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Title: Chronic wound state associated with cytoskeletal defects and exacerbated by oxidative stress in Pax6+/- aniridia-related keratopathy
Author: Ou, Jingxing
ISNI:       0000 0004 2674 6361
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2008
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This work used Pax6+/- mice as a model for Pax6-realted corneal diseases and assessed the roles of oxidative stress and epithelial injury in the aetiology of ARK. Histological investigation revealed epithelial lesions in Pax6+/- corneas. Proteomic analysis demonstrated reduced levels of protective enzymes, transketolase, aldehyde dehydrogenase 3A1 and glutathione S-transferase α4, and cytoskeletal proteins. Keratin 5 and 12 in Pax6+/- adult mouse corneas. These physical/structural and chemical defects imply that Pax6+/- corneas may be in a chronic ‘stressed and wounded’ state. Using a DNPH/protein oxidation assay, Pax6+/- corneal protein oxidation was found to be consistently higher than that in wild-type (WT), and to get worse with age, in parallel with the development of corneal opacity. H2O2 was used to induce oxidative stress in mouse corneas and this was found to activate the Ca2+ (protein kinase C/ phospholipase C) → p38/p42/p44 mitogen activated kinase signalling pathway. Oxidative stress-induced Pax6 exclusion form cell nucleus led to abnormal expression of non-corneal epithelial markers, indicating a metaplasia process that may cause normally transparent epithelial cells to become opaque. This report for the first time describes cytoskeleton architectures in vivo using flat-mount mouse corneal epithelial by fluorescent staining and confocal microscopy, which is potentially applicable to studies interested in cytoskeleton in vivo. Keratin, desmoplakin and actin cytoskeletal structures were found to be heterogeneous and defective in Pax6+/- cells. Twenty-one hours after wounding WT corneal epithelia in vivo, healing cells developed desmoplakin and actin structural features, intercellular gaps, interdigitated filopodia-like processes and vesicles similar to the unscratched Pax6+/- corneal epithelia. These data support the hypothesis of a ‘chronic wounded’ state in apparently uninjured Pax6+/- corneal epithelia and reveal the cytoskeletal origins of poor adhesion and cellular structure.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Wound healing ; Wounds and injuries