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

了解毛细胞机电转导在年龄相关性和噪声性听力损失中的作用

• 批准号: BB/X000567/1
• 负责人: Stuart Johnson
• 金额: $ 59.51万
• 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: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX000567%2F1
• 关键词: Understanding; role; hair; cell; mechanoelectrical

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.

年龄相关性听力损失（ARHL）是一种进行性感觉神经性听力损失，代表最常见的感觉缺陷，也是老年人最常见的慢性疾病之一。英国约有 1200 万人，全球约有 5 亿人患有残疾性听力损失，其中 ARHL 是最大的原因（预计到 2050 年，人数将超过 9 亿）。 ARHL 使人们无法进行基本的日常交流，这与严重的心理和医学发病率有关，包括社会孤立和抑郁。中年时期的听力损失是痴呆症的最大可改变危险因素。ARHL 的进展是由我们的基因决定的，这可能会使个体容易出现听力损失。它还可能受到环境因素的影响，例如暴露在有害的噪音水平下，这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控制正常内在衰老过程的相同机制而加剧 ARHL，或者是否会导致叠加在其上的其他病理。声音是由位于耳内的极其敏感的感觉细胞（称为毛细胞）检测的。内耳中称为耳蜗的骨结构。它们的名字来源于头发状的元素（立体纤毛），这些元素从顶端表面突出，形成一种称为发束的复杂结构。当声音进入耳朵时，发束会产生微小的振动。这些振动引发毛细胞内声波转换成电信号，并传递到神经纤维。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破坏性影响的目标。发束中存在的关键蛋白质之一是钙粘蛋白-23，它是启动将声音转换为电信号所必需的。这种蛋白质通过基因突变而发生的改变与早发性 ARHL 以及对噪音损伤的更易感性有关。然而，我们对这种蛋白质的突变如何影响毛细胞对衰老和噪音侵害的敏感性，以及这些听力退化的不同过程如何在发束水平上相互作用仍然知之甚少。在这个项目中，我们将研究研究人员研究了 cadherin-23 突变小鼠和正常小鼠的发束功能，并比较了发束特性如何随衰老和对破坏性噪音水平的反应而变化。通过这样做，我们将确定因衰老和噪音暴露共同导致的毛束功能和结构变化，并确定这是否是哺乳动物耳蜗中 ARHL 发生和进展的关键因素。该项目还将确定 cadherin-23 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，它们虽然有益，但距离遥远。从此能够恢复正常听力。如果没有对为什么我们在噪音暴露和衰老过程中逐渐丧失听力的原因有一个基本的了解，我们将无法开发出有效的治疗方法来预防或治愈听力损失。小鼠基因替代技术的最新发展凸显了潜在有前途的治疗途径。然而，这些类型的方法的成功依赖于对噪声和与年龄相关的听力损失的病理学有基本的科学理解，这属于本提案的范围。