Regeneration in the vestibular system

描述（由申请人提供）：平衡障碍和眩晕是美国的一个重要健康问题，是老年人跌倒受伤的主要原因。虽然有许多因素导致平衡障碍，但前庭感觉器官的病理学被认为是主要的贡献者。随着年龄的增长，半规管嵴和黄斑中的毛细胞数量逐渐减少。功能测试显示，随着年龄的增长，外周前庭功能也有类似的下降。目前还没有有效的治疗方法来恢复外周前庭功能。在过去的20年里，有几个报告表明，新的毛细胞可以产生在前庭感觉上皮。一些更有希望的数据来自嵴的研究，特别是在龙猫;然而，还没有确切的证据表明，新的毛细胞可以在成年哺乳动物嵴中产生。基本的问题是，可用于研究像龙猫这样的物种的毛细胞再生的工具相当有限。大多数这些研究都是用传统的形态学分析进行的，无法充分评估耳毒性药物的任何恢复是否是由于从头毛细胞再生、现有支持细胞的转分化或受损毛细胞的修复。在最近一项关于小鼠内耳Notch信号的研究中，我们发现，虽然这种发育信号通路在成熟的耳蜗中不再活跃，但它似乎在嵴的支持细胞中活跃。我们推断，如果Notch通路在成熟的小鼠嵴中仍然活跃，我们可以通过转分化刺激毛细胞替代。在初步研究中，我们发现Notch通路的药理学调节剂，支持细胞可以转分化成成熟小鼠嵴毛细胞的证据。我们建议使用小鼠中可用的广泛遗传工具来跟踪这些新发现，以确定（1）Notch信号传导在成熟哺乳动物嵴中是否保持活性（2）通过抑制Notch通路可以诱导支持细胞转分化为毛细胞（3）成熟哺乳动物嵴可以通过从头生成或转分化在体内再生毛细胞。我们进一步提出，试图刺激毛细胞更换成熟的小鼠嵴在体内通过操纵的Notch途径，并进行功能分析，以确定是否有任何形态学证据的毛细胞更换与功能恢复。目前还没有可行的方法来恢复前庭上皮中的毛细胞，因为它们随着年龄的增长而丢失。如果我们发现我们可以通过Notch途径的药理学操作刺激该系统的恢复，这可能会为数百万老年人提供益处，以改善他们的生活质量并降低他们受伤的风险。 公共卫生相关性：平衡障碍和眩晕在美国是一个严重的健康问题，也是老年人跌倒受伤的主要原因。虽然有许多因素导致平衡障碍，但前庭感觉器官的病理学被认为是主要的贡献者。如果我们发现我们可以通过Notch途径的药理学操作刺激该系统的恢复，这可能会为数百万老年人提供益处，以改善他们的生活质量并降低他们受伤的风险。

DESCRIPTION (provided by applicant): Balance disorders and vertigo are a significant health problem in the US, and are a leading cause of injures from falling in the elderly. While there are many factors that contribute to disorders in balance, pathology in the vestibular sense organs is thought to be a major contributor. There is a progressive loss in hair cell number in the semicircular canal cristae and the maculae of people as they age. Functional testing shows a similar decline in peripheral vestibular function with increasing age. There are currently no effective treatments to restore peripheral vestibular function. Over the past 20 years, there have been several reports that suggest new hair cells can be generated in the vestibular sensory epithelia. Some of the more promising data come from studies of the cristae, particularly in the chinchilla; however, there is as yet, no definitive proof that new hair cells can be generated in the adult mammalian cristae. The basic problem is that the tools available for studies of hair cell regeneration in species like the chinchilla are fairly limited. Most of these studies have been carried out with traditional morphological analyses, which cannot adequately assess whether any recovery from ototoxic drugs is due to de novo hair cell regeneration, transdifferentiation from existing support cells, or repair of the damaged hair cells. In a recent study of Notch signaling in mouse inner ear, we found that while this developmental signaling pathway is no longer active in the mature cochlea, it appears to be active in the support cells of the cristae. We reasoned that if the Notch pathway was still active in the mature mouse cristae, we could stimulate hair cell replacement through transdifferentiation. In preliminary studies, with pharmacological regulators of the Notch pathway, we have found evidence that support cells can transdifferentiate into hair cells in mature mouse cristae. We propose to follow-up on these new findings using the extensive genetic tools available in the mouse to determine whether (1) Notch signaling remains active in the mature mammalian cristae (2) Support cells can be induced to transdifferentiate into hair cells through inhibition of the Notch pathway (3) The mature mammalian cristae can regenerate hair cells in vivo by de novo generation or transdifferentiation. We further propose to attempt to stimulate hair cell replacement in mature mouse cristae in vivo through manipulations of the Notch pathway, and carry out functional analysis to determine whether any morphological evidence for hair cell replacement correlates with functional recovery. At the present time there are no viable methods to restore hair cells in the vestibular epithelia as they are lost with aging. If we find that we can stimulate recovery in this system with pharmacological manipulations in the Notch pathway, this could offer benefit to millions of elderly individuals to improve their quality of life and decrease their risk of injury. PUBLIC HEALTH RELEVANCE: Balance disorders and vertigo are a significant health problem in the US, and are a leading cause of injures from falling in the elderly. While there are many factors that contribute to disorders in balance, pathology in the vestibular sense organs is thought to be a major contributor. If we find that we can stimulate recovery in this system with pharmacological manipulations in the Notch pathway, this could offer benefit to millions of elderly individuals to improve their quality of life and decrease their risk of injury.