Understanding the mechanisms and significance of the changes in intercellular communication between the non-sensory cells of the ageing cochlea

老年性听力损失(ARHL)是老年人最常见的健康状况。大约一半的70多岁的成年人表现出严重的ARHL，足以影响交流。预计到2030年，英国将有大约1450万人受到听力损失的影响，ARHL是最大的单一原因。ARHL是一种进行性疾病，会降低理解语言的能力，特别是在嘈杂的环境中。急性淋巴细胞性白血病还与社会孤立和抑郁有关。虽然助听器和人工耳蜗植入物是有益的，但它们不能恢复听力，特别是当耳朵中的细胞缺失或不起作用时，这两个都是ARHL的特征。阻碍ARHL新疗法发展的主要障碍是缺乏对为什么我们随着年龄的增长而逐渐丧失听力的理解，这使得预防、减缓甚至逆转ARHL变得困难。声音是由极其敏感的感觉细胞--称为毛细胞--探测到的，这些细胞位于内耳的一个称为耳蜗骨的骨骼结构中。它们的名字来源于它们顶端表面突出的毛发状元素(立体纤毛)。当声音进入耳道时，它会产生立体声纤毛的微小振动。这些振动通过带电离子在毛细胞立体纤毛中存在的机械门控通道中移动，启动了声波到电流的转换；这一过程被称为机械-电转换。这些微小的电流比手机充电器的电流小10亿倍，通过神经纤维传递到大脑，使我们能够感知语音和音乐等声音。与大脑类似，毛细胞持续工作，因此它们需要大量能量，这些能量由营养等分子提供，通过血管在体内传播。然而，有一个问题是，毛细胞与进入耳蜗的血管相距很远。这是因为流经血管的血液引起的运动会被毛细胞拾取，导致我们耳朵里有脉动的背景噪音。因此，大自然开发了一个复杂的管道网络，将营养从血管输送到毛细胞。这个网络是由大量被称为非感觉细胞的细胞组成的，这些细胞存在于毛细胞和血管周围。当营养物质，如葡萄糖，被血管“释放”时，它们进入非感官细胞，并通过专门的渠道从一个细胞到另一个细胞，直到到达毛细胞。这些通道也被称为缝隙连接，是由一种名为连接蛋白的蛋白质组成的。连接蛋白对听力至关重要，因为在人类出生时存在的所有听力障碍病例中，近一半是由于这些蛋白质的突变造成的。我们的初步工作已经确定了连接蛋白的功能及其在非感觉细胞中的分布随年龄的变化。这些变化似乎在毛细胞发生任何退化之前就发生了，这使得非感觉细胞和连接蛋白缝隙连接可能是随着年龄增长而导致听力恶化的关键因素。因此，我们计划在这个项目中检验的假设是，非感觉细胞是ARHL进展的关键决定因素。在这个项目中，我们将使用表现出急性淋巴细胞性白血病迹象的老年小鼠。老鼠是一种理想的动物，因为它们的听觉系统的结构和功能与人类惊人地相似，也因为对听力功能至关重要的基因之间的高度一致性。这个项目将提供一个更好的理解为什么以及如何非感觉细胞导致急性淋巴细胞性白血病的发展。研究结果将有助于确定靶向基因，从而促进人类急性淋巴细胞性白血病的诊断和治疗干预措施的发展。

Age-related hearing loss (ARHL) is the most common health condition in the elderly. Approximately half of adults in their 70s exhibit ARHL severe enough to affect communication. It is expected that approximately 14.5M people in the UK will be affected by hearing loss by 2030, with ARHL being the single biggest cause. ARHL is a progressive disorder decreasing the ability to understand speech, especially in a noisy environment. ARHL is also associated with social isolation and depression. Although hearing aids and cochlear implants are beneficial, they cannot restore hearing, especially if the cells in the ear are missing or do not function, which are both characteristic features in ARHL. The major obstacle preventing the development of new treatments for ARHL is a lack of understanding about why we progressively lose our sense of hearing with age, making it difficult to prevent, slow down or even reverse ARHL.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. When sound enters the ear canal it produces minute vibrations of the stereocilia. These vibrations initiate the conversion of sound waves into an electrical current by the movement of charged ions through mechanically-gated channels present in the hair cell stereocilia; a process known as mechano-electrical transduction. These tiny electrical currents, which are a billion time smaller than the current of a phone charger, are sent to the brain via nerve fibres, allowing us to perceive sound such as speech and music.Similar to the brain, the hair cells work constantly and as such they require a lot of energy, which is provided by molecules such as nutrients, travelling in the body through the blood vessels. One problem, however, is that the hair cells are very far from the blood vessels entering the cochlea. This is because the movement caused by the blood flowing through the vessels would be picked up by the hair cells, leading to a pulsating background noise in our ears. Therefore, nature has developed an intricate network of conduits that bring the nutrients from the blood vessels to the hair cells. This network is formed by a large number of cells, called non-sensory cells, that are present all around the hair cells and the blood vessels. When nutrients, such as glucose, are "released" by the blood vessels, they enter the non-sensory cells and travel from cell-to-cell via specialised channels until they reach the hair cells. These channels, also known as gap-junctions, are made by proteins called connexins. Connexins are vital for hearing since nearly half of all cases of hearing impairment present at birth in humans are due to mutations in these proteins.Our preliminary work has identified age-related changes in the way connexins function and how they are distributed in the non-sensory cells. These changes appear to occur before any degeneration is observed in the hair cells, making the non-sensory cells and connexin gap-junctions potentially key instigators of the deterioration of hearing that occurs with ageing. Therefore, the hypothesis we plan to test in this project is that non-sensory cells are a key determinant of the progression of ARHL. In this project we will use aged mice that show signs of ARHL. Mice are an ideal animal because the structure and function of their auditory system is strikingly similar to that of the human, and also because of the high level of concordance between genes critical for hearing function. This project will provide a better understanding of why and how non-sensory cells lead to the development of ARHL. The outcomes will contribute to the identification of targetable genes that will facilitate the development of diagnostic and therapeutic interventions for ARHL in humans.