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Title: The control of alternative splicing in vascular endothelial growth factor and its effect on ocular angiogenesis
Author: Carter, James G.
ISNI:       0000 0004 2741 3016
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2012
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The pathological growth of blood vessels within the eye is a major source of blindness for the developed world. The growth of new vessels, angiogenesis, is mediated by vascular endothelial growth factor (VEGF). As such, many of the current therapies for the treatment of angiogenic eye disease are focused on the therapeutic effects of blocking the activity of this protein. However VEGF can be alternatively spliced at the terminal exon to create two functionally distinctive isoform families (the VEGFxxx and VEGFxxxb isoforms). These two groups of VEGF isoforms have disparate activities; VEGFxxxb isoforms actively inhibit VEGFxxx mediated endothelial cell growth making them potent anti-angiogenic molecules. Yet despite this, the mechanisms by which the splicing of VEGF is changed between pro- and anti-angiogenic isoforms is poorly understood. This thesis examines the role of VEGF isoform expression in the eye, and how this can be altered in proliferative diabetic retinopathy (PDR). From this study, a novel method for the identification of VEGFxxx isoforms was developed and used to show how the balance of VEGF isoforms in the eye exists in a state highly susceptible to angiogenesis. The role of genetic variation was also assessed, both in response to anti-VEGF therapy in patients, and how splice factor variants can influence the risk of developing both PDR and exudative age-related macular degeneration (exAM D). The latter half of this thesis explores the role of different splice factors, and their ability to manipulate VEGF splicing. In particular, the role of ASFjSF2 and SRPKl and their importance in the expression of VEGF isoforms is demonstrated, with the caveat that the function of these splicing components may be cell specific. Finally, this thesis shows a novel association of three other components of the spliceosome (FBP21, CPSF6, SF3B4) with alterations in VEGF splicing, and developed a theoretical model for their actions in relation to VEGF isoform selection. It is the author's hope that this body of work has contributed to a wider understanding of the mechanisms of VEGF terminal splice site selection, and how this control of splicing may be influential in both the prognosis and treatment of angiogenic eye disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available