Epigenetic mechanisms underlying hearing impairment

听力障碍的表观遗传机制

• 批准号: MR/R004625/1
• 负责人: Andrea Streit
• 金额: $ 72.37万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR004625%2F1
• 关键词: Epigenetic; mechanisms; underlying; hearing; impairment

Sound and the perception of hearing is an extremely important means of communication, and losing the ability to hear often leads to social isolation and psychological trauma. There are many causes of hearing loss. Some, like listening to loud music, is preventable. Others, like genetic disorders and the normal process of ageing, are beyond our control. Hearing loss is therefore a major health concern and yet we are still unable to prevent or restore hearing successfully after damage to the ear. However, the more we understand about the genes that cause hearing loss in ageing and genetic disorders, the closer we can get to discovering ways of preventing and restoring hearing. This research project proposes to study how two genes called Chd7 and Chd4 control hearing and cause hearing loss in genetic disorders such as CHARGE syndrome using mouse models that resembles human CHARGE syndrome.The project will use genetic tools to inactivate Chd7 and Chd4 in different cells of the ear to study how Chd7/4 affects survival of cells that perceive sound and how these molecules act to maintain their function. This will provide an entry point to understand how these processes are controlled. The project will investigate the importance of both factors in fine-tuning the levels of many genes required for development and survival of cells in the ear that are essential for hearing. Combining state of the art molecular techniques with genetically modified mice will allow isolation of different cell types in the ear and identify which genes change when Chd7 or Chd4 are deleted. This is a powerful approach that will not only provide insight into the function of Chd7 and Chd4, but also provide new tools to design strategies to restore hearing. Chd7 and -4 belong to a family of proteins that change the DNA without changing its sequence. This is called epigenetic change, and such changes are reversible as they do not affect the DNA sequence. Since Chd7 and -4 mediate reversible processes, they are potentially amenable to therapeutic drug treatments. There are many molecules that work in a similar fashion and understanding the function of Chd7/4 may also shed light on the epigenetic changes that accompany ear development and ageing. Therefore, this research is expected to have widespread implications on hearing research and our understanding of hearing loss during ageing.In summary, while this is fundamental research, it is necessary to understand the causes of hearing loss in mammals as it may lead to developing new strategies to restore hearing in the elderly as well as in genetic disorders like CHARGE.

声音和听觉是一种极其重要的交流手段，失去听力往往会导致社会孤立和心理创伤。听力损失的原因有很多。有些是可以预防的，比如听大声的音乐。其他的，如遗传疾病和正常的衰老过程，是我们无法控制的。因此，听力损失是一个主要的健康问题，但我们仍然无法在耳朵受损后成功地预防或恢复听力。然而，我们对衰老和遗传疾病中导致听力损失的基因了解得越多，我们就越能找到预防和恢复听力的方法。本研究项目拟利用类似人类CHARGE综合征的小鼠模型，研究Chd7和Chd4两个基因如何控制听力并导致CHARGE综合征等遗传性疾病的听力损失。该项目将使用基因工具使耳朵不同细胞中的Chd7和Chd4失活，以研究Chd7/4如何影响感知声音的细胞的存活，以及这些分子如何发挥作用以维持其功能。这将为理解如何控制这些过程提供一个切入点。该项目将研究这两个因素在微调耳朵细胞发育和存活所需的许多基因水平方面的重要性，这些基因对听力至关重要。将最先进的分子技术与转基因小鼠相结合，将允许分离耳朵中不同类型的细胞，并确定当Chd7或Chd4被删除时哪些基因发生了变化。这是一种强有力的方法，不仅可以深入了解Chd7和Chd4的功能，还可以为设计恢复听力的策略提供新的工具。Chd7和-4属于一个改变DNA而不改变其序列的蛋白质家族。这被称为表观遗传变化，这种变化是可逆的，因为它们不影响DNA序列。由于Chd7和-4介导可逆过程，它们可能适用于治疗性药物治疗。有许多分子以类似的方式工作，了解Chd7/4的功能也可能揭示伴随耳朵发育和衰老的表观遗传变化。因此，这项研究有望对听力研究和我们对衰老过程中听力损失的理解产生广泛的影响。总之，虽然这是基础研究，但有必要了解哺乳动物听力损失的原因，因为它可能导致开发新的策略来恢复老年人以及遗传疾病（如CHARGE）的听力。

项目成果

The chromatin remodelling factor Chd7 protects auditory neurons and sensory hair cells from stress-induced degeneration.

• DOI: 10.1038/s42003-021-02788-6
• 发表时间: 2021-11-03
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Ahmed M;Moon R;Prajapati RS;James E;Basson MA;Streit A
• 通讯作者: Streit A

The chromatin remodelling factor Chd7 protects auditory neurons and sensory hair cells from stress-induced degeneration

染色质重塑因子 Chd7 保护听觉神经元和感觉毛细胞免受压力引起的退化

• DOI: 10.1101/2021.01.05.425431
• 发表时间: 2021
• 作者: Ahmed M