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Title: The role of oxidative stress in photoreceptor degeneration
Author: Vlachantoni, Dafni
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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The aim of this thesis was to investigate the role of oxidative stress in disease progression using mouse models of human RP. The mouse mutants retinal degeneration 1 (rdl/rd), atypical retinal degeneration 1 (atrd1/atrd1), rhodopsin knockout (rho-/-) and peripherin/retinal degeneration slow (rds-/-) were firstly investigated for evidence of oxidative damage by analysis of oxidative stress markers. Secondly, the mutants were crossed to a superoxide dismutase 2 heterozygous mouse (sod2+/-), with decreased mitochondrial antioxidant activity, to examine the effect on disease progression. Thirdly, mutants were treated with a mitochondrially targeted ubiquinone derivative (MitoQ), which is a powerful antioxidant, to try and slow the rate of retinal degeneration. MitoQ was administered orally during pregnancy and for an extended postnatal period and uptake, toxicity, breeding behaviour and survival were assessed. Rates of photoreceptor degeneration were estimated by morphometric and apoptosis assays, while the cellular redox status was assessed by glutathione assays and by measuring the activities of the mitochondrial enzymes NADH:ubiquinone oxidoreductase (complex I), which is oxidative stress-sensitive, compared with citrate synthase, which is oxidative stress-insensitive. All retinal degeneration mutants were found to show significantly reduced complex I activities, while citrate synthase was unchanged, indicating mitochondrial oxidative stress. Rates of photoreceptor degeneration were unchanged either by crossing to a sod2+/- genetic background or by MitoQ administration. Only the rds-/- mutant, with the slowest rate of degeneration, showed a significant increase in complex I activity after MitoQ administration. Although mitochondrial oxidative stress is shown to be present in all of the retinal degeneration mutants, altering the oxidative status of the retina had no effect on photoreceptor survival.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available