Replacement of vestibular hair cells in normal and damaged adult mice

描述(申请人提供)：前庭上皮含有感觉毛细胞(HCS)，将空间运动转换为平衡和协调所需的神经信号。与损伤或衰老相关的HC死亡在全球数百万人中导致平衡障碍。成年哺乳动物，包括人类，表现出很小的能力来取代丢失的HCS。大多数研究表明，支持细胞(SC)在HC丢失后直接转化为HC，极少数(如果有的话)是直接从SC分裂中产生的。然而，哺乳动物在失去HC后，仅有有限的HC再生，不足以恢复前庭功能。这项研究的长期目标是开发基于生物学的方法来再生所有丢失的HC，并改善人类患者的生活质量。为了实现这一目标，需要完全了解成年哺乳动物在正常条件下的HC和SC种群动态。一般认为，在成熟哺乳动物的前庭上皮细胞中，除非发生损伤，否则不会添加HCs。然而，来自几个实验室的间接证据表明，成年啮齿动物的前庭HC在没有损伤的情况下可能经历正常的翻转。例如，在正常成年啮齿动物的前庭器官中，已检测到未成熟的HCS和正在经历凋亡或吞噬的HCS。这项拟议的研究将利用几个转基因小鼠系来标记和跟踪正常(未受损)成年小鼠前庭上皮中的HC和SC种群。这些方法将被用来检验这样的假设：在没有HC损伤的情况下，新的HCs不断地添加到成年小鼠的前庭上皮细胞中，而SCs直接转化为HCs。此外，这一方法将被用于检验HC损失不会增加HC添加的正常速率的假设。这项研究将有助于描述成年和老年哺乳动物前庭上皮中存在的毛细胞替代的自然机制，并可在不久的将来开发更好的平衡障碍治疗方法。

DESCRIPTION (provided by applicant): Vestibular epithelia contain sensory hair cells (HCs) that transduce spatial movements to neural signals necessary for balance and coordination. HC death associated with damage or aging causes balance disorders in millions of people worldwide. Adult mammals, including humans, demonstrate a small capacity to replace lost HCs. Most studies suggest that supporting cells (SCs) directly convert into HCs after HC loss, and very few, if any, HCs are born directly from SC division. However, only limited HC regeneration occurs naturally in mammals after HC loss, and it is not sufficient to restore vestibular function. The long-term goal of this research is to develop biologically based methods to regenerate all lost HCs and to improve the quality of life of human patients. Complete understanding of HC and SC population dynamics in adult mammals under normal conditions is needed to achieve this goal. It is generally assumed that HCs are not added to the vestibular epithelia of mature mammals unless damage occurs. However, indirect evidence from several laboratories suggests that vestibular HCs in adult rodents may undergo normal turnover in the absence of damage. For example, immature HCs and HCs undergoing apoptosis or phagocytosis, have been detected in normal adult rodent vestibular organs. This proposed research will utilize several transgenic mouse lines to label and track HC and SC populations in the vestibular epithelia of normal (undamaged) adult mice over time. These methods will be used to test the hypotheses that new HCs are continually added to the vestibular epithelia of adult mice, and SCs directly convert into HCs, in the absence of HC damage. Further, this approach will be applied to test the hypothesis that HC loss does not increase the normal rate of HC addition. This research will help characterize natural mechanisms for hair cell replacement that are present within adult and aged mammalian vestibular epithelia and can be exploited to develop better therapies for balance disorders in the near future.