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dc.contributor.advisorBotchkarev, Vladimir A.
dc.contributor.advisorBotchkareva, Natalia V.
dc.contributor.advisorSharpe, David T.
dc.contributor.authorLewis, Christopher J.*
dc.date.accessioned2015-07-09T15:59:21Z
dc.date.available2015-07-09T15:59:21Z
dc.date.issued2015-07-09
dc.identifier.urihttp://hdl.handle.net/10454/7337
dc.description.abstractBone morphogenetic proteins (BMPs) and their receptors (BMPRs) coordinate tissue development and postnatal remodelling by regulating proliferation, differentiation and apoptosis. However, their role in wound healing remains unclear. To study this, transgenic mice overexpressing Smad1 (K14-caSmad1) or the BMP antagonist Noggin (K14-Noggin) were utilised, together with human and mouse ex vivo wound healing models and in vitro keratinocyte culture. In wild-type mice, transcripts for Bmpr-1A, Bmpr-II, Bmp ligands and Smad proteins were decreased following tissue injury, whilst Bmpr-1B expression was up-regulated. Furthermore, immunohistochemistry revealed a down-regulation of BMPR-1A in hair follicles adjacent to the wound in murine skin, whilst in murine and human wounds, BMPR-1B and phospho-Smad-1/5/8 expression was pronounced in the wound epithelial tongue. K14-caSmad1 mice displayed retarded wound healing, associated with reduced keratinocyte proliferation and increased apoptosis, whilst K14-Noggin mice exhibited accelerated wound healing. Furthermore, microarray analysis of K14-caSmad1 epidermis revealed decreased expression of distinct cytoskeletal and cell motility-associated genes including wound-associated keratins (Krt16, Krt17) and Myo5a versus controls. Human and mouse keratinocyte proliferation and migration were suppressed by BMP-4/7 both in vitro and ex vivo, whilst they were stimulated by Noggin. Additionally, K14-caSmad1 keratinocytes showed retarded migration compared to controls when studied in vitro. Furthermore, Bmpr-1B silencing accelerated migration and was associated with increased expression of Krt16, Krt17 and Myo5a versus controls. Thus, this study demonstrates that BMPs inhibit proliferation, migration and cytoskeletal re-organization in epidermal keratinocytes during wound healing, and raises a possibility that BMP antagonists may be used for the future management of chronic wounds.en_US
dc.language.isoenen_US
dc.rights<a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>.eng
dc.subjectWound healing; Bone morphogenetic protein; BMP; Skin; Keratinocyte; Noggin; Smaden_US
dc.titleThe role of bone morphogenetic protein signalling in the control of skin repair after wounding. Cellular and molecular mechanisms of cutaneous wound healing mediated by bone morphogenetic proteins and their antagonist Noggin.en_US
dc.type.qualificationleveldoctoralen_US
dc.publisher.institutionUniversity of Bradfordeng
dc.publisher.departmentMedical Biosciences School of Life Sciencesen_US
dc.typeThesiseng
dc.type.qualificationnamePhDen_US
dc.date.awarded2013
refterms.dateFOA2018-07-25T12:06:49Z


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