Investigating the mechanisms of stereocilia length regulation and innovative strategies for restoring hearing

研究静纤毛长度调节机制和恢复听力的创新策略

基本信息

  • 批准号:
    10678569
  • 负责人:
  • 金额:
    $ 36.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-04-10 至 2023-09-30
  • 项目状态:
    已结题

项目摘要

Abstract Sensorineural hearing loss is a debilitating condition with no cure that directly impacts >30 million people. A common cause of inherited hearing loss is the disruption of cochlear hair cell stereocilia, which are essential for transducing sound vibrations to the brain. For proper function, stereocilia must be tall enough to reach the tectorial membrane (TM) and form stereocilia-TM junctions (STJs). Stereocilia elongation greatly depends on actin regulation; as such, disruption of actin regulatory proteins and other cytoskeletal elements cause profound hearing loss in humans and model organisms. Thus, it is critical to elucidate the dynamic regulation of stereocilia lengths to understand normal hearing and determine how to rescue stereocilia-related hearing loss. Previous work demonstrated that stereocilia actin filament elongation depends on epidermal growth factor pathway substrate 8 (Eps8), an actin-regulatory protein that is critical for hearing in both mice and humans. Eps8 paradoxically contains domains with both actin filament capping and bundling activities, which are typically associated with shortening or elongation of actin filaments, respectively. Moreover, it was found that two other deafness-associated proteins essential for stereocilia elongation, Myosin-XVa (MyoXVa) and whirlin, bind to Eps8 at stereocilia tips in a tripartite complex. Preliminary data show that stereocilin, another deafness-associated protein which links stereocilia to the TM at STJs, is not properly targeted to stereocilia tips in Eps8, MyoXVa, or whirlin knockout (KO) mice, and that all these mice lack normal STJs. Moreover, early (≤postnatal day 1) adeno-associated virus (AAV)-mediated delivery of Eps8 can rescue stereocilia elongation, stereocilin localization, and STJs in Eps8 KO mouse apical hair cells, suggesting that it may be possible to rescue hearing function. This proposal tests the hypothesis that Eps8 regulates stereocilia elongation and the proper formation of STJs by directly regulating actin bundle growth through its C-terminal actin capping and bundling regions and indirectly regulating stereocilia growth through interactions with MyoXVa and whirlin. Further, it is proposed that there is a critical window of hair cell maturation during which stereocilia plasticity is sufficient for full rescue. To test these hypotheses, an AAV-mediated delivery of Eps8 mutants lacking either or both capping and bundling domains (Aim 1) or Eps8 mutants lacking MyoXVa-, whirlin-, or actin-binding activity (Aim 2) in Eps8 KO models will be used. In addition, novel light- and chemically-inducible Eps8 mice will be employed to explore cochlear plasticity and define the critical window for restoring hair cell function in vivo (Aim 3A). The potential for partial reprogramming to expand or restore the critical window for rescuing hair cell function (Aim 3B) will be investigated. Thus, by combining advanced genetic tools, high-resolution imaging, and hearing assays, the basic cell biological mechanisms of stereocilia length regulation will be elucidated and innovative strategies for restoring hearing will be developed.
摘要 感音神经性听力损失是一种无法治愈的衰弱性疾病,直接影响超过3000万人。一 遗传性听力损失的常见原因是耳蜗毛细胞静纤毛的破坏, 将声音振动传递到大脑。为了正常的功能,静纤毛必须足够高, 形成静纤毛-TM连接(STJ)。静纤毛的伸长在很大程度上取决于 肌动蛋白调节;因此,肌动蛋白调节蛋白和其他细胞骨架元件的破坏引起 人类和模式生物的严重听力损失。因此,阐明其动态调节是至关重要的 了解正常听力和确定如何挽救静纤毛相关的听力 损失以往的工作表明静纤毛肌动蛋白丝的伸长依赖于表皮生长因子 途径底物8(Eps 8),一种肌动蛋白调节蛋白,对小鼠和人类的听力至关重要。 自相矛盾的是,eps 8包含既具有肌动蛋白丝帽化又具有成束活性的结构域, 通常分别与肌动蛋白丝的缩短或伸长有关。此外,还发现, 另外两种对静纤毛伸长至关重要的生长相关蛋白,肌球蛋白-XVa(MyoXVa)和whirlin, 在三重复合体中的静纤毛尖端与Eps 8结合。初步数据显示,在Eps 8中,另一种将静纤毛连接到STJ处的TM的与生殖相关的蛋白质--静纤毛蛋白没有正确地靶向静纤毛尖端, MyoXVa或旋转蛋白敲除(KO)小鼠,所有这些小鼠都缺乏正常的STJ。此外,早期(≤产后) 第1天)腺相关病毒(AAV)介导的Eps 8的递送可以挽救静纤毛伸长、静纤毛蛋白 定位,和STJ在Eps 8 KO小鼠顶端毛细胞,这表明它可能是可能的救援听力 功能这一提议验证了Eps 8调节静纤毛伸长和正确形成的假设。 通过其C末端肌动蛋白帽和捆绑区域直接调节肌动蛋白束生长来抑制STJ 并通过与MyoXVa和whirlin的相互作用间接调节静纤毛的生长。进一步应 提出有一个毛细胞成熟的关键窗口,在此期间,静纤毛的可塑性足以 全力救援。为了检验这些假设,使用AAV介导的Eps 8突变体的递送, 加帽和捆绑结构域(Aim 1)或缺乏MyoXVa-、whirlin-或肌动蛋白-结合活性的Eps 8突变体 (Aim 2)在Eps 8中将使用KO模型。此外,新的光诱导和化学诱导的Eps 8小鼠将在 用于探索耳蜗可塑性,并确定恢复毛细胞功能的关键窗口(目的 3A)。部分重编程扩大或恢复拯救毛细胞的关键窗口的潜力 功能(目标3B)将被研究。因此,通过结合先进的遗传工具,高分辨率成像, 和听力测定,阐明静纤毛长度调节的基本细胞生物学机制, 将制定恢复听力的创新战略。

项目成果

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Uri Manor其他文献

Uri Manor的其他文献

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{{ truncateString('Uri Manor', 18)}}的其他基金

Investigating the mechanisms of stereocilia length regulation and innovative strategies for restoring hearing
研究静纤毛长度调节机制和恢复听力的创新策略
  • 批准号:
    10995187
  • 财政年份:
    2023
  • 资助金额:
    $ 36.79万
  • 项目类别:

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