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Title: Transgenic approaches for the investigation of putative airway stem cells as potential targets for gene correction therapy
Author: Whitaker, D.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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A mouse model designed to evaluate the efficiency of gene correction (GC) was created, and a transgenic approach was taken to the investigation of a putative progenitor cell population in the adult murine respiratory tract. The full potential of a GC strategy to provide a single-dose, permanent solution to a genetically-diseased tissue will only be realised once the therapy is able to target resident stem cells (SCs). For CF lung disease, this will require the prior identification of SCs in the respiratory epithelium. Previous work has indicated that potential SCs are spatially coincident with small groups of cells expressing high levels of keratin 5 (K5) in the proximal murine trachea. In order to investigate lineage arising from this putative SC niche, transgenic mice have been generated which express an inducible form of Cre recombinase from the K5 promoter. Preliminary experiments demonstrate recombination of a conditional reporter gene after induction of Cre activity in K5-expressing tissue. Comparison of the inducible system with a constitutive K5-driven Cre line validated the choice of the former, as the clarity of data obtained from the conventional system was undermined as a result of K5 expression causing reporter gene activation prior to the onset of the experiment. In the course of these studies it became evident that the conventional Cre line gave rise to segregating patterns of reporter gene activation. While some mice displayed the expected K5-derived expression profile, other animals demonstrated ubiquitous expression. Constitutive activation of the conditional reporter was detected only in animals derived from females carrying the Cre transgene, and was found to be the result of unanticipated production of Cre protein in the maternal germline. This transgenic line is unusual and valuable in offering a choice of tissue-specific and generalised recombination of floxed alleles.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available