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.
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