My goal is to be an academic vascular surgeon who has an independent research laboratory and teaches vascular surgery in a university setting. My long-term research interest, including my Ph.D. studies, has been inhibition of vascular smooth muscle Cell proliferation by nitric oxide, a process clinically relevant to vascular surgery. Proliferation of smooth muscle cells is critical to the development of both atherosclerosis and post- surgical disorders such as restenosis and vein graft failure. In this proposal l will use a variety of molecular approaches, including dominant negative mutants and anti sense constructs, as well as analysis of kinase and cyclin activity, to define the intracellular mechanisms involved in the antiproliferative effect of nitric oxide.
The Specific Aims are: 1) To examine the role of cyclic necleotides and cyclic necleotide-dependent kinases in mediating the anti-proliferative effects of nitric oxide, 2) To determine the effect of nitric oxide on expression of the cell cycle- dependent proto-oncogenes (e.g. fos, myc, myb) and the potential role of inhibition of proto-oncogene expression in growth inhibition by nitric oxide, 3) To determine the mechanism of induction of the cyclin- dependent kinase inhibitor p21 by nitric oxide and the importance of p21 in mediating growth arrest by nitric oxide. The effects of modulation of these intracellular pathways will be evaluated in cultured smooth muscle cells treated with exogenous nitric oxide. These investigations under the guidance of my sponsors, coupled with the courses, seminars and collaborations in this Research Career Award, will substantially broaden my scientific experience and allow me to approach future problems in vascular biology with a wide array of fundamental experimental techniques. Definition of these mechanisms is important to understanding both the physiologic inhibition of pathologic smooth muscle cell proliferation by endothelium and potential new therapeutic strategies for proliferative vascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL004435-02
Application #
6388687
Study Section
Special Emphasis Panel (ZHL1-CSR-G (M1))
Program Officer
Schucker, Beth
Project Start
2000-09-01
Project End
2005-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$129,708
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Huang, James; Lin, Stephanie C; Nadershahi, Afshin et al. (2008) Role of redox signaling and poly (adenosine diphosphate-ribose) polymerase activation in vascular smooth muscle cell growth inhibition by nitric oxide and peroxynitrite. J Vasc Surg 47:599-607
Tang, Gale L; Chang, David S; Sarkar, Rajabrata et al. (2005) The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia. J Vasc Surg 41:312-20
Dahi, Sia; Lee, Jackie G; Lovett, David H et al. (2005) Differential transcriptional activation of matrix metalloproteinase-2 and membrane type-1 matrix metalloproteinase by experimental deep venous thrombosis and thrombin. J Vasc Surg 42:539-45
Chang, David S; Su, Hua; Tang, Gale L et al. (2003) Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscle oxygen tension and induces arteriogenesis in ischemic rat hindlimb. Mol Ther 7:44-51
Brevetti, Lucy S; Chang, David S; Tang, Gale L et al. (2003) Overexpression of endothelial nitric oxide synthase increases skeletal muscle blood flow and oxygenation in severe rat hind limb ischemia. J Vasc Surg 38:820-6
Brevetti, Lucy S; Chang, David S; Sarkar, Rajabrata et al. (2002) Effect of adenoviral titer and instillation pressure on gene transfer efficiency to arterial and venous grafts ex-vivo. J Vasc Surg 36:263-70
Sarkar, Rajabrata (2002) Evolution of the management of mesenteric occlusive disease. Cardiovasc Surg 10:395
Messina, Louis M; Brevetti, Lucy S; Chang, David S et al. (2002) Therapeutic angiogenesis for critical limb ischemia: invited commentary. J Control Release 78:285-94
Paek, Robert; Chang, David S; Brevetti, Lucy S et al. (2002) Correlation of a simple direct measurement of muscle pO(2) to a clinical ischemia index and histology in a rat model of chronic severe hindlimb ischemia. J Vasc Surg 36:172-9
Brevetti, L S; Paek, R; Brady, S E et al. (2001) Exercise-induced hyperemia unmasks regional blood flow deficit in experimental hindlimb ischemia. J Surg Res 98:21-6

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