edison - a novel model of otitis media

Thesis

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, edison, was generated by N-ethyl-N-nitrosourea (ENU) mutagenesis and discovered in a recessive screen at MRC Harwell.

Homozygous edison 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 Jeff and Junbo mutants, edison shows raised levels of Vegfa, Tnfα and Il-1β in middle ear fluids. A putative functional mutation was identified, resulting in a missense Leu972Pro change in a relatively unknown gene, Nischarin (Nisch). The identification of additional ENU-induced Nisch alleles, and subsequent characterisation, validated Nisch as the causative gene in edison.

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 Nisch and Itga5 exists and impacts upon development of chronic OM. Mice heterozygous for Itga5-null and homozygous for edison alleles show a significantly increased penetrance and severity of chronic OM. Analysis of downstream pathways suggests that the edison allele is impacting upon both RAC1 and TGF-β/SMAD signalling.

I also explored the potential use of the edison mouse as a model for bacterial challenge with the human otopathogen, NTHi. Similar to the Junbo infection model at MRC Harwell, the edison mouse was identified as a robust OM model for bacterial NTHi infection.

The edison 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.

Authors: Crompton, M

• Publication date: 2014
• DOI: 10.5287/ora-e2avrga09
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: deafness; genetics; mouse; otitis media
• Subjects: Molecular genetics; Biology; Genetics (life sciences)