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Title: An investigation of murine trachea cellular kinetics : implications for stem cell gene therapy
Author: Borthwick, Duncan William
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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Submucosal glands were found to the major site of CFTR expression in the mouse trachea (an observation similar to that previously reported in humans). Reduced CFTR expression in this region may have the consequence of raising chloride concentrations in the airway surface fluid. In this thesis, data is presented showing that both the human and mouse homologue of the β-defensin-1 peptide shows a selective salt dependent antimicrobial activity. This may in part explain the higher susceptibility to colonisation by certain bacteria in the CF lung. In the search for possible progenitor cell populations in the mouse trachea, studies were conducted into the development of the submucosal glands and the kinetics of the tracheal epithelium in steady state and after damage. Through the study of aggregation chimaeric mice, evidence is presented to suggest that mouse submucosal glands are clonally derived from a single progenitor cell. In the mouse tracheal epithelium, basal cells were found to be the epithelial cell type with greatest proliferative capacity. Furthermore, a discrete niche of cells exhibiting stem cell characteristics were found in the submucosal gland ciliated duct. These cells were observed to be proliferative in times of stress and damage to produce migrating transit amplifying cells which repopulate and maintain the local epithelium. Experiments were conducted using liposome mediated gene therapy to approach the issue of targeting the tracheal progenitor cell populations. Although positive results for tissue transfection in vivo and in utero were obtained, the levels were disappointingly low. This thesis concludes that firstly, the mouse provides a useful animal model in which to study human tracheal kinetics and secondly, cells of high proliferative capacity displaying stem cell characteristics exist in the tracheal epithelium. The targeting of these progenitor cells may be of considerable importance in the future development of CF gene therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available