Induction of angiogenesis in a mouse model using engineered transcription factors
| Autor: | Andrew C. Jamieson, Lei Zhang, Casey C. Case, Reed Hickey, David F. Meoli, Anjali K. Nath, Frank J. Giordano, Bingliang Chen, Edward J. Rebar, Yan Huang, Lei Xu, S. Kaye Spratt, Alan P. Wolffe, Yuxin Liang, Sameer K. Nath |
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| Rok vydání: | 2002 |
| Předmět: |
Vascular Endothelial Growth Factor A
Angiogenesis Molecular Sequence Data Artificial transcription factor Neovascularization Physiologic Endogeny Biology Protein Engineering General Biochemistry Genetics and Molecular Biology Mice Complementary DNA Animals Amino Acid Sequence Transcription factor Regulation of gene expression Zinc Fingers 3T3 Cells Genetic Therapy General Medicine Molecular biology Recombinant Proteins Cell biology Vascular endothelial growth factor A Gene Expression Regulation Drug Design Models Animal Angiogenesis Inducing Agents Transcription Factors |
| Zdroj: | Nature Medicine. 8:1427-1432 |
| ISSN: | 1078-8956 |
| DOI: | 10.1038/nm795 |
| Popis: | The relationship between the structure of zinc-finger protein (ZFP) transcription factors and DNA sequence binding specificity has been extensively studied. Advances in this field have made it possible to design ZFPs de novo that will bind to specific targeted DNA sequences. It has been proposed that such designed ZFPs may eventually be useful in gene therapy. A principal advantage of this approach is that activation of an endogenous gene ensures expression of the natural array of splice variants. Preliminary studies in tissue culture have validated the feasibility of this approach. The studies reported here were intended to test whether engineered transcription factors are effective in a whole-organism model. ZFPs were designed to regulate the endogenous gene encoding vascular endothelial growth factor-A (Vegfa). Expression of these new ZFPs in vivo led to induced expression of the protein VEGF-A, stimulation of angiogenesis and acceleration of experimental wound healing. In addition, the neovasculature resulting from ZFP-induced expression of Vegfa was not hyperpermeable as was that produced by expression of murine Vegfa(164) cDNA. These data establish, for the first time, that specifically designed transcription factors can regulate an endogenous gene in vivo and evoke a potentially therapeutic biophysiologic effect. |
| Databáze: | OpenAIRE |
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