Protein sorting in the maturation of inner ear cells

摘要我们听到各种声音的能力有赖于耳朵听觉部分内数千个特殊的感官感受器。这些“毛细胞”也在内耳的平衡器官中发现，在那里它们让我们感觉到头部的运动，并欣赏重力的影响。这些细胞的发育错误与许多疾病中发现的听力损失和平衡障碍有关，而毛细胞的进行性丧失很可能是大多数与年龄相关的听力损失和老年人跌倒的原因。毛细胞承载着一个机械上敏感的装置，称为“发束”，这个微妙的结构必须放置在正确的位置和正确的方向上，才能对声音和头部运动提供的微观液体运动最敏感。这一过程是由许多相互作用的基因指导的，这些基因的变异可能会导致遗传性听力损失和平衡问题，从而导致复杂的综合症。目前还不清楚参与构建毛细胞束的基本构件和信号分子是如何在正确的时间被引导到毛细胞的正确位置的。这个项目有几个目标。我们希望确定在正常发育过程中，毛束形状和方向的复杂性是如何在分子水平上受到调节的，以及在某些神经系统疾病期间，这种调节是如何受到影响的。我们的目标是找出必需的蛋白质是如何输送到毛细胞的特定区域的。我们想知道这种蛋白质分类途径是否有助于毛细胞的持续替换和内耳损伤后的修复。最后，我们想知道胚胎发育期间毛束形状的分子调节器是否随后在支持功能成熟的内耳方面发挥相当明显的作用。我们的研究将提供有助于内耳正常发育的机制的详细分析，解释这些机制如何受到遗传疾病的影响，以及未来如何利用这些机制来修复受损后的内耳或在老年期间通过替换丢失的毛细胞或延长其寿命。这些机制可能在神经系统的其他区域也很重要，因此我们的结果将具有更广泛的重要性，并可能有助于未来神经疾病的治疗。

SummaryOur ability to hear a vast range of sounds relies on thousands of specialised sensory receptors inside the auditory part of the ear. These "hair cells" are also found in balance organs within the inner ear, where they allow us to sense movements of our head and appreciate the effects of gravity. Errors in the development of these cells are associated with hearing loss and balance deficits found in a number of diseases, and progressive loss of hair cells most likely contributes to the majority of cases of age-related hearing loss and falls in the elderly.Hair cells bear a mechanically sensitive apparatus, known as the "hair bundle", and this delicate structure must be placed in the right place and in the correct orientation to be most sensitive to the microscopic fluid movements provided by sound and head movements. This process is instructed by numerous interacting genes, and variations in these genes can cause forms of inherited hearing loss and balance problems that contribute to complex syndromes. It is not currently understood how the essential building blocks and signalling molecules that are involved in building the bundle are directed to be in the right place in hair cells, at the right time.This project has several goals. We wish to determine how the complexity of hair bundle shape and orientation is regulated at a molecular level during normal development, and how this regulation is affected under conditions during certain diseases of the nervous system. We aim to find out how essential proteins are delivered to specific regions of a hair cell. We want to know if this protein sorting pathway contributes to ongoing replacement of hair cells and repair after damage to the inner ear. Finally, we want to know if a molecular regulator of hair bundle shape during embryonic development can subsequently play quite distinct roles in support of the functionally mature inner ear. Our studies would provide a detailed analysis of mechanisms contributing to the normal development of the inner ear, explain how these mechanisms are affected by genetic disease, and how they may be harnessed in the future in order to repair the inner ear following damage or during old age, by replacing lost hair cells or by prolonging their lifespan. These mechanisms are likely to be important in other regions of the nervous system, and so our results will be of wider importance, and may contribute to future treatments of neural disorders.