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Title: The cellular and molecular effects of UVA1 on human skin in vivo : impact on human health
Author: Tewari, Angela
ISNI:       0000 0004 7659 954X
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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The incidence of non-melanoma and melanoma is increasing and becoming a greater public health concern. Despite extensive research into the action spectra for the induction of skin cancers, the relative contributions of the different wavebands of ultraviolet radiation (UVR): UVB (290-320 nm), UVA2 (320-340 nm) and UVA1 (340-400 nm) are largely unknown. Until recently, UVA1 was thought to be relatively insignificant despite making up 75% of environmental UVR, as well as being the major spectral region in tanning lamps. High dose UVA1 is also used in phototherapy. Recent work demonstrating UVA1-induced cyclobutane pyrimidine dimers (CPD) in vitro and human skin ex vivo provides a clear indication to examine its effects in vivo in humans. The aims of this thesis was to assess DNA damage and other biological markers, in skin type I/II individuals after environmentally relevant doses of UVA1, and study its genetic effects using whole genome analysis. UVA1 formed CPD in human skin, predominantly in the basal epidermis, in contrast to erythemally equivalent doses of UVB of which these lesions were 3-4 times more frequent and were preferentially located in the upper layers of the epidermis. Previous studies suggest that repair of UVA1 CPD is slower than that induced by UVB. Our studies show that CPD repair kinetics were the same for both UVB and UVA1 when the whole epidermis was examined, however UVA1 CPD were poorly repaired over a 48 hour (h) period when assessment was restricted to the basal layer. We show that this is probably due to an overexpression of basal epidermal p63 by UVA1, and a concomitant lack of apoptosis of damaged cells. Overall, this is likely to make UVA1 CPD more mutagenic, as they persist for longer and are more likely to be incorporated as mutations during replication. Whole genome microarray studies showed distinct time dependent changes in many cellular pathways, with inflammation through TH17 signalling being the top upregulated pathway at 6h, and extracellular matrix remodelling being the top upregulated pathway at 24h. We found a dramatic upregulation in MMP12 gene expression by UVA1 at 24h. MMP12 protein is predominantly formed by UVA1 and also exhibits elastolytic activity. Our studies may explain how UVA1 contributes to late solar elastosis characterized by elastin degradation, and clinically by 'sagging' of the skin. MMP12 is a good marker of UVA1 exposure and MMP12 inhibition may be a new therapeutic approach for delaying photoageing and also photocarcinogenesis. To conclude, these results necessitate the long term follow up of patients receiving UVA1 phototherapy and clearer information for public health measures on photoprotection and tanning lamp legislation.
Supervisor: Young, Antony Richard Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available