Atherosclerosis 'is a key pathological process underlying the development and progression of three major diseases of the vascular system- coronary artery disease, cerebro-vascular and peripheral vascular disease. Chronic vascular wall inflammation is considered as a principal cause in the initiation and progression of atherosclerosis. Intimal thickening that develops in arteries and veins as an adaptive response to an injury has many similarities with atherosclerosis, but at the same time represents a unique pathological entity. This Thesis explores the utility of applying a novel DNAzyme based approach that targets "master-regulator" transcription factors c-jun and Egr-1 to in vivo and in vitro models of acute inflammation and intimal thickening. Studies included in this Thesis reveal that transcription factor c-jun plays a, key regulatory role in controlling leucocyte movement during an acute inflammation induced by IL-1 f3 through regulation of the expression of adhesion molecules ICAM, VCAM-1, E-selectin and VE-cadherin. Similarly, by applying ED5, a DNAzyme that targets transcription factor Egr-1 to the rat model of mesenteric microcirculation I demonstrate that Egr-1 controls leucocyte movement during an acute inflammation as evidenced by almost complete inhibition of leucocyte flux, adhesion and extravasation by ED5. The rabbit model of bypass grafting shows that Dz13 (a DNAzyme targeting transcription factor c-jun) significantly reduces intimal thickening in bypassed vein grafts of chow-fed animals at 28 days in vivo and in culture-grown human saphenous veins in vitro. Taken together these findings suggest that a DNAzyme based approach of targeting transcription factor c-jun has the potential to be used as a modulator of the acute inflammatory response and of intimal thickening formation. Further work needs to be done before this technology is ready for clinical use in humans.
| Identifer | oai:union.ndltd.org:ADTP/258331 |
| Date | January 2008 |
| Creators | Waldman, Alla, Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Publisher:University of New South Wales. Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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