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

Eps8 样家族基因及其相互作用伙伴的静纤毛束生长和维持的生理和分子基础。

• 批准号: BB/S006257/1
• 负责人: Walter Marcotti
• 金额: $ 101.9万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS006257%2F1
• 关键词: Physiological; molecular; basis; stereociliary; bundle

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).

声音是由位于内耳的极其敏感的感觉细胞（称为毛细胞）检测到的。它们的名字来源于从其顶面突出的毛发状元素（静纤毛）。为了让内耳分析声波携带的信息（例如频率，强度和时间），它必须采用复杂和相互关联的机制的组合。声音进入耳道，并产生微小的振动毛细胞静纤毛。这启动了声音转换成电信号，该电信号由带电离子通过静纤毛中存在的机械门控通道的开口的运动产生;该过程被称为机械-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，如语音和音乐以及危险警告。毛细胞静纤毛是声音感知中最重要的任务之一，其复杂的结构以及它们的形成和功能需要数百个分子的相互作用。每个静纤毛的长度精确地缩放以形成具有楼梯状结构的2-3排静纤毛（发束）束，类似于教堂管风琴上的管道。值得注意的是，一排内静纤毛的高度不仅在单个毛束内相似，而且在相邻毛细胞上的毛束之间也相似，这表明静纤毛的长度在这些感觉细胞中受到非常精确的控制和紧密的协调。控制这一机制的分子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，Eps 8是小鼠听毛细胞静纤毛中的一个重要分子。我们已经证明，缺乏Eps 8的小鼠的机械敏感的静纤毛束不能完全生长，导致它们失聪。最近，同事们还表明，人类EPS 8的突变会导致人们的深度耳聋。尽管Esp 8在声音检测中起着重要作用，但我们仍然不了解Esp 8用于调节静纤毛生长的机制，这对正常听力至关重要。我们将通过一系列旨在确定Eps 8调节静纤毛束形成和功能的机制的实验来解决人类生物学的这一重要方面。这些信息将被用于开发一种策略，通过在体内将正常分子递送到耳朵中来修复Eps 8诱导的耳聋，目的是恢复听力功能。拟议的项目非常具有挑战性，因为它需要结合几种复杂的技术，从分子和细胞到遗传，这些技术很难在同一个研究机构内找到。因此，为了实现我们恢复听力的重要目标，我们将谢菲尔德大学和MRC Harwell研究所（牛津大学）的专业知识结合起来。

项目成果

Neuroplastin genetically interacts with Cadherin 23 and the encoded isoform Np55 is sufficient for cochlear hair cell function and hearing

Neuroplastin 与钙粘蛋白 23 发生遗传相互作用，编码的亚型 Np55 足以维持耳蜗毛细胞功能和听力

• DOI: 10.1101/2021.11.10.468016
• 发表时间: 2021
• 作者: Newton S

Neuroplastin genetically interacts with Cadherin 23 and the encoded isoform Np55 is sufficient for cochlear hair cell function and hearing.

神经塑料与钙粘蛋白23的遗传相互作用，编码的同工型NP55足以足以完成耳蜗功能和听力。

• DOI: 10.1371/journal.pgen.1009937
• 发表时间: 2022-01
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Newton S;Kong F;Carlton AJ;Aguilar C;Parker A;Codner GF;Teboul L;Wells S;Brown SDM;Marcotti W;Bowl MR
• 通讯作者: Bowl MR

Loss of Baiap2l2 destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness.

• DOI: 10.1113/jp280670
• 发表时间: 2021-03
• 期刊: The Journal of physiology
• 作者: Carlton AJ;Halford J;Underhill A;Jeng JY;Avenarius MR;Gilbert ML;Ceriani F;Ebisine K;Brown SDM;Bowl MR;Barr-Gillespie PG;Marcotti W
• 通讯作者: Marcotti W