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.

与年龄相关的听力损失（ARHL）是一种渐进的听力损失形式，是老年人最常见的感觉缺陷和健康状况之一。在第七个十年中，大约一半的成年人表现出影响他们日常生活的听力损失。这进一步与重大的心理和医学发病率有关，包括社会隔离，脆弱和抑郁。听力损失的人数正在增加。预计到2050年，英国有超过1500万人的听力损失将受到听力损失的影响，其中大多数将与衰老有关（世界卫生组织）。但是，ARHL基础的机制仍然很少理解。这部分是因为ARHL是一种复杂的疾病，具有许多因素，包括遗传易感性和诸如噪声暴露等环境因素。已知噪声暴露会加速ARHL的发作和进展，但是发生这种情况的机制在很大程度上是未知的。在哺乳动物的耳蜗中，声音被称为毛细胞的感觉细胞传递。这些细胞形成专门的突触，称为色带突触，这些突触是神经递质释放到听觉传入神经元的位置。声音强度和时机之类的信息被这些突触编码为神经活动，这是我们感知声音所必需的。许多最近的证据表明，丝带突触是噪声暴露后的耳蜗中的第一个结构，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声过度刺激时，它们会释放出过量的谷氨酸，从而通过激活钙依赖性蛋白酶（兴奋性毒性）引起毒性。因此，该项目的目的是研究突触传播如何受到哺乳动物耳蜗的噪声侮辱的影响。使用离体和体内方法，我将确定对色带突触有害的谷氨酸释放水平，以及在Cochlear Synapses Synapses Synapses Synapse sysise noise sosisions syneys syneapse的机制中造成的粘液性突触释放水平。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。通过贴片钳电生理学和功能成像，将在体外研究噪声暴露引起的更持续的突触变化。此外，我还将研究蛋白质降解途径，作为噪声引起的损害的关键机制。论来，该项目将确定噪声如何影响毛细胞与传入神经元之间的通信以及能力障碍的机制之间的通信，这将允许为噪声相关的听力障碍的治疗发展，例如年龄与年龄与年龄相关的听力损失。