Abstract

The proliferation of vasculature, at levels that are either excessive or insufficient, is key in many diseases including arthritis, diabetes, cancer, and diseases of the heart and eye. The ability to selectively manipulate the transcription of genes controlling angiogenic and anti-angiogenic factors and receptors is, therefore, anticipated to have a significant impact on the treatment of disease. The study proposed here capitalizes on our development of designed transcription factors that enable the transcription of endogenous genes to be either activated or repressed. Polydactyl zinc finger proteins can now be prepared that specifically bind 18 bp DNA target sequences. When fused to activation or repression domains, these proteins become potent regulators of the transcriptional activity of the target gene. This proposal focuses on the development of transcriptional regulators of genes that have been identified to be key in either the promotion or inhibition of angiogenesis.
We aim to explore the potential of targeted angiogenic gene modulation in cancer. The efficacy of this approach will be studied using in vivo assays of angiogenesis and coregulation of genes will be studied in order to optimize the desired anti- angiogenic effect. We will address the therapeutic potential of Controlling angiogenesis in several murine cancer models. In collaborative studies angiogenic gene modulation will be applied to diseases of the eye, cardiovascular, and cerebrovascular disease. It is anticipated that the results of this work will provide researchers with novel tools to study the molecular mechanisms of disease as well as a new strategy to treat it.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086258-02
Application #
6377885
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (J1))
Program Officer
Goldman, Stephen
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$347,065
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Mandell, Jeffrey G; Barbas 3rd, Carlos F (2006) Zinc Finger Tools: custom DNA-binding domains for transcription factors and nucleases. Nucleic Acids Res 34:W516-23
Dreier, Birgit; Fuller, Roberta P; Segal, David J et al. (2005) Development of zinc finger domains for recognition of the 5'-CNN-3' family DNA sequences and their use in the construction of artificial transcription factors. J Biol Chem 280:35588-97
Chen, Emily I; Florens, Laurence; Axelrod, Fumiko T et al. (2005) Maspin alters the carcinoma proteome. FASEB J 19:1123-4
Blancafort, Pilar; Chen, Emily I; Gonzalez, Beatriz et al. (2005) Genetic reprogramming of tumor cells by zinc finger transcription factors. Proc Natl Acad Sci U S A 102:11716-21
Popkov, Mikhail; Jendreyko, Nina; McGavern, Dorian B et al. (2005) Targeting tumor angiogenesis with adenovirus-delivered anti-Tie-2 intrabody. Cancer Res 65:972-81
Lund, Caren V; Popkov, Mikhail; Magnenat, Laurent et al. (2005) Zinc finger transcription factors designed for bispecific coregulation of ErbB2 and ErbB3 receptors: insights into ErbB receptor biology. Mol Cell Biol 25:9082-91
Jendreyko, Nina; Popkov, Mikhail; Rader, Christoph et al. (2005) Phenotypic knockout of VEGF-R2 and Tie-2 with an intradiabody reduces tumor growth and angiogenesis in vivo. Proc Natl Acad Sci U S A 102:8293-8
Crotty, Justin W; Etzkorn, Christopher; Barbas 3rd, Carlos F et al. (2005) Crystallization and preliminary X-ray crystallographic analysis of Aart, a designed six-finger zinc-finger peptide, bound to DNA. Acta Crystallogr Sect F Struct Biol Cryst Commun 61:573-6
Magnenat, Laurent; Blancafort, Pilar; Barbas 3rd, Carlos F (2004) In vivo selection of combinatorial libraries and designed affinity maturation of polydactyl zinc finger transcription factors for ICAM-1 provides new insights into gene regulation. J Mol Biol 341:635-49
Lund, Caren V; Blancafort, Pilar; Popkov, Mikhail et al. (2004) Promoter-targeted phage display selections with preassembled synthetic zinc finger libraries for endogenous gene regulation. J Mol Biol 340:599-613

Showing the most recent 10 out of 17 publications