VEGF (vascular endothelial growth factor) is an endothelial cell-specific mitogen that has been shown to stimulate the development of collateral arteries in animal models of peripheral ischemia. Recent clinical studies on the angiogenic activity of VEGF have established that VEGF gene therapy can benefit patients with peripheral artery disease. The applicants propose to use recent advances in zinc finger DNA binding protein design to create novel transcriptional activator proteins capable of increasing VEGF gene expression in vivo. Chimeric activator proteins will be designed to bind to relevant target sites in the VEGF promoter region and activate VEGF transcription. The applicants will determine the ability of the designed proteins to activate VEGF mRNA and protein expression in mammalian cells through transient transfection assays and the production of stable cell lines. Activation of VEGF transcription will be determined by measuring the level of reporter gene expression in the absence and presence of zinc finger binding protein. This innovative research will lead directly to the development of novel gene therapy approaches for diseases associated with peripheral artery disease (PAD).
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