Understanding the role of hair cell mechanoelectrical transduction in age-related and noise-induced hearing loss

老年性听力损失（ARHL）是一种进行性感音神经性听力损失，是老年人最常见的感觉障碍，也是最常见的慢性疾病之一。英国约有1200万人和全球约5亿人患有致残性听力损失，ARHL是最大的单一原因（预计到2050年将有9亿人）。ARHL将人们排除在基本的日常交流之外，这与严重的心理和医学疾病有关，包括社会孤立和抑郁。中年听力损失是痴呆症最大的可改变的风险因素。ARHL的进展受我们的基因影响，这可能使个体易于发生听力损失。它也可能受到环境因素的影响，例如暴露于破坏性的噪音水平，这可能会加剧听力随着年龄的增长而逐渐下降。然而，目前尚不清楚噪声暴露是否会通过影响正常内在衰老过程的相同机制来加剧ARHL，或者是否会导致额外的病理变化。声音由位于内耳称为耳蜗的骨性结构内的称为毛细胞的极其敏感的感觉细胞检测到。它们的名字来源于毛发样的元素（静纤毛），从它们的顶端表面突出，形成一个复杂的结构，称为毛束。当声音进入耳朵时，它会使发束产生微小的振动。这些振动在毛细胞内启动声波转化为电信号，并传递到神经纤维上。这种电信号被大脑接收，使我们能够感知语音和音乐。发束在声音传导中的关键作用使其成为衰老和噪音的破坏性影响的目标。存在于毛束中的关键蛋白质之一是钙粘蛋白-23，它是启动声音转化为电信号所必需的。通过基因突变，这种蛋白质的改变与早发性ARHL和对噪音损伤的更大易感性有关。然而，我们仍然对这种蛋白质的突变如何影响毛细胞对衰老和噪音损伤的易感性知之甚少，也不知道这些不同的听力退化过程如何在毛束水平上相互作用。在这个项目中，我们将研究具有钙粘蛋白-23突变的小鼠和正常小鼠的毛束功能，并比较束特性如何随老化和响应于破坏性噪声水平而变化。通过这样做，我们将确定的功能和结构的变化，导致从老化和噪声暴露的组合，并确定这是否是一个关键的贡献者的ARHL在哺乳动物耳蜗的启动和发展。该项目还将确定钙粘蛋白-23的突变如何加剧ARHL的进展，以及它是否也是噪声损伤期间的主要目标。目前，改善听力损失的唯一选择是助听器和人工耳蜗植入，这是有益的，但远远不能恢复正常的听力。如果不对我们在噪音暴露后和衰老过程中逐渐丧失听力的原因有一个基本的了解，我们将无法开发有效的治疗方法来预防或治疗听力损失。小鼠基因替代技术的最新发展突出了潜在的有前途的治疗途径。然而，这些类型的方法的成功依赖于对噪声和年龄相关听力损失的病理学有基本的科学理解，这在本提案的范围内。

Age-related hearing loss (ARHL) is a progressive sensorineural hearing loss representing the most common sensory deficit and one of the most prevalent chronic diseases in the elderly. About 12 million people in the UK and ~500 million worldwide have disabling hearing loss, with ARHL being the single biggest cause (>900 million people expected by 2050). ARHL excludes people from basic day-to-day communication, which is associated with significant psychological and medical morbidity, including social isolation and depression. Hearing loss in mid-life is the largest modifiable risk factor for dementia.The progression of ARHL is shaped by our genes, which can predispose an individual to developing hearing loss. It can also be influenced by environmental factors, such as exposure to damaging noise levels, which can exacerbate the progressive decline of hearing with age. However, it is not clear whether noise exposure exacerbates ARHL by affecting the same mechanisms governing the normal intrinsic ageing process, or whether it causes additional pathologies that superimpose onto it.Sound is detected by extremely sensitive sensory cells named hair cells that are located inside a bony structure called the cochlea in the inner ear. Their name derives from the hair-like elements (stereocilia) that project from their apical surface to form an intricate structure called the hair bundle. When sound enters the ear, it produces minute vibrations of the hair bundle. These vibrations initiate the conversion of sound waves into an electrical signal within the hair cells that is relayed onto nerve fibres. This electrical signal is received by the brain, allowing us to perceive speech and music for example.The pivotal role of the hair bundle in sound transduction makes it a target for the damaging effects of ageing and noise. One of the key proteins present in the hair bundle is cadherin-23, which is required to initiate the conversion of sound into an electrical signal. Alterations in this protein, through genetic mutation, have been linked with early onset ARHL and a greater susceptibility to noise insult. However, we still know very little about how mutations in this protein affect the susceptibility of the hair cells to ageing and noise insult, nor how these distinct processes of hearing deterioration interact at the level of the hair bundle.In this project we will investigate the function of the hair bundle in mice that have a mutation in cadherin-23, as well as normal mice, and compare how the bundle properties change with ageing and in response to damaging noise levels. By doing this we will identify the functional and structural changes to the hair bundle that result from the combination of ageing and noise exposure and establish whether this is a key contributor to the initiation and progression of ARHL in the mammalian cochlea. The project will also establish how mutation in cadherin-23 exacerbates the progression of ARHL and whether it is also a primary target during noise insult.Currently, the only options available to ameliorate hearing loss are hearing aids and cochlear implants, which are beneficial but far from able to restore normal hearing. Without a fundamental understanding of why we progressively lose hearing following noise exposure and during ageing, we will not be able to develop effective treatments to either prevent or cure hearing loss. Recent developments in gene replacement technologies in mice have highlighted potentially promising therapeutic avenues. However, the success of these types of approaches relies on having a basic scientific understanding of the pathology underlying noise and age-related hearing loss, which is within the remit of this proposal.