Vasospasm occurs in the blood vessels used for vascular bypass operations. This spasm is due to impaired relaxation of the smooth muscle. Relaxation is mediated by cyclic nucleotide-dependent signaling pathways. We have demonstrated that the phosphorylation of a small heat shock protein, HSP20 represents a point in which the cyclic nucleotide signaling pathways converge to cause relaxation. The hypotheses of this investigation are that vasorelaxing molecules, engineered to include HSP20 motifs and protein transduction domains, will prevent 1) short term vein graft failure due to vasospasm and 2) long term graft failure by better preservation of the graft during harvest and by the prevention of intimal hyperplasia.
The specific aims of this investigation are: #1: Generate recombinant HSP20 linked to a protein transduction domain (PTD) and determine if this engineered protein reverses human vascular smooth muscle spasm ex vivo. #2: Determine the effect of PTD-HSP20 on dynamic cytoskeletal processes relevant to intimal hyperplasia. #3: Determine the feasibility of protein transduction of HSP20 analogues of vein grafts in vivo. The goal of this project is to engineer biomolecules that enhance vein graft preservation by directly introducing the analogues of an endogenous relaxing protein (HSP20) into the smooth muscle. Vein grafts represent an ideal target for these therapeutic approaches in that the graft can be treated ex vivo, thus providing an optimal environment for the localization of engineered protein/peptide therapeutics. This represents a novel approach in that the receptors and signaling cascades are """"""""bypassed"""""""" and the effector protein/peptide is directly introduced into the target cell. This represents a """"""""post-genomic"""""""" platform for engineering biologically active protein/peptide molecules.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070715-02
Application #
6721453
Study Section
Special Emphasis Panel (ZRG1-SSS-W (02))
Program Officer
Barouch, Winifred
Project Start
2003-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$373,750
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Cheung-Flynn, Joyce; Song, Jun; Voskresensky, Igor et al. (2017) Limiting Injury During Saphenous Vein Graft Preparation For Coronary Arterial Bypass Prevents Metabolic Decompensation. Sci Rep 7:14179
Komalavilas, Padmini; Luo, Weifeng; Guth, Christy M et al. (2017) Vascular surgical stretch injury leads to activation of P2X7 receptors and impaired endothelial function. PLoS One 12:e0188069
Luo, Weifeng; Feldman, Daniel; McCallister, Reid et al. (2017) P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis. Purinergic Signal 13:579-590
Guth, Christy M; Luo, Weifung; Jolayemi, Olukemi et al. (2017) Adenosine triphosphate as a molecular mediator of the vascular response to injury. J Surg Res 216:80-86
Wise, Eric S; Hocking, Kyle M; Evans, Brian C et al. (2017) Unregulated saphenous vein graft distension decreases tissue viscoelasticity. Perfusion 32:489-494
Boire, Timothy C; Balikov, Daniel A; Lee, Yunki et al. (2016) Biomaterial-Based Approaches to Address Vein Graft and Hemodialysis Access Failures. Macromol Rapid Commun 37:1860-1880
Osgood, Michael J; Sexton, Kevin; Voskresensky, Igor et al. (2016) Use of Brilliant Blue FCF during vein graft preparation inhibits intimal hyperplasia. J Vasc Surg 64:471-478
Hocking, Kyle M; Luo, Weifeng; Li, Fan Dong et al. (2016) Brilliant blue FCF is a nontoxic dye for saphenous vein graft marking that abrogates response to injury. J Vasc Surg 64:210-8
Hocking, Kyle M; Putumbaka, Gowthami; Wise, Eric S et al. (2016) Papaverine Prevents Vasospasm by Regulation of Myosin Light Chain Phosphorylation and Actin Polymerization in Human Saphenous Vein. PLoS One 11:e0154460
Wise, Eric S; Hocking, Kyle M; Luo, Weifeng et al. (2016) Traditional graft preparation decreases physiologic responses, diminishes viscoelasticity, and reduces cellular viability of the conduit: A porcine saphenous vein model. Vasc Med 21:413-421

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