Deciphering the molecular heterogeneity of spiral ganglion neurons by single-cell gene expression profiling.

通过单细胞基因表达谱解读螺旋神经节神经元的分子异质性。

• 批准号: MR/S002510/1
• 负责人: Mirna Mustapha
• 金额: $ 278.16万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS002510%2F1
• 关键词: Deciphering; molecular; heterogeneity; spiral; ganglion

The human ear is an extraordinary sensory organ, in which sensory cells and their nerve connections are able to analyse an impressive range of sound frequencies and intensities. The role of the sensory hair cells is to convert sound information from the outside world into electrical signals that are sent to the brain via specialized nerve fibres, allowing us hear speech and music. The development of the auditory organ, the cochlea, is an extremely ordered process, which allows to build sensory cells and nerve connections that, for example, respond preferencially to either low- or high-frequency sound depending on their location along the sensory organ.Age-related hearing impairment (ARHI) is a complex disorder caused by a combination of genetic and environmental factors. Noise exposure is the major environmental factor that causes ARHI. It is clinically very difficult to distinguish between these two most common forms of hearing impairment: noise-induced and age-related hearing impairments (NIHI and ARHI respectively). The large impact of NIHI and ARHI on human health is caused by the continuous increase in the average lifespan of the population, and by the fact that our ears are not well adapted to cope with long-lasting exposure of loud sounds characteristic of modern society. Currently, the only option available to ameliorate hearing loss is using hearing aids and cochlear implants, which are beneficial but they are far from restoring normal hearing. The problem is that we still know very little about the biological mechanisms causing NIHI and ARHI to be able to develop effective alternative treatments to either prevent or cure this disease.Until very recently the sensory cells have been considered the most vulnerable elements to aging and noise exposure but recent finding have shown that their nerve connections are more easily damaged during insults. In the adult auditory system, each sensory cell in the ear (inner hair cell) is contacted by multiple nerve connections that are anatomically and physiologically diverse, and as such able to carry a different sound intensity and frequencies to the brain. In particular, it has been suggested that the nerve connections having the highest detectable sound intensities seem more vulnerable to noise and aging, resulting in their specific damage. However, there is no direct evidence as to why these specific nerve connections are predominantly affected by aging and/or noise exposure as compared to those responding to lowest detectable intensity sound. Therefore, the ability to identifying genetic factors and molecules that render these nerve connections more susceptible to aging and/or noise trauma is essential for devising early diagnostic, intervention and/or treatments for both ARHI & NIHI. Identifying the genetic factors and molecules in humans has been hampered by many inherent difficulties: 1) not all individuals with the same genetic defects have the same clinical presentations, probably depending on the intensity and the duration of the noise exposed to; 2) similar environmental exposures sometimes have different effects on individuals, probably because of differences in their underlying genetic makeup.For these reasons we will address this important aspect of human biology by studying gene-noise interaction in mice where both factors can be controlled and we know that the structure and physiology of the ear is similar to that of humans. In the proposed project, we will combine expertise in genetic and physiology to evaluate gene expression and function in the nerve connections. Our approach will generate new mouse models to address why a specific population of nerve connections is selectively damaged to noise and aging. These steps are important towards understanding the etiology of human noise-induced and age related hearing impairment (long-term goal), and will take us closer to the goal of developing a suitable therapeutic intervention to treat patients.

人类的耳朵是一个非凡的感觉器官，其中感觉细胞及其神经连接能够分析令人印象深刻的声音频率和强度范围。感觉毛细胞的作用是将来自外部世界的声音信息转换为电信号，通过专门的神经纤维发送到大脑，使我们能够听到语音和音乐。听觉器官（耳蜗）的发育是一个非常有序的过程，它允许建立感觉细胞和神经连接，例如，根据它们沿感觉器官的沿着位置，对低频或高频声音产生优先反应。听觉相关性听力障碍（ARHI）是一种由遗传和环境因素共同引起的复杂疾病。噪声暴露是引起ARHI的主要环境因素。在临床上很难区分这两种最常见的听力损伤：噪声引起的听力损伤和年龄相关的听力损伤（分别为NIHI和ARHI）。NIHI和ARHI对人类健康的巨大影响是由于人口平均寿命的持续增加，以及我们的耳朵不能很好地科普现代社会特有的长时间暴露于响亮的声音。目前，改善听力损失的唯一选择是使用助听器和人工耳蜗植入物，这是有益的，但它们远远不能恢复正常的听力。问题是我们对NIHI和ARHI能够开发出有效的替代疗法来预防或治疗这种疾病的生物学机制仍然知之甚少。直到最近，感觉细胞一直被认为是最容易受到老化和噪音暴露的元素，但最近的研究表明，它们的神经连接更容易受到损伤。在成人听觉系统中，耳朵中的每个感觉细胞（内毛细胞）都与多个神经连接接触，这些神经连接在解剖学和生理学上是不同的，因此能够将不同的声音强度和频率传递到大脑。特别是，有人提出，具有最高可检测声音强度的神经连接似乎更容易受到噪音和老化的影响，从而导致其特定的损伤。然而，没有直接的证据表明为什么这些特定的神经连接主要受老化和/或噪声暴露的影响，而不是对最低可检测强度声音的反应。因此，识别使这些神经连接更容易受到老化和/或噪音创伤的遗传因素和分子的能力对于设计ARHI和NIHI的早期诊断，干预和/或治疗至关重要。识别人类的遗传因子和分子受到许多固有困难的阻碍：1）并非所有具有相同遗传缺陷的个体都具有相同的临床表现，这可能取决于暴露于噪声的强度和持续时间; 2）相似的环境暴露有时对个体有不同的影响，可能是因为他们潜在的遗传组成的差异。出于这些原因，我们将通过研究基因来解决人类生物学的这一重要方面。在老鼠的实验中，这两个因素都可以控制，我们知道耳朵的结构和生理学与人类相似。在拟议的项目中，我们将结合联合收割机在遗传学和生理学方面的专业知识，以评估神经连接中的基因表达和功能。我们的方法将产生新的小鼠模型，以解决为什么特定群体的神经连接会选择性地受到噪音和衰老的损害。这些步骤对于理解人类噪声引起的和年龄相关的听力损伤的病因学（长期目标）非常重要，并将使我们更接近开发合适的治疗干预措施来治疗患者的目标。

项目成果

Pathophysiological changes in inner hair cell ribbon synapses in the ageing mammalian cochlea.

• DOI: 10.1113/jp280018
• 发表时间: 2020-10
• 期刊: The Journal of physiology
• 作者: Jeng JY;Ceriani F;Olt J;Brown SDM;Holley MC;Bowl MR;Johnson SL;Marcotti W
• 通讯作者: Marcotti W

Age-related changes in the biophysical and morphological characteristics of mouse cochlear outer hair cells.

• DOI: 10.1113/jp279795
• 发表时间: 2020-09
• 期刊: The Journal of physiology
• 作者: Jeng JY;Johnson SL;Carlton AJ;De Tomasi L;Goodyear RJ;De Faveri F;Furness DN;Wells S;Brown SDM;Holley MC;Richardson GP;Mustapha M;Bowl MR;Marcotti W
• 通讯作者: Marcotti W

POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment.

• DOI: 10.1016/j.clim.2023.109326
• 发表时间: 2023-04
• 期刊: Clinical immunology
• 影响因子: 8.6
• 作者: C. Mehawej;E. Chouery;S. Azar-Atallah;W. Shebaby;V. Delague;I. Mansour;M. Mustapha;G. Lefranc;A. Mégarbané