Vascular occlusion, leading to attenuated flow in the microcirculation and tissue ischemia, is the proximate cause of angina, myocardial infarction, transplant vasculopathy, hypertension and stroke. The overall goal and integrating theme of our proposed Program of research is to develop effective gene therapy approaches for the treatment of vaso-occlusive disorders. The objectives of the Program deal with the outstanding issues that will need to be addressed before the potential benefits of gene th3rapy for this group of disorders can be fully realized. The objectives are as follows: 1. To develop strategies for accurate, efficient gene delivery to various relevant vascular structures. 2. To study the kinetic profiles of gene expression using different vectors and gen transfer strategies such that absolute level and durability of gene expression can be tailored to a given therapeutic approach. 3. To develop a generic strategy that can be used to monitor the expression of therapeutic transgenes in preclinical and clinical studies 4. To develop and optimize promising gene therapy approaches to the treatment of vaso-occlusive diseases. The program comprises four mutually reinforcing projects which, with core facility support, will collective address the objectives of the overall Program. Project 1 will employ a novel vascular stent seeded with genetically modified smooth muscle cells to deliver VEGF into the coronary circulation to induce angiogenesis in a porcine model of chronic total coronary occlusion. Project 2 will study adenoviral and lentiviral vectors for genetic modification of cardiac allotransplants and will go on to test the value of eNOS gene transfer for the control of post-transplant vasculopathy in rat and porcine models. Project 3 will use adenoviral vectors to transfer heme subarachnoid hemorrhage. Project 4 will develop a generally applicable strategy to monitor in vivo the expression of any vector encoded transgene. These synergistic studies are supported by an Administrative/Biostatistics Core and by a Vector Core support function that has been incorporated into Project 4. Together, the project leaders, collaborators, co-directors and members of the Internal Advisory Board have formed a highly interactive, collegial group with the collective knowledge, experience, motivation, and ability to address the state objectives in the context of this Program Project Grant.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Tolunay, Eser
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Mayo Clinic, Rochester
United States
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Ricci, D; Mennander, A A; Miyagi, N et al. (2010) Prolonged cardiac allograft survival using iodine 131 after human sodium iodide symporter gene transfer in a rat model. Transplant Proc 42:1888-94
Katusic, Zvonimir S; d'Uscio, Livius V; Nath, Karl A (2009) Vascular protection by tetrahydrobiopterin: progress and therapeutic prospects. Trends Pharmacol Sci 30:48-54
Santhanam, Anantha Vijay R; d'Uscio, Livius V; Peterson, Timothy E et al. (2008) Activation of endothelial nitric oxide synthase is critical for erythropoietin-induced mobilization of progenitor cells. Peptides 29:1451-5
He, Tongrong; Lu, Tong; d'Uscio, Livius V et al. (2008) Angiogenic function of prostacyclin biosynthesis in human endothelial progenitor cells. Circ Res 103:80-8
Ricci, Davide; Mennander, Ari A; Pham, Linh D et al. (2008) Non-invasive radioiodine imaging for accurate quantitation of NIS reporter gene expression in transplanted hearts. Eur J Cardiothorac Surg 33:32-9
Miyagi, Naoto; Rao, Vinay P; Ricci, Davide et al. (2008) Efficient and durable gene transfer to transplanted heart using adeno-associated virus 9 vector. J Heart Lung Transplant 27:554-60
Metharom, Pat; Liu, Chunsheng; Wang, Shaohua et al. (2008) Myeloid lineage of high proliferative potential human smooth muscle outgrowth cells circulating in blood and vasculogenic smooth muscle-like cells in vivo. Atherosclerosis 198:29-38
Rao, Vinay P; Branzoli, Stefano E; Ricci, Davide et al. (2007) Recombinant adenoviral gene transfer does not affect cardiac allograft vasculopathy. J Heart Lung Transplant 26:1281-5
Nath, Karl A; Katusic, Zvonimir S; Gladwin, Mark T (2004) The perfusion paradox and vascular instability in sickle cell disease. Microcirculation 11:179-93
Russell, Stephen J; Peng, Kah-Whye (2003) Primer on medical genomics. Part X: Gene therapy. Mayo Clin Proc 78:1370-83

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