Regeneration in the vestibular system

前庭系统的再生

• 批准号: 7870831
• 负责人: Olivia Mary Bermingham-McDonogh
• 金额: $ 20.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870831
• 关键词: Adult; Age; Aging; Bromodeoxyuridine; Cell Count; Cell physiology; Chinchilla (genus); Cochlea; Crista ampullaris; Data; Development; Disease; Elderly; Epithelium; Equilibrium; Generations; Genetic; Hair Cells; Health; Hippocampus (Brain); In Situ Hybridization; In Vitro; Individual; Injury; Label; Labyrinth; Lateral; Ligands; Methods; Mus; Natural regeneration; Nervous system structure; Organ; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Quality of life; Recovery; Recovery of Function; Reporter; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Risk; Semicircular canal structure; Sense Organs; Sensory; Signal Pathway; Signal Transduction; Supporting Cell; System; Testing; Time; Vertigo; adult neurogenesis; cell injury; effective therapy; equilibration disorder; falls; follow-up; hair cell regeneration; improved; in vivo; injured; macula; notch protein; novel; progenitor; public health relevance; recombinase; repaired; subventricular zone; tool; transdifferentiation

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.

描述（由申请人提供）：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。虽然导致平衡障碍的因素有很多，但前庭感觉器官的病理被认为是一个主要因素。随着年龄的增长，人们的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，外周前庭功能也出现类似的下降。目前尚无有效的治疗方法可以恢复外周前庭功能。过去20年里，有几份报告表明前庭感觉上皮细胞可以生成新的毛细胞。一些更有希望的数据来自对嵴的研究，特别是龙猫的嵴。然而，目前还没有明确的证据表明成年哺乳动物的嵴可以产生新的毛细胞。基本问题是，可用于研究龙猫等物种毛细胞再生的工具相当有限。这些研究大多数都是通过传统的形态学分析进行的，无法充分评估耳毒性药物的恢复是否归因于毛细胞的从头再生、现有支持细胞的转分化或受损毛细胞的修复。在最近对小鼠内耳中的 Notch 信号传导的研究中，我们发现虽然这种发育信号传导途径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 通路在成熟小鼠嵴中仍然活跃，我们就可以通过转分化刺激毛细胞替