How biological systems orchestrate their development and how complex signals are processed by mature neuronal networks are major challenges in the quest to understand human biology and disease. The auditory system provides an ideal model with which to address these questions, primarily because it involves a highly ordered array of a very small number of sensory cells with well-defined neuronal circuitry.
Sound is detected by extremely sensitive sensory receptors called hair cells that are located in the cochlea. The name 'hair cell' derives from the hair-like elements (stereocilia) that project from the cell’s apical surface. During sound stimulation, the stereocilia vibrate, initiating the conversion of sound into an electrical response. This initial electrical response is then shaped by various ion channels present in the basal surface of the hair cells and relayed to the brain enabling us to hear different sounds.
The major challenges in the Marcotti, Johnson and Corns laboratories are to understand the molecular and cellular mechanisms involved in the development, function and ageing of the mammalian auditory system. This is critical for our understanding of numerous different forms of hearing loss and deafness and for the development of gene-based therapies.
Current projects include:
The development and function of the mammalian auditory circuitry
The aim of this project is to unravel how electrical activity controls the maturation of sensory hair cells and the development of topographic maps in the brainstem. Moreover, we are interested in understanding how specialized auditory ribbon synapses shape the transfer of information from hair cells to the auditory fibres in vitro and in vivo.
This work is funded by the Wellcome Trust (Marcotti) and the Royal Society (Johnson).
Physiological and molecular basis of stereociliary bundle growth and maintenance by the Eps8-like family genes and their interacting partners
The stereociliary bundle of cochlear hair cells is the site of mechanotransduction, where sound energy is converted into an electrical signal. We have previously shown that the Eps8 family of actin binding proteins, which are associated with deafness, play a crucial role in hair bundle formation (Eps8) and maintenance (Eps8L2).
Currently, we still have very limited knowledge of the molecular factors that regulate actin dynamics in hair cell stereocilia. Therefore, the aims of this project are to identify the interactome of the Eps8-like proteins that control actin dynamics in hair cells, how it operates and how this knowledge can be used to treat hearing loss. This project will be addressed in collaboration with Professor S. Brown and Dr M. Bowl at the MRC Harwell Institute.
This work is funded by the BBSRC to Marcotti/Johnson (Sheffield) and Brown/Bowl (MRC Harwell).
Unravelling the roles of the Usher1 proteins in mechanoelectrical transduction
Stereocilia are organized in a staircase-like architecture, the hair bundle, resembling the staggered pipes on a church organ. Their formation and function require the interplay of a large number of molecules, including the Usher proteins myosin 7a and harmonin. Mutations in these molecules lead to deafness in mice and humans. This project aims to understand the role of these Usher syndrome proteins in the formation and function of the hair bundle of cochlear hair cells, and to determine why their absence lead to severe-to-profound forms of deafness. This project will be addressed in collaboration with Professor CJ. Kros at the University of Sussex.
This work is funded by Action on Hearing Loss to Marcotti (Sheffield) and Kros (Sussex).
Age-related hearing loss: understanding molecular and genetic mechanisms
Age-related hearing loss (ARHL) is a complex disorder caused by a combination of genetic and environmental factors. Approximately half of all adults in their seventh decade exhibit hearing loss that is severe enough to affect day-to-day communication. It is expected that about 14.5 million people in the UK and more than 500 million worldwide will be affected by ARHL by 2030. Currently, we have very little understanding into the mechanisms underlying ARHL, which hampers the development of effective treatments for the disease. The overall aim of this project is to identify the mechanisms underlying ARHL and targetable genetic pathways for future therapeutic intervention against ARHL and possibly cognitive impairment. This project will be addressed in collaboration with Prof Brown & Dr Bowl (MRC Harwell Institute).
A part of this work has been funded by Action on Hearing Loss (PhD studentship) to Marcotti/Corns (Sheffield) and Bowl (MRC Harwell).
- Professor Mimoun Azzouz (SITraN, University of Sheffield)
- Professor Steve D.M. Brown (MRC Harwell, UK)
- Dr Mike Bowl (MRC Harwell, UK)
- Professor Corne J. Kros (University of Sussex, UK)
- Professor Guy P. Richardson (University of Sussex, UK)
- Professor David N. Furness (Keele University, UK)
- Dr Saaid Safieddine (Pasteur Institut, France)
- Professor Jutta Engel (Saarland University, Germany)
- Professor Fabio Mammano (University of Padova, Italy)
- Professor Sergio Masetto (University of Pavia, Italy)
- Professor Dwayne D. Simmons (Baylor University, USA)
- Professor Henrique von Gersdorff (Vollum Institute, USA)