PREVENTION OF VEIN GRAFT SPASM

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DESCRIPTION (provided by applicant): 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.