Physiological and molecular basis of stereociliary bundle growth and maintenance by the Eps8-like family genes and their interacting partners.

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Sound is detected by extremely sensitive sensory cells named hair cells that are located in the inner ear. Their name derives from the hair-like elements (stereocilia) that project from their apical surface. In order for the inner ear to analyse the information carried by sound waves (e.g. frequency, intensity and timing) it has to employ a combination of intricate and interrelated mechanisms. Sound enters the ear canal and produces minute vibrations of the hair cell stereocilia. This initiates the conversion of sound into an electrical signal generated by the movement of charged ions through the opening of mechanically gated channels present in the stereocilia; a process known as mechano-electrical transduction. It is this electrical signal that is sent to the brain via specialized nerve fibres, allowing us to perceive different forms of sound such as speech and music and warnings of danger.It is well established that hair cell stereocilia perform one of most important tasks in sound perception, which is paralleled by their complex structure and the fact that their formation and function require the interplay of several hundred molecules. The length of each stereocilium is scaled precisely to form bundles of 2-3 row of stereocilia (hair bundle) with a staircase-like architecture, similar to the pipes on a church organ. What it is remarkable is that the height of stereocilia within a row is similar not only within a single hair bundle but also between bundles on adjacent hair cells, indicating that stereociliar length is very precisely controlled and tightly coordinated in these sensory cells. Mutations in the molecules that control this mechanism lead to different degrees of hearing loss including profound deafness.Previous work from our group has shown that Eps8 is an essential molecule present in the stereocilia of mouse auditory hair cells. We have shown that the mechanically sensitive stereociliary bundles of mice lacking Eps8 do not fully grow, causing them to be deaf. More recently, colleagues have also shown that a mutation in the human EPS8 causes profound deafness in people. Despite the essential role of Eps8 in sound detection, we still do not understand the mechanisms used by Esp8 to regulate stereocilia growth, which is crucial for normal hearing. This knowledge is essential to develop suitable diagnostic protocols and therapies.We will address this important aspect of human biology by performing a series of experiments designed to identify the mechanisms used by Eps8 to regulate the formation and function of the stereociliary bundle. This information will be used to develop a strategy to repair Eps8-induced deafness by the in vivo delivery into the ear of normal molecules with the aim to restore hearing function.The proposed project is very challenging because it requires the combination of several complex techniques, from the molecular and cellular to genetic, which are difficult to find all within the same research institution. Therefore, to achieve our important goal of restoring hearing, we have created a unique combination of expertise from PIs at the University of Sheffield and the MRC Harwell Institute (Oxford).