Epigenetic mechanisms underlying hearing impairment

声音和听觉的感知是一种极其重要的交流手段，而失去听觉的能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，比如听吵闹的音乐，是可以预防的。其他的，像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，我们就越接近发现预防和恢复听力的方法。本研究计划利用与人类CHARGE综合征相似的小鼠模型，研究Chd 7和Chd 4这两种基因在CHARGE综合征等遗传性疾病中控制听力和导致听力丧失的机制，并利用遗传学工具将Chd 7和Chd 4在耳朵的不同细胞中复制，研究Chd 7/4如何影响感知声音的细胞的存活，以及这些分子如何维持其功能。这将提供一个切入点，以了解如何控制这些过程。该项目将研究这两个因素在微调许多基因水平方面的重要性，这些基因是耳朵细胞发育和存活所必需的，而这些细胞对听力至关重要。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Chd 7或Chd 4缺失时哪些基因发生变化。这是一种强大的方法，不仅可以深入了解Chd 7和Chd 4的功能，还可以提供新的工具来设计恢复听力的策略。Chd 7和Chd-4属于改变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Chd 7和-4介导可逆过程，因此它们可能适合于治疗性药物治疗。有许多分子以类似的方式工作，了解Chd 7/4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的听力以及CHARGE等遗传疾病。

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.