Funded by the Medical Research Council.
Medical Research Council: Interaction between sensory and supporting cells in the organ of Corti
We study interaction between sensory outer hair cells and the supporting cells of the mammalian cochlea that comprise a restraining, complex, flexible, fluid filled cage that is proposed to optimise exchange and control of energy between outer hair cells and the cochlear partition, including the basilar membrane. Cochlear hair cells die and are not replaced when damaged by exposure to intense sounds, disease, age, and genetic disorders. Recently, however, we have shown that supporting cells can be converted into hair cells at various postnatal stages, but remain immature. Hair cell immaturity is likely due to lack of interaction with surrounding supporting cells, which is why it is essential to understand this interaction for restoration of hearing. To this end, we will systematically modify and delete the motor protein, prestin, in outer hair cells and cytoskeletal proteins in supporting cells in mice and produce mouse models of age-related and congenital hearing loss. With mice that express channel rhodopsins in outer hair cells and supporting cells, we can excite and reversibly change the mechanical properties of the cochlea with light flashes. Through modelling, based on in vivo and in vitro acoustical, mechanical, and electrical measurements, our understanding of the functional significance of interaction between outer hair cells and their supporting cell cages can be developed and tested, leading to the detailed understanding necessary to fully exploit the exciting regenerative possibilities now becoming available.
This project commenced in September 2015 and will end in August 2020.
Our prime aim is to study interaction between individual cells and other elements of the complex sensory epithelium of the organ of Corti of the mammalian cochlea that determines the exquisite sensitivity and frequency selectivity of mammalian audition. Understanding this interaction is essential for future development of successful treatments for hearing loss, especially those involving recovery of damaged, or replacement of dead, sensory hair cells.
£1,564,907, Medical Research Council Programme Grant
Outcomes of our research will be of immediate relevance to those who investigate and model the workings of the cochlea and explore ways of repairing and replenishing the sensory epithelium of the organ of Corti. We will provide fundamental information about sensory processing in the cochlea that should contribute to the training and knowledge base of neuroscientists, medical practitioners and bioengineers. Techniques and approaches that will be employed in the proposed research programme have potential utility in research fields outside neuroscience. Hearing research at £1.34 per person affected is massively underfunded compared with cardiovascular and vision research at £49.74 and £14.50 respectively (Action on Hearing Loss, 2013). One outcome of underfunding is lack of basic understanding of the peripheral auditory system that is necessary to produce effective and radical new treatments. A main objective of our proposed research is to contribute towards filling this knowledge gap. A potential outcome of immediate to medium-term application in public health is a validated model of hearing impairment that could be used to investigate the behaviour of different types of cochlear implant and prostheses in terms of their action at the cochr level. This might inspire novel strategies for signal processing or implant stimulation, which exploit particular features of the impaired cochlea. A better model of the hearing-impaired cochlea would drive the development of hearing loss simulation algorithms and hence enable better and more reliable testing of new signal processing strategies for hearing prostheses.
Andrei Lukashkin (PI)Ian RussellVictoria LukashkinaPatrício Simões
Burwood GWS, Russell IJ, Lukashkin AN (2017). Rippling pattern of distortion product otoacoustic emissions evoked by high-frequency primaries in guinea pigs. J. Acoust. Soc. Am. 142:855–862. (DOI:10.1121/1.4998584)
Lukashkina VA, Yamashita T, Zuo J, Lukashkin AN, Russell IJ (2017). Amplification mechanisms differ along the length of the mouse cochlea as revealed by connexin 26 deletion from specific gap junctions. Sci. Rep. 7:5185. (DOI:10.1038/s41598-017-04279-3)
Lukashkina VA, Levic S, Lukashkin AN, Strenzke N, Russell IJ (2017). A connexin30 mutation rescues hearing and reveals roles for gap junctions in cochlear amplification and micromechanics. Nat. Commun. 8:14530. (DOI: 10.1038/ncomms14530)
Jones GP, Russell IJ, Elliott SJ, Lukashkin AN (2015). Modified protein expression in the tectorial membrane of the cochlea reveals roles for the striated sheet matrix. Biophys. J. 108: 203–210.
Brighton and Sussex Medical School
University of Southampton
Queen Mary, University of London
St. Jude Children’s Research Hospital
University Medicine Gottingen