complicated arterial flow;complicated flow directly stimulates SMC Akt activity, leading to SMC proliferation, suppression of apoptosis, and ultimately vessel restenosis. This proposal will examine the response to CA in an animal model, including development of a novel surgical model of complicated flow, development of MRI techniques to assess flow velocity distribution and wall shear stress, and examination of the role of Akt using knockout mice. The response of SMC directly to laminar and complicated flow in vitro will be examined with molecular biological techniques.
The specific aims are: 1. Determine the effects of carotid angioplasty on flow in vivo. 2. Determine the effects of carotid angioplasty on Akt and mTOR pathway activation. 3. Compare the effects of simple and complicated flow on SMC proliferation and apoptosis. The information obtained in this proposal will provide a framework to rationally examine and direct therapy for our patients. The academic environment, diverse resources, and enthusiasm for research at Yale will maximize the potential for Dr Dardik to establish an academic career as a clinician scientist. This proposal seeks to understand the complex mechanisms by which vascular intervention such as angioplasty or bypass surgery fail prematurely. By developing techniques to detect abnormal flow patterns and understanding the effects of these flow patterns on smooth muscle cells, we hope to develop vascular interventions that are longer-lasting and minimize patient suffering.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL079927-04
Application #
7616413
Study Section
Special Emphasis Panel (ZHL1-CSR-O (F1))
Program Officer
Commarato, Michael
Project Start
2006-09-18
Project End
2009-07-19
Budget Start
2009-06-01
Budget End
2009-07-19
Support Year
4
Fiscal Year
2009
Total Cost
$133,110
Indirect Cost
Name
Yale University
Department
Surgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kondo, Yuka; Muto, Akihito; Kudo, Fabio A et al. (2011) Age-related Notch-4 quiescence is associated with altered wall remodeling during vein graft adaptation. J Surg Res 171:e149-60
Magri, Dania; Vasilas, Penny; Muto, Akihito et al. (2011) Elevated monocytes in patients with critical limb ischemia diminish after bypass surgery. J Surg Res 167:140-50
Muto, Akihito; Yi, Tai; Harrison, Kenneth D et al. (2011) Eph-B4 prevents venous adaptive remodeling in the adult arterial environment. J Exp Med 208:561-75
Dardik, Alan (2010) Vascular surgeons have observed many gender specific demographic trends in patients presenting with abdominal aortic aneurysms. J Surg Res 159:484-5
Muto, A; Nishibe, T; Miyauchi, Y et al. (2010) Prostaglandin receptors EP2 and IP are detectable in atherosclerotic arteries and plaques. Int Angiol 29:43-8
Fitzgerald, Tamara N; Muto, Akihito; Fancher, Tiffany T et al. (2010) Surgically implantable magnetic resonance angiography coils improve resolution to allow visualization of blood flow dynamics. Ann Vasc Surg 24:242-53
Chaar, Cassius Iyad Ochoa; Fitzgerald, Tamara N; Dewan, Michael et al. (2009) Endovascular aneurysm repair is associated with less malnutrition than open abdominal aortic aneurysm repair. Am J Surg 198:623-7
Muto, Akihito; Nishibe, Toshiya; Dardik, Herbert et al. (2009) Patches for carotid artery endarterectomy: current materials and prospects. J Vasc Surg 50:206-13
Bazan, Hernan A; Lu, Yan; Thoppil, Deepu et al. (2009) Diminished omega-3 fatty acids are associated with carotid plaques from neurologically symptomatic patients: Implications for carotid interventions. Vascul Pharmacol 51:331-6
Rivera, Mariangela; Muto, Akihito; Feigel, Amanda et al. (2009) Venous and arterial identity: a role for caveolae? Vascular 17 Suppl 1:S10-4

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