GRL - Prof Steel

Lead Research Organisation: MRC Human Genome Mapping Project

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Special contribution relates to the transfer of Professor Steels programme from MRC Institute of Hearing research to the Wellcome Trust Sanger institute. Abstract: Hearing impairment is very common in humans, but it is also a very heterogeneous disorder, with a wide range of causes. For example, there are probably several hundred genes involved in deafness, any one of which can be mutated and cause deafness in an individual. This makes it difficult to study directly in humans. The long-term aim of the work described here is to develop medical treatments for hearing impairment to provide an alternative to the imperfect approaches of amplification and cochlear implantation presently available. Developing new approaches must build upon improved understanding of the causes of hearing impairment and accurate diagnosis. A genetic approach, using hearing-impaired mouse mutants, is adopted to identify the key molecules in the development and function of hearing. As we assemble more of the molecular components, we not only will facilitate the development of generic approaches to treatment, but also establish which are most commonly involved in deafness in the human population. Further work can then focus upon the most common causes of human deafness. In this proposal, I outline plans to build upon the current work of my group to a) investigate the molecular basis of the development of sensory patches in the inner ear, b) investigate the role of key molecules in hair cell development and function, c) use mutants we have studied with a broad range of specific defects to develop diagnostic tools for particular pathologies, and d) screen newly-generated mouse mutants for evidence of hearing and/or balance defects, characterise their pathology, and ask which of the genes involved are associated with deafness in humans.

Publications

10 25 50

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Bergman JE (2010) Study of smell and reproductive organs in a mouse model for CHARGE syndrome. in European journal of human genetics : EJHG

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Bosman EA (2013) Omi, a recessive mutation on chromosome 10, is a novel allele of Ostm1. in Mammalian genome : official journal of the International Mammalian Genome Society

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Calvert JA (2011) A missense mutation in Fgfr1 causes ear and skull defects in hush puppy mice. in Mammalian genome : official journal of the International Mammalian Genome Society

 
Description British Tinnitus Association roundtable at the House of Commons
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Election to Royal Society Council
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Membership of Royal Society Science Policy Committee
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Royal Society Grants Committee
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Assisted transfer strategic award
Amount £1,500,000 (GBP)
Funding ID WT100669MA 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 09/2018
 
Description BBSRC project grants
Amount £447,982 (GBP)
Funding ID BB/M02069X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2015 
End 06/2018
 
Description Characterising new mouse knockouts of candidate genes from human hearing studies
Amount £159,920 (GBP)
Funding ID G73 
Organisation Action on Hearing Loss 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 01/2018
 
Description Diagnostic tools for stratifying age-related progressive hearing loss by pathological features
Amount £160,000 (GBP)
Funding ID G86 
Organisation Action on Hearing Loss 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2017 
End 01/2020
 
Description EUMODIC
Amount £2,000,000 (GBP)
Funding ID 37188 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2007 
End 01/2012
 
Description Exploration of lipidomics as a diagnostic tool for different forms of hearing loss
Amount £10,000 (GBP)
Funding ID F97 
Organisation Action on Hearing Loss 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2019 
End 03/2020
 
Description ITN LISTEN
Amount € 2,584,755 (EUR)
Funding ID 722098 - LISTEN 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 12/2016 
End 11/2020
 
Description MRC project grant
Amount £640,097 (GBP)
Funding ID MR/N012119/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2016 
End 06/2019
 
Description PhD Studentship
Amount £76,500 (GBP)
Funding ID S28 Steel 
Organisation Action on Hearing Loss 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Title Development of advanced protocols for ABR analysis of auditory function 
Description We have developed a new battery of tests that we use to ask if mouse mutants show any defects in frequency selectivity or temporal processing. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Main research is in progress. 
 
Title New deaf mouse mutants 
Description The funding has contributed to the production of many new mouse mutants affecting genes thought to be involved in auditory development or function 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2009 
Provided To Others? Yes  
Impact These new mutants are in the early stages of study, but it looks as if many unexpected genes underlie deafness, while other genes previously thought to be good candidates do not in fact lead to deafness. Around 3% (9/313) of all genes screened so far are associated with hearing impairment, and additional genes are associated with supra-threshold anomalies that we are currently following up. 
 
Title Software and other support for ABR recordings 
Description We supply software that we developed for optimised recording and analysis of Auditory Brainstem Response measurements to assess hearing ability in mice. Also, we supply details of the equipment needed and we host visits by researchers wanting to set the system up in their own lab. 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact The ABR screen using this method has been adopted by the International Mouse Phenotyping Consortium and new data from targeted mouse mutants will emerge to add to our own screening data currently from over 600 new mutant lines, all available on the Sanger Institute Mouse portal 
 
Description Analysis of Synaptojanin2 mutant mouse 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution We generated the derived tm1b allele from the original tm1a mutation, carried out ABRs, DPOAEs, expression studies, scanning electron microscopy, confocal imaging of innervation of hair cells, and characterisation of the effects of the allele on expression levels.
Collaborator Contribution Single hair cell recordings.
Impact So far a chapter in the student's thesis which is being adapted to form the basis of a publication.
Start Year 2014
 
