edison - a novel model of otitis media
<p>Otitis media (OM) is characterised by inflammation of the middle ear and is a common cause of conductive hearing impairment that places a substantial social, medical and economic burden on healthcare systems globally. Despite the importance of the disease, the aetiology of chronic middle ea...
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| Format: | Thesis |
| Language: | English |
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2014
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| _version_ | 1826315844197548032 |
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| author | Crompton, M |
| author2 | Brown, S |
| author_facet | Brown, S Crompton, M |
| author_sort | Crompton, M |
| collection | OXFORD |
| description | <p>Otitis media (OM) is characterised by inflammation of the middle ear and is a common cause of conductive hearing impairment that places a substantial social, medical and economic burden on healthcare systems globally. Despite the importance of the disease, the aetiology of chronic middle ear inflammatory disease remains poorly understood. The development and persistence of chronic OM is multi-factorial with a significant genetic component. A new mouse model of chronic OM, <em>edison</em>, was generated by <em>N</em>-ethyl-<em>N</em>-nitrosourea (ENU) mutagenesis and discovered in a recessive screen at MRC Harwell.</p> <p>Homozygous <em>edison</em> mice have craniofacial abnormalities, an emphysema-like lung phenotype and spontaneously develop a conductive hearing loss at 28 days as measured by ABR. Histological analysis shows the hearing loss is associated with the development of chronic OM in the middle ear, characterised by mucosal inflammation and highly cellular ear exudates. Similar to the <em>Jeff</em> and <em>Junbo</em> mutants, <em>edison</em> shows raised levels of <em>Vegfa</em>, <em>Tnfα</em> and <em>Il-1β</em> in middle ear fluids. A putative functional mutation was identified, resulting in a missense Leu972Pro change in a relatively unknown gene, <em><em>Nisch</em>arin</em> (<em>Nisch</em>). The identification of additional ENU-induced <em>Nisch</em> alleles, and subsequent characterisation, validated <em>Nisch</em> as the causative gene in <em>edison</em>.</p> <p>NISCH selectively binds ITGA5, which is thought to have a role in modulating VEGF signalling through SRC and FAK kinases. A significant genetic interaction between <em>Nisch</em> and <em>Itga5</em> exists and impacts upon development of chronic OM. Mice heterozygous for <em>Itga5</em>-null and homozygous for <em>edison</em> alleles show a significantly increased penetrance and severity of chronic OM. Analysis of downstream pathways suggests that the <em>edison</em> allele is impacting upon both RAC1 and TGF-β/SMAD signalling.</p> <p>I also explored the potential use of the <em>edison</em> mouse as a model for bacterial challenge with the human otopathogen, NT<em>Hi</em>. Similar to the <em>Junbo</em> infection model at MRC Harwell, the <em>edison</em> mouse was identified as a robust OM model for bacterial NTHi infection.</p> <p>The <em>edison</em> mouse highlights a new candidate gene for susceptibility to chronic OM and will provide further insight into the genetic pathways and pathogenic processes involved in chronic OM.</p> |
| first_indexed | 2024-03-06T19:32:53Z |
| format | Thesis |
| id | oxford-uuid:1e13bb89-893e-434e-acc1-f39d0563d6cb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:33:37Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:1e13bb89-893e-434e-acc1-f39d0563d6cb2024-12-01T16:48:45Zedison - a novel model of otitis mediaThesishttp://purl.org/coar/resource_type/c_db06uuid:1e13bb89-893e-434e-acc1-f39d0563d6cbMolecular geneticsBiologyGenetics (life sciences)EnglishOxford University Research Archive - Valet2014Crompton, MBrown, SBurton, M<p>Otitis media (OM) is characterised by inflammation of the middle ear and is a common cause of conductive hearing impairment that places a substantial social, medical and economic burden on healthcare systems globally. Despite the importance of the disease, the aetiology of chronic middle ear inflammatory disease remains poorly understood. The development and persistence of chronic OM is multi-factorial with a significant genetic component. A new mouse model of chronic OM, <em>edison</em>, was generated by <em>N</em>-ethyl-<em>N</em>-nitrosourea (ENU) mutagenesis and discovered in a recessive screen at MRC Harwell.</p> <p>Homozygous <em>edison</em> mice have craniofacial abnormalities, an emphysema-like lung phenotype and spontaneously develop a conductive hearing loss at 28 days as measured by ABR. Histological analysis shows the hearing loss is associated with the development of chronic OM in the middle ear, characterised by mucosal inflammation and highly cellular ear exudates. Similar to the <em>Jeff</em> and <em>Junbo</em> mutants, <em>edison</em> shows raised levels of <em>Vegfa</em>, <em>Tnfα</em> and <em>Il-1β</em> in middle ear fluids. A putative functional mutation was identified, resulting in a missense Leu972Pro change in a relatively unknown gene, <em><em>Nisch</em>arin</em> (<em>Nisch</em>). The identification of additional ENU-induced <em>Nisch</em> alleles, and subsequent characterisation, validated <em>Nisch</em> as the causative gene in <em>edison</em>.</p> <p>NISCH selectively binds ITGA5, which is thought to have a role in modulating VEGF signalling through SRC and FAK kinases. A significant genetic interaction between <em>Nisch</em> and <em>Itga5</em> exists and impacts upon development of chronic OM. Mice heterozygous for <em>Itga5</em>-null and homozygous for <em>edison</em> alleles show a significantly increased penetrance and severity of chronic OM. Analysis of downstream pathways suggests that the <em>edison</em> allele is impacting upon both RAC1 and TGF-β/SMAD signalling.</p> <p>I also explored the potential use of the <em>edison</em> mouse as a model for bacterial challenge with the human otopathogen, NT<em>Hi</em>. Similar to the <em>Junbo</em> infection model at MRC Harwell, the <em>edison</em> mouse was identified as a robust OM model for bacterial NTHi infection.</p> <p>The <em>edison</em> mouse highlights a new candidate gene for susceptibility to chronic OM and will provide further insight into the genetic pathways and pathogenic processes involved in chronic OM.</p> |
| spellingShingle | Molecular genetics Biology Genetics (life sciences) Crompton, M edison - a novel model of otitis media |
| title | edison - a novel model of otitis media |
| title_full | edison - a novel model of otitis media |
| title_fullStr | edison - a novel model of otitis media |
| title_full_unstemmed | edison - a novel model of otitis media |
| title_short | edison - a novel model of otitis media |
| title_sort | edison a novel model of otitis media |
| topic | Molecular genetics Biology Genetics (life sciences) |
| work_keys_str_mv | AT cromptonm edisonanovelmodelofotitismedia |