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Title: The role of BPIFA1 in otitis media
Author: Mulay, Apoorva
ISNI:       0000 0004 5989 3018
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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Otitis Media (OM) is the most common paediatric disease and a leading cause of conductive hearing impairment. This multifactorial disease shows significant involvement of innate immunity genes and epithelial abnormalities are also commonly implicated. BPIFA1, a member of BPI fold containing family of putative innate defence proteins, is one of the most abundant secretory proteins in the upper airways and SNPs in BPIFA1 have been associated with OM susceptibility. Recent studies suggest that BPIFA1 plays a pleiotropic host defense role. This thesis describes experiments aimed at investigating the role of BPIFA1 in protection of the middle ear and in the development of OM. Bpifa1-/- mice do not spontaneously develop OM and do not demonstrate increased nasopharyngeal carriage of the human otopathogen, NTHi. However, deletion of Bpifa1 in Junbo (Evi1Jbo/+) mice, an established model of chronic OM, leads to significant exacerbation of OM severity and ME mucosal thickness. This thesis also describes the development of a novel in vitro model of the murine middle ear epithelium. Using a combination of transcriptional and proteomic approaches, I demonstrate that the model closely mimics the native middle ear epithelium and differentiates into ciliated cells, goblet cells and secretory cells and also supports infection by NTHi. Attempts were made to recapitulate the OM phenotype in vitro using this culture system. Overall, the data from this thesis indicate that BPIFA1 is involved in maintaining homeostasis within the middle ear under steady state conditions through nonspecific defence of the middle ear mucosa. Loss of BPIFA1 in presence of infection or inflammation increases the sensitivity of the epithelium and leads to an exacerbated host defence response and excessive epithelial remodelling. Furthermore, the novel in vitro culture system can be applied as an effective tool to study the interaction between the middle ear epithelium and various otopathogens.
Supervisor: Bingle, Lynne ; Bingle, Colin ; Cheeseman, Michael Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available