Cardiovascular disease and cancer are the two most common causes of death worldwide. Angiogenesis plays a critical role tumourigenesis and atherogenesis. As a member of the basic region-leucine zipper protein family, c-Jun, has been linked with cell proliferation, migration and cell survival. However, the relationship between c-Jun and angiogenesis has not been firmly established. In this thesis, strategies targeting c-Jun mRNA such as DNAzyme and siRNA have been designed and evaluated for their ability to inhibit the c-Jun mRNA and c-Jun protein expression in vitro and in vivo. These agents block c-Jun expression and inhibit DNA binding activity of c-Jun. Luciferase assay showed that c-Jun siRNA suppressed c-Jun/AP-1-dependent reporter activity. The processes of cell proliferation, migration, invasion and tube formation were all down-regulated after treatment with c-Jun targeting agents. In vivo, c-Jun DNAzymes and siRNA inhibit angiogenesis in multiple models of angiogenesis in multiple models of angiogenesis, including tumour angiogenesis and growth, matrix angiogenesis, corneal angiogenesis and retinal neovascularization. This is mediated, at least in part, by c-Jun siRNA or DNAzyme inhibition of MMP-2 expression. These findings demonstrate the critical role played by c-Jun in the involvement of neovascularization and suggest that DNAzymes or siRNAs are efficient gene-silencing agents. The ability to identify and control key genes in angiogenesis provides opportunities for developing therapeutic molecular tools to treat cancer or other angiogenesis related diseases.
| Identifer | oai:union.ndltd.org:ADTP/235125 |
| Date | January 2006 |
| Creators | Zhang, Guishui, Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Guishui Zhang, http://unsworks.unsw.edu.au/copyright |
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