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Title: Evaluation of apoptosis in cystic fibrosis epithelial cells
Author: Chen, Q.
ISNI:       0000 0004 2722 5330
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease which is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although CF can affect all exocrine organs, CF lung disease is the major cause of morbidity and mortality in CF patients. In addition to the chronic infection and inflammation found in the CF airways, there are some publications looking at apoptosis in CF epithelial cells although the findings from these studies are unclear. In this work, I examined the relationship between the ~F508 CFTR mutation, ER stress activation and ER-stress related apoptosis in CF airway epithelial cells. However, there was no evidence of ER stress in our CF cells and therefore no suggestion of ER stress-induced apoptosis as evidenced by an absence of caspase-4 activation. However, caspase-3 and caspase-8 were found to have upregulated activity in CF cells compared to non-CF controls and this upregulation was demonstrated to be associated with CFTR mutation. Meanwhile, studies focusing on the extrinsic pathways revealed that upregulated Fas at both mRNA arid protein level might contribute to the increased caspase-3 & -8 activation in CF cells. However, low level of DNA fragmentation found in CF cells indicated no increased apoptosis in these cells and subsequent activation with a Fas activating antibody showed significantly increased apoptosis in CF cells compared to non-CF cells. Measurement of several apoptotic regulators including lAPs, Bcl-2 and c-FLIP suggested a cell-type dependent, but not CFTR mutation dependent, inhibition of apoptosis in CF tracheal and bronchial cells. Further studies are required to elucidate the entire signalling pathway in CF cells from Fas activation to caspase-3 activation and in addition further work is needed to show why caspase activation in basal cells does not lead to downstream activation of apoptotic mediators beyond caspase-3.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available