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Induction of angiogenesis in a mouse model using engineered transcription factors

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 tha... Full description

Journal Title: Nature medicine 2002-12, Vol.8 (12), p.1427-1432
Main Author: Giordano, Frank J
Other Authors: Rebar, Edward J , Huang, Yan , Hickey, Reed , Nath, Anjali K , Meoli, David , Nath, Sameer , Chen, Bingliang , Xu, Lei , Liang, Yuxin , Jamieson, Andrew C , Zhang, Lei , Spratt, S Kaye , Case, Casey C , Wolffe, Alan
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/12415262
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recordid: cdi_proquest_miscellaneous_72716781
title: Induction of angiogenesis in a mouse model using engineered transcription factors
format: Article
creator:
  • Giordano, Frank J
  • Rebar, Edward J
  • Huang, Yan
  • Hickey, Reed
  • Nath, Anjali K
  • Meoli, David
  • Nath, Sameer
  • Chen, Bingliang
  • Xu, Lei
  • Liang, Yuxin
  • Jamieson, Andrew C
  • Zhang, Lei
  • Spratt, S Kaye
  • Case, Casey C
  • Wolffe, Alan
subjects:
  • 3T3 Cells
  • Amino Acid Sequence
  • Angiogenesis Inducing Agents
  • Animals
  • Drug Design
  • Gene Expression Regulation
  • Genetic Therapy
  • Mice
  • Models, Animal
  • Molecular Sequence Data
  • Neovascularization, Physiologic
  • Protein Engineering - methods
  • Recombinant Proteins
  • Transcription Factors - genetics
  • Transcription Factors - physiology
  • Vascular Endothelial Growth Factor A
  • Zinc Fingers - physiology
ispartof: Nature medicine, 2002-12, Vol.8 (12), p.1427-1432
description: 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.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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titleInduction of angiogenesis in a mouse model using engineered transcription factors
creatorGiordano, Frank J ; Rebar, Edward J ; Huang, Yan ; Hickey, Reed ; Nath, Anjali K ; Meoli, David ; Nath, Sameer ; Chen, Bingliang ; Xu, Lei ; Liang, Yuxin ; Jamieson, Andrew C ; Zhang, Lei ; Spratt, S Kaye ; Case, Casey C ; Wolffe, Alan
creatorcontribGiordano, Frank J ; Rebar, Edward J ; Huang, Yan ; Hickey, Reed ; Nath, Anjali K ; Meoli, David ; Nath, Sameer ; Chen, Bingliang ; Xu, Lei ; Liang, Yuxin ; Jamieson, Andrew C ; Zhang, Lei ; Spratt, S Kaye ; Case, Casey C ; Wolffe, Alan
descriptionThe 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.
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languageeng
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subject3T3 Cells ; Amino Acid Sequence ; Angiogenesis Inducing Agents ; Animals ; Drug Design ; Gene Expression Regulation ; Genetic Therapy ; Mice ; Models, Animal ; Molecular Sequence Data ; Neovascularization, Physiologic ; Protein Engineering - methods ; Recombinant Proteins ; Transcription Factors - genetics ; Transcription Factors - physiology ; Vascular Endothelial Growth Factor A ; Zinc Fingers - physiology
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descriptionThe 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.
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03T3 Cells
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4Drug Design
5Gene Expression Regulation
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titleInduction of angiogenesis in a mouse model using engineered transcription factors
authorGiordano, Frank J ; Rebar, Edward J ; Huang, Yan ; Hickey, Reed ; Nath, Anjali K ; Meoli, David ; Nath, Sameer ; Chen, Bingliang ; Xu, Lei ; Liang, Yuxin ; Jamieson, Andrew C ; Zhang, Lei ; Spratt, S Kaye ; Case, Casey C ; Wolffe, Alan
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03T3 Cells
1Amino Acid Sequence
2Angiogenesis Inducing Agents
3Animals
4Drug Design
5Gene Expression Regulation
6Genetic Therapy
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9Molecular Sequence Data
10Neovascularization, Physiologic
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12Recombinant Proteins
13Transcription Factors - genetics
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15Vascular Endothelial Growth Factor A
16Zinc Fingers - physiology
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abstractThe 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.
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pmid12415262
doi10.1038/nm1202-795
tpages6