Description Bioinformatic analysis of microarray data 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated the microarray data and carried out the remaining experiments required for each study, and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators have analysed out microarray data and provided descriptions and analyses of the results and contributed to the interpretation and writing up of the data.
Impact 19363478
Start Year 2008
 
Description Chinese deaf children 
Organisation Chongqing University
Country China 
Sector Academic/University 
PI Contribution We have proposed candidate genes for involvement in deafness from our mouse studies, and our collaborators included these genes in their targeted pulldown design followed by sequencing of DNA samples from affected children. We have followed up by further analysis of the specific mutations discovered associated with deafness
Collaborator Contribution See above. The Chinese collaborators recruited a very large sample of deaf children for DNA analysis, carried out the pulldown and sequencing, and followed up by looking at parents.
Impact The first joint paper was published this year, Bunillo et al. in EMBO Molecular Medicine.
Start Year 2011
 
Description Emx2 in pituitary gland 
Organisation University of Michigan
Country United States 
Sector Academic/University 
PI Contribution Our contribution was to provide genotyped, embedded and sectioned material of Emx2 mutants and littermate controls for analysis by our collaborators. We contributed to the design of the relevant part of the work, the conduct, and the writing up of the work.
Collaborator Contribution Our collaborators carried out the majority of the research described.
Impact 19407506
Start Year 2007
 
Description Functional analysis of Mir96 mutant hair cells 
Organisation University of Sheffield
Department Department of Biomedical Science
Country United Kingdom 
Sector Academic/University 
PI Contribution We have contributed to the collection of experimental data and to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators have contributed to the collection of experimental data and the analysis, interpretation and writing up of the findings.
Impact 21245307
Start Year 2008
 
Description Genotype/phenotype analysis in Usher syndrome 
Organisation University College London
Department Institute of Ophthalmology UCL
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided the sequencing of the patient DNA and the initial sequence analysis and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators carried out the detailed clinical assessments of the patients in this study and contributed to the design, conduct, analysis and writing up of the work.
Impact 21487335
Start Year 2007
 
Description Hearing in the Cx30 T5M mutant 
Organisation Venetian Institute of Molecular Medicine
Country Italy 
Sector Academic/University 
PI Contribution We established our own in house breeding colony of these mutants, used offspring of all genotypes to measure endocochlear potential in the cochlea, and contributed to writing the manuscript.
Collaborator Contribution Our collaborators carried out experimental work on the mutant mice and contributed to the design, materials, conduct, analysis and writing up of the work.
Impact 20858605
Start Year 2009
 
Description Human exome sequence analysis for age-related hearing loss 
Organisation Medical University of South Carolina
Country United States 
Sector Academic/University 
PI Contribution We are analysing the exome sequence, selecting candidate variants, knocking these into mice and investigating the effects on hearing.
Collaborator Contribution The collaborators have assembled a large cohort of people with very well-characterised hearing function, mostly with hearing impairment, and collected samples for exome sequencing.
Impact One publication, Lewis et al 2018. Yes, highly multi-disciplinary.
Start Year 2017
 
Description Investigations of Mir96 role in hearing 
Organisation Hospital Ramón y Cajal
Country Spain 
Sector Hospitals 
PI Contribution We are analysing two mouse lines with hiuman MIR96 mutations knocked in.
Collaborator Contribution They have identified the human mutations and are now investigating the possibility of using nasal biopsy cultures for drug screening.
Impact Lewis et al 2009 Mencia et al 2009
Start Year 2009
 
Description Mir96 in human and mouse deafness 
Organisation Hospital Ramón y Cajal
Country Spain 
Sector Hospitals 
PI Contribution We have contributed all of the work on the mouse mutation in Mir96 including identification of the gene involved as a microRNA and characterisation of the phenotype of the mouse.
Collaborator Contribution Our collaborators have contributed to our combined effort to identify the mutations responsible for progressive hearing loss in mice and humans, in particular carrying out all of the work on human families.
Impact 19363479; 19363478
Start Year 2006
 
Description Modelling of a new Isl1 mutation 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution We discovered the mutation, established the phenotype, and designed the experiments, carried out the experimental work, analysed the results and wrote the paper.
Collaborator Contribution Our collaborator modelled the new mutation in Isl1 and its probable effect on protein interactions and drafted the text describing this for the publication
Impact 21936904
Start Year 2011
 
Description Phenotypes of Tbx1 and Chd7 mouse mutants 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution We prepared the inner ears for paint-filling and analysed the malformations, and contributed to writing the relevant parts of the paper.
Collaborator Contribution Dr Scambler and his colleagues carried out the mouse breeding experiments and detailed analysis of head development, and provided fixed inner ears for us to examine and analyse.
Impact 19855134
Start Year 2008
 
Description Role of Wnt5a in ear development 
Organisation Emory University
Department Emory School of Medicine
Country United States 
Sector Academic/University 
PI Contribution We have carried out a scanning electron microscopic analysis of the organ of Corti in Wnt5a mutant mouse samples from our collaborator and contributed to the design, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators have carried out a detailed analysis of the development of the organ of Corti in the Wnt5a mouse mutant and contributed to the design, conduct, analysis and writing up of the work.
Impact 17433286
Start Year 2006
 
Description Role of twinfilin in hair cells 
Organisation University of Helsinki
Country Finland 
Sector Academic/University 
PI Contribution We carried out experimental work on the role of twinfilin in the development of stereocilia bundles on hair cells. We contributed to the design, materials, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators provided essential materials for the analysis of the role of twinfilin in hair cell development and carried out some of the exeriments in Helsinki. They contributed to the design, conduct, analysis and writing up of the work.
Impact 19774077
Start Year 2007
 
Description Smell and reproductive organs in Chd7 mice 
Organisation University Medical Center Gronigen
Country Netherlands 
Sector Hospitals 
PI Contribution We carried out all the work jointly with the clinician student from Groningen in my laboratory. We contributed to the design, materials, conduct, analysis and writing up of the work.
Collaborator Contribution Our collaborators sent a clinician student to my laboratory to carry out basic mouse research and contributed to the design, analysis and writing up of the work.
Impact 19809474
Start Year 2007
 
Description Study of Ildr4 mutation 
Organisation National Institute on Deafness and Other Communication Disorders (NIDCD)
Country United States 
Sector Public 
PI Contribution Phalloidin labelling to examine hair bundles in the mutants and littermate controls. Endocochlear potential measurements and ABR analysis. Analysing and writing up relevant parts of the publication.
Collaborator Contribution The partners carried out the rest of the analyses published.
Impact A publication was the result.
Start Year 2014
 
Title Popcorn, a software for linking genes to upstream regulators in a network 
Description Popcorn, a software for linking genes to upstream regulators in a network. Used for analysis of networks, linking genes that are not otherwise discoverable using existing software. The details will be published soon, but it is available on GitHub now. Software written and developed by Dr Morag Lewis. 
Type Of Technology Software 
Year Produced 2020 
Open Source License? Yes  
Impact We have used this software to draw up a network, soon to be published (Lewis et al). 
 
Title Popcorn, a software for linking genes to upstream regulators in a network 
Description Popcorn, a software for linking genes to upstream regulators in a network. Used for analysis of networks, linking genes that are not otherwise discoverable using existing software. The details will be published soon, but it is available on GitHub now. Software written and developed by Dr Morag Lewis. 
Type Of Technology Software 
Year Produced 2020 
Open Source License? Yes  
Impact We have used this software to draw up a network, soon to be published (Lewis et al). 
 
Title Software for recording and analysing auditory responses 
Description Software for recording and analysing auditory responses 
Type Of Technology Software 
Year Produced 2008 
Impact We have distributed this software free of charge to around ten other laboratories working on recording auditory responses from mutant mice, around the world. 
 
Description AoHL supporters laboratory visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact We hosted a visit of around 30 active supporters of the charity Action on Hearing Loss plus 6 charity staff, who visited the labs, watched demonstrations of research methods, listened to talks and posters, and discussed our research.
Year(s) Of Engagement Activity 2018
 
Description Brain prize talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I presented a talk at the Brain Prize ceremony, attended by many Danish lay people, politicians, health researchers, etc.

Requests for further outreach talks in Denmark
Year(s) Of Engagement Activity 2012
 
Description ECNP plenary talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Over 1000 clinical psychologists attended

Not known yet
Year(s) Of Engagement Activity 2013
 
Description Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interview and article with The Scientist magazine
Year(s) Of Engagement Activity 2015
 
Description Interview for Naked Scientist 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Not known yet
Year(s) Of Engagement Activity 2013
 
Description Interview for journal article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact I was interviewed for an on-line video and/or journal frontpiece article for four articles.

Nothing known
Year(s) Of Engagement Activity 2010,2011,2012
 
Description Interview on BBC TV programme See Hear 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact An extended interview was broadcast, resulting in a number of positive comments about the content and manner of the interview.

None known
Year(s) Of Engagement Activity 2010
 
Description Participation and presentation of a talk at a Zellweger syndrome patient group support weekend 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact I attended a weekend retreat organised for families affected by Zellweger disease, presented a talk about hearing loss in Zellweger and answered questions at the formal session as well as informally during the weekend.
Year(s) Of Engagement Activity 2019
 
Description Public talk in Denmark 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Much interest from the 500 members of the public afterwards - over an hour answering questions after talk.

Not known yet
Year(s) Of Engagement Activity 2013
 
Description Radio interview 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Not known yet
Year(s) Of Engagement Activity 2013
 
Description Telephone interviews about research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Talking about my work on deafness using mouse models to the media.

Nothing known
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Women in Science event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Around 40 people attended an evening event on "Women in Science" organised by Action on Hearing Loss. Many were scientists supported by the charity, others were active or potential supporters. There were 4 talks and Karen Steel gave one of these. There was lively discussion afterwards, and the supporters expressed appreciation of the work done.
Year(s) Of Engagement Activity 2018