Genetics & Pathobiology of Deafness

Lead Research Organisation: MRC Mammalian Genetics Unit

Abstract

Infection and inflammation of the middle ear (otitis media) is common in infants and is an important cause of deafness in children. Most middle ear infections are self-limiting but in persistent cases that do not respond to antibiotic therapy may require surgery. In western world, placement of grommets to treat chronic otitis media is one of the commonest surgical procedures performed on children. The discovery at Harwell that mutations in two genes, Fbxo11 and Evi1, predispose to otitis media in mice offers a novel way of studying the biology of this disease. The programme aims at a better understanding of the mechanisms of disease development and progression including interactions between hypoxia, bacterial pathogens and the immune system. Potential benefits include identifying common pathways of disease development that could suggest new therapeutic targets for medical treatments and new mouse models for the development and testing of novel treatments.

Technical Summary

Inflammatory disease of the middle ear, otitis media (OM), is an important cause of childhood deafness. The most effective current treatment for persistent forms of OM in children is the surgical placement of ventilation tubes or grommets in the eardrum. This procedure is the commonest operation in the UK (30,000 per annum). However, surgery is variable in its effectiveness and medical treatments are not always an alternative. In case controlled clinical trials, medical treatments are found to be largely ineffective for the commonest form of OM, glue ear.||This programme investigates OM using two new mouse models, Jeff and Junbo. These are the first good mouse models of chronic lifelong OM in otherwise healthy mice. Junbo carries a mutation in the Evi1 transcription factor that represses the TGF-beta signalling pathway by binding the key intracellular messenger, phosphorylated Smad3. The Jeff mutant carries a mutation in an F-box gene, Fbxo11, a member of a large family of proteins that are specificity factors for the SCF E3 ubiquitin ligase complex and targets molecules for ubiquitination and proteasomal degradation. One of the Fbxo11 partners, spectrin beta2 plays a critical role in the shuttling of phosphorylated Smad3 and Smad4 to the nucleus and the action of TGF-beta signalling pathways. This is a critical finding since Evi1 is a repressor of Smad3 and suggests that both mutations lead to OM through dysregulation of Smad3 function and consequent effects on downstream pathways. ||Low oxygen tension (hypoxia) in the inflamed middle ear bulla is a feature of OM in Junbo, and first theme of the programme is to explore the effect hypoxia on immune cell (macrophage and neutrophil function). There are possible connections between TGF-beta pathways and hypoxic responses mediated by HIF-1? pathways suggesting that impairment of localized innate immunity function may play a role in predisposition to OM. One translational aspect of these studies is a proof of concept trial that anti-hypoxic drugs are a novel therapeutic approach to OM treatment.||In both mutants, the OM phenotype is dependent on the microbiological status of the mice. The first mutant Junbo tested in germ-free conditions (that is in the absence of bacteria and viruses) develop OM, but later than they do in specific pathogen free conditions where they have normal commensal staphylococcal and streptococcal bacteria in the nasopharynx. This remarkable result confirms the importance of genetics in predisposition to OM and shows that bacteria may accelerate the onset of disease but that other inflammatory triggers may initiate OM. One translational opportunity is to use germ free mice in challenge models with human OM pathogens to test new treatments and vaccines.

Publications

10 25 50
 
Description MRCT Development Gap Fund A853 0092
Amount £112,000 (GBP)
Organisation LifeArc 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2008 
End 09/2012
 
Description MRCT Development Gap Fund A853 0114
Amount £251,000 (GBP)
Organisation LifeArc 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 06/2013
 
Description University of Sheffield PhD Studentship
Amount £69,000 (GBP)
Organisation University of Sheffield 
Sector Academic/University
Country United Kingdom
Start 09/2012 
End 09/2015
 
Title A mouse model for infection studies of the middle ear 
Description Junbo mutant mice are predisposed to developing otitis media spontaneously Junbo mice can be infected intranasally with an important human otopathogen non-typeable Haemophilus influenzae This model can be used for vaccine and antibiotic testing 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2015 
Provided To Others? Yes  
Impact the model is available through Medical Research Council Technology and funded by MRCT DG grant A853-0114 Michael Cheeseman PI 
URL http://www.licensingopportunities.co.uk/research-tools/79/otitis-media/
 
Description NVD collaboration 
Organisation Novartis
Department Vaccines and Diagnostics
Country United States 
Sector Private 
PI Contribution Pre-clinical testing
Collaborator Contribution supply of reagents
Impact validation of model
Start Year 2012
 
Title Compounds Targeting the VEGF and or HIF pathway such as Sorafenib or Vatalanib for use in the treatment of otitis media 
Description Compounds Targeting the VEGF and or HIF pathway such as Sorafenib or Vatalanib for use in the treatment of otitis media 
IP Reference WO2011117568 
Protection Patent application published
Year Protection Granted 2011
Licensed No
Impact The patent application was allowed to lapse after MRCT were unable to get support from a pharma partner or University of Edinburgh
 
Description Deafness UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Supporters
Results and Impact Deafness UK: 3rd Recent Advances in Molecular Biology of Otology meeting.
'Mouse Models of Otitis Media'
CBI Conference Centre London, 21-Mar-2011

Talk about animal models in deafness research


met a researcher and have gone on to examine one of her PhD students, and reviewed papers and grant applications from that group
Year(s) Of Engagement Activity 2011
 
Description LAVA meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact talk to Laboratory Animal Veterinary Association about use of animal models in hearing research

Laboratory Animals Veterinary Association: The laboratory mouse. 'Modelling Haemophilus influenzae middle ear infection in Junbo mice' York, 24-25 Sept 2012


met with Named Veterinary Surgeons including those I have begun to work with
Year(s) Of Engagement Activity 2012
 
Description Mouse pathology meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Wellcome Trust Conference
organizing committee
'Mouse Models of Disease-linking in vivo observations to pathology end points'
Sanger Institute, Hinxton, 1-3 Feb 2012


further meeting planned 2014
Year(s) Of Engagement Activity 2011
 
Description RCVS teaching 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact BVSc intercalated pathology course, Royal Veterinary College, London University
Lecturing
'Mouse models of human disease'
'Mouse models of deafness'
Dec 2010 and Dec 2011


engagement with undergraduate veterinarians
undergraduate project set up

invitation to talk to Edinburgh vet students 2014
Year(s) Of Engagement Activity 2010,2011