Exploiting mouse genomics to understand the workings of the cochlea

Lead Research Organisation: University of Sussex
Department Name: Sch of Life Sciences

Abstract

Our aim is to understand how the different elements of the hearing organ, the cochlea, interact with each other by making measurements from mice that have modifications of specific proteins in the cochlea. Through discovering the workings of the cochlea using this approach we will understand the basis of some forms of congenital deafness and provide the basis for eventual treatments. Environmental and genetic factors as well as the effects of ageing all lead to damage of the cochlea and consequent irreparable loss of hearing. Genetic disorders account for deafness in approximately 1 in every 1,000 births; more than 25% of the population aged over 75 has significant hearing loss. Our research depends heavily on the work of our colleagues who identify the proteins and produce the genetically modified mice, including mouse models of human inherited deafness. In this multidisciplinary approach to the study of hearing and deafness, we have developed special techniques for measuring the electrical responses from the cochlea and nano-scale movements of its different components

Technical Summary

The frequency selectivity, sensitivity and dynamic range of the cochlea depend on how the outer hair cells produce active mechanical feedback and interact with the major extracellular matrices of the cochlea, namely the basilar and tectorial membranes. We intend to make electrophysiological and micromechanical measurements in vivo from the cochleae of mice with modifications in outer hair cell motor proteins and extracellular matrix proteins of the basilar and tectorial membranes. The aims of these experiments are to understand how the outer hair cells interact with the tectorial and basilar membranes to amplify and tune the cochlea?s responses and to determine if the motor protein prestin can fully account for amplification in the cochlea. In mouse mutants that are models for human hereditary deafness, where tectorial membrane proteins are miss-expressed, we will investigate how interaction between the outer hair cells and tectorial membrane is impaired.

Publications

10 25 50
 
Description MRC Programme Grant
Amount £1,836,200 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2009 
End 02/2014
 
Description Cloth-ears 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We measured acoustic and electrophysiological properties of the cochleae of the "cloth-ear" mice
Collaborator Contribution Provided and genotyped cloth-ear mice
Impact 19737145
Start Year 2008
 
Description Prestin mice 
Organisation St Jude Children's Hospital
Country United States 
Sector Hospitals 
PI Contribution We made electrophysiological, micromechanical and acoustic measurements from the mice
Collaborator Contribution Provided Prestin KO mice and Prestin 499 KI mice
Impact 18516034 18234980 18221877
Start Year 2006
 
Description Supporting cells and cochlear amplification 
Organisation University of Kentucky
Department Department of Otolaryngology
Country United States 
Sector Academic/University 
PI Contribution Our collaborator Hongbo Zhao supplies us with mice with genetically modified connexin 26 links between the Deiters cells and outer hair cells of the cochlea. We make acoustical, electrical and mechanical measurements from the cochlea. The purpose of these measurements is to investigate the "tensioning" influence of supporting cells on amplification by the cochlea
Collaborator Contribution The collaboration has enabled us to tackle an interesting and usually technically inaccessible probel, which is the mechanical influence of the supporting cells on amplification in the cochlea. This is part of our programme and offers an approach that was not available at the time of writing the programme
Impact We are still making measurements This is multidisciplinary project involving, molecular genetics, molecular biology, cellular physiology, systems physiology, biophysics and computational and analytical modelling.
Start Year 2011
 
Description Tectorin mice 
Organisation University of Sussex
Department School of Life Sciences Sussex
Country United Kingdom 
Sector Academic/University 
PI Contribution Made acoustic, electrophysiological and micromechanical measurements from the mice
Collaborator Contribution Provided and genotyped alpha tectorin, exon 18, beta tectorin mice
Impact 19853029 8797289 7220887 23129639
Start Year 2006