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dc.contributor.authorSimpson, Charlotte Louise
dc.date.accessioned2015-10-05T09:26:48Z
dc.date.available2015-10-05T09:26:48Z
dc.date.issued2015
dc.identifier.citationSimpson, C.L. 2015. Molecular Mechanisms Regulating the Epithelial Barrier: Key Roles for Cx26 and ADAM17 during Bacterial Infection. Queen Mary University of London.en_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/9059
dc.descriptionPhDen_US
dc.description.abstractThis study investigated how gastrointestinal and skin bacterial infections were affected by differential expression of connexin (Cx) 26 and a disintegrin and metalloprotease (ADAM) 17 in vitro. Cx26 is a component of gap junctions, which facilitate the transfer of small molecules between two cells. Recessive mutations in Cx26 cause non syndromic hearing loss (NSHL), and in certain populations, specific mutations account for the majority of Cx26 related NSHL. Their common occurrence suggests that they may provide a heterozygous, protective advantage to carriers. In this study adherence by the attaching and effacing pathogen Enteropathogenic Escherichia coli (EPEC) was significantly reduced in cells expressing mutant Cx26 compared to wild type Cx26. Furthermore, EPEC adherence and invasion of an alternative enteric pathogen, Shigella flexneri were reduced following treatment with Cx26 short-interfering-RNA in intestinal cells. These findings suggest that the loss of functional Cx26 expression improves protection against enteric bacteria. ADAM17 releases substrates including tumour necrosis factor alpha and ligands of the epidermal growth factor receptor and therefore is involved in the induction of immune responses and maintenance of the epidermal barrier. This study demonstrated that ADAM17 provides protection during Staphylococcus aureus infection of keratinocytes. Subsequently the protective effects of ADAM17 mediated protection were explored. Secretion of the proinflammatory cytokines Interleukins 6 and 8 correlated with ADAM17 activity. Additionally gene expression profiling was performed which identified the IL-17 signalling pathway, which is known to be important during S. aureus infection, as a potential downstream target of ADAM17. In summary, based on these findings, Cx26 and ADAM17 may represent potential therapeutic targets for gastrointestinal and skin bacterial pathogensen_US
dc.description.sponsorshipBarts and the London School of Medicine and Dentistry; Medical Research Council, UKen_US
dc.language.isoenen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectMedicineen_US
dc.subjectGastrointestinal infectionsen_US
dc.subjectSkin infectionsen_US
dc.subjectConnexin (Cx) 26en_US
dc.subjectADAM17en_US
dc.titleMolecular Mechanisms Regulating the Epithelial Barrier: Key Roles for Cx26 and ADAM17 during Bacterial Infection.en_US
dc.typeThesisen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author


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