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Title: Analysis of the pulmonary inflammatory phenotype of the CF mutant mouse
Author: Morrison, Gillian M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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Studies using isolated alveolar macrophages, led to the hypothesis that the pulmonary inflammatory cells of the Cftrtm1HGU mouse function normally when given a direct inflammatory stimulus and that another aspect of the host defence system is not functioning adequately to deal with repeated exposure to low level non-specific bacteria. Recent studies on the human airway defensin molecule, hBD-1, reveal that its bactericidal properties are inactivated by high salt concentrations. It is possible that the airway surface fluid of CF patients has a raised NaCl concentration and relates to a defective host defence system caused by the CFTR mutation. This thesis describes the identification and characterisation of a mouse β-defensin gene, Defb1, sometimes referred to as mBD-1, which was shown to be homologous to the human airway beta defensin hBD-1. It was found that Defb1 was expressed in a variety of tissues including the airways and like hBD-1 is not upregulated by LPS. A genomic targeting vector was constructed and Defb1 successfully knocked out in the mouse. This study also led to the isolation of a 150kb BAC contig which was shown to contain members of both the alpha and beta defensin gene families. Using low stringency hybridisation a novel murine beta defensin gene was identified which is not highly expressed in the airways under normal conditions although it appears to be weakly upregulated by LPS. A second human beta defensin gene, hBD-2, was recently identified which was shown to be upregulated in the airways by inflammatory stimuli, thus this novel murine gene is similar to hBD-2 both in structure and function. It is hoped that the study of the murine beta defensin gene family will lead to a clearer understanding of the normal function of defensins as well as of the consequences of their dysfunction in CF.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available