Understanding the mechanisms underlying noise-induced damage of hair cell ribbon synapses

了解噪声引起的毛细胞带突触损伤的机制

• 批准号: BB/Z514743/1
• 负责人: Jing-Yi Jeng
• 金额: $ 53.24万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FZ514743%2F1
• 关键词: Understanding; mechanisms; underlying; noise; induced

Age-related hearing loss (ARHL) is a progressive form of hearing loss and is one of the most common sensory deficits and health conditions in the elderly. Approximately half of all adults in their seventh decade exhibit hearing loss that affect their daily lives. This is further associated with significant psychological and medical morbidity, including social isolation, frailty and depression.The number of people with hearing loss is increasing. It is expected that more than 15 million people in the UK will be affected by hearing loss by 2050, the majority of which will be related to ageing (World Health Organisation). However, the mechanisms underlying ARHL remain poorly understood. This is partly because ARHL is a complex disorder with many contributing factors, including genetic predisposition and environmental factors such as noise exposure. Noise exposure is known to accelerate the onset and progression of ARHL but the mechanisms by which this occurs are largely unknown.In the mammalian cochlea, sound is transduced by sensory cells called hair cells. These cells form specialised synapses, called ribbon synapses, which are the sites of neurotransmitter release onto auditory afferent neurons. Information such as sound intensity and timing is encoded by these synapses into neural activity, which is required for us to perceive sound. A lot of recent evidence has shown that ribbon synapses are the first structures within the cochlea to be lost after noise exposure, which is likely to be the primary cause of hearing loss in these cases. I hypothesise that when the hair cells are over-stimulated by noise they release an excessive amount of glutamate, which causes toxicity by activating calcium-dependent proteases (excitotoxicity). Therefore, the aim of this project is to investigate how synaptic transmission is affected by noise insult in the mammalian cochlea.Using both ex vivo and in vivo approaches, I will determine the level of glutamate release that is detrimental to ribbon synapses, as well as the mechanisms that underlie excitotoxicity at cochlear synapses exposed to noise. I will quantify the synaptic vesicle release by using in vivo functional imaging during noise exposure. The more sustained synaptic changes that result from noise exposure will be investigated in vitro using both patch-clamp electrophysiology and functional imaging. In addition, I will also investigate the protein degradation pathway as a key mechanism underlying noise-induced damage.Overall, this project will establish how noise affects the communication between hair cells and afferent neurons and the mechanisms underlying dysfunction, which will allow the development of treatments for noise-associated hearing dysfunction such as age-related hearing loss.

老年性听力损失（ARHL）是一种渐进性听力损失，是老年人最常见的感觉障碍和健康状况之一。大约有一半的成年人在70岁时表现出影响日常生活的听力损失。这进一步与严重的心理和医学疾病有关，包括社会孤立、脆弱和抑郁。听力损失患者的人数正在增加。预计到2050年，英国将有超过1500万人受到听力损失的影响，其中大部分与老龄化有关（世界卫生组织）。然而，ARHL的机制仍然知之甚少。这部分是因为ARHL是一种复杂的疾病，有许多促成因素，包括遗传易感性和环境因素，如噪音暴露。已知噪声暴露会加速ARHL的发作和进展，但其发生的机制在很大程度上尚不清楚。在哺乳动物耳蜗中，声音是由称为毛细胞的感觉细胞传导的。这些细胞形成专门的突触，称为带状突触，这是神经递质释放到听觉传入神经元的部位。诸如声音强度和时间的信息被这些突触编码成神经活动，这是我们感知声音所必需的。最近的大量证据表明，带状突触是耳蜗内在噪声暴露后首先丢失的结构，这可能是这些情况下听力损失的主要原因。我假设，当毛细胞被噪音过度刺激时，它们会释放过量的谷氨酸盐，这会通过激活钙依赖性蛋白酶（兴奋性毒性）引起毒性。因此，本项目的目的是研究噪声如何影响哺乳动物耳蜗的突触传递，采用离体和体内方法，我将确定谷氨酸的释放水平，这是有害的带状突触，以及耳蜗突触暴露于噪声的兴奋性毒性的机制。我将通过在噪声暴露期间使用体内功能成像来量化突触囊泡的释放。更持久的突触变化，噪声暴露的结果将在体外研究使用膜片钳电生理学和功能成像。此外，作为噪声损伤的关键机制，蛋白质降解途径也将被研究。总之，本项目将明确噪声如何影响毛细胞和传入神经元之间的通信，以及功能障碍的机制，从而为开发与噪声相关的听力障碍（如年龄相关性听力损失）的治疗方法奠定基础。