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Title: Connexin (Cx) expression in human chronic wounds : the role Cx43, Cx26 and Cx30 play in the persistence of venous leg, diabetic foot and pressure ulcers
Author: Sutcliffe, J. E. S.
ISNI:       0000 0004 8497 7555
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Abstract:
Chronic wounds are a growing global healthcare problem attributed to increases in obesity, diabetes and a more aged population. It is integral to increase our comprehension of the ulcerated environment in order to develop new therapeutics and treatment regimes. One way that this can be achieved is by the identification of differences between stalled and acute repair. One group of proteins that have been found to be integral to repair are connexins (Cx). Previous studies in rodents have indicated that Cx43, Cx26 and Cx30 are dynamically altered post-wounding (Coutinho et al., 2003). Within the first 24-48 hours, the expression of Cx43 at the wound edge declines and this corresponds to an in increase in the expression of Cx26 and Cx30. Manipulation of Cx43 in vitro and in vivo confirmed that down-regulation is required for cellular migration throughout re-epithelialisation and the granulation phase (Mendoza-Naranjo et al. 2012; Wang et al., 2007; Qiu et al. 2003). I sought to establish the relationship between these three Cxs and repair in ulcerated tissue and to identify morphological differences between the biopsies obtained from each chronic wound type and intact skin. Cx43, Cx26 and Cx30 were all found to be highly expressed in venous leg, diabetic foot and pressure ulcers when compared to patient matched arm tissue. This supported the negative association previously reported between repair and the expression of Cx43. This study also highlighted Cx26 and Cx30 for investigation via down-regulatory studies. Cx26 was targeted using an antisense oligodeoxynucleotide (asODN) approach. Sequences were tested in vivo to examine target knockdown and the effect upon re-epithelialisation. Two candidates were carried through to an extended study. Here it was discovered that a single application was not sufficient to effect the expression of Cx26. For this to be achieved the asODN has to be continually released over an extended period of time. One of the other observations from the chronic wound study was that both the organization and composition of the dermal extracellular matrix was abnormal. There was a switch from a collagen type I dominant to collagen type III rich environment. In many samples this corresponded to a diminished abundance of elastin. This was explored using second harmonic and multiphoton imaging. The dermal cellularity was also increased primarily due to a sustained inflammatory presence but in some cases, an abundance of Cx43 positive contractile myofibroblasts. Overall the incorporation of re-epithelialisation induction into standard wound care regimes is integral to better patient outcomes. This would be achieved via Cx43 and/or Cx26 knockdown. When used in combination with SHG imaging to identify and excise, abnormal damaged tissue an acute repair response may be able to be induced. This would help to reduce the burden of chronic wounds on healthcare resources and importantly increase the quality of life of afflicted individuals.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.790381  DOI: Not available
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