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

声音是由位于内耳的名为毛细胞的极其敏感的感觉细胞探测到的。它们的名字来源于它们顶端表面突出的毛发状元素(立体纤毛)。为了让内耳分析声波携带的信息(如频率、强度和时间)，它必须使用复杂和相互关联的机制的组合。声音进入耳道，产生毛细胞立体纤毛的微小振动。这启动了将声音转换为电信号的过程，该电信号是由带电离子通过打开存在于立体纤毛中的机械门控通道而产生的；这一过程被称为机械-电转导。正是这种电信号通过特殊的神经纤维发送到大脑，使我们能够感知不同形式的声音，如语音、音乐和危险警告。众所周知，毛细胞立体纤毛在声音感知中扮演着最重要的任务之一，其复杂的结构和它们的形成和功能需要数百个分子的相互作用。每个立体纤毛的长度被精确地缩放，形成2-3排立体纤毛(发束)的束，具有楼梯状的建筑，类似于教堂管风琴上的管子。值得注意的是，一排毛细胞内的纤毛高度不仅在单个毛束内，而且在相邻毛细胞上的毛束之间也是相似的，这表明在这些感觉细胞中，立体纤毛的长度得到了非常精确的控制和紧密的协调。控制这一机制的分子的突变会导致不同程度的听力损失，包括深度耳聋。我们小组以前的工作表明，Eps8是小鼠听觉毛细胞立体纤毛中存在的一种必不可少的分子。我们已经证明，缺乏Eps8的小鼠对机械敏感的立体纤毛束不能完全生长，导致它们耳聋。最近，同事们还表明，人类EPS8基因的突变会导致人类严重耳聋。尽管Esp8在声音检测中起着至关重要的作用，但我们仍然不了解Esp8调节体毛生长的机制，这对正常的听力至关重要。这些知识对于开发合适的诊断方案和治疗方法是必不可少的。我们将通过进行一系列实验来解决人类生物学的这一重要方面，以确定EPS8用于调节立体纤毛束的形成和功能的机制。这些信息将被用来开发一种策略，通过将正常分子体内传递到耳朵中来修复Eps8引起的耳聋，以恢复听力功能。拟议的项目非常具有挑战性，因为它需要几种复杂技术的组合，从分子、细胞到基因，这些技术很难在同一研究机构内找到。因此，为了实现我们恢复听力的重要目标，我们创造了谢菲尔德大学PI和MRC Harwell Institute(牛津)的独特专业组合。

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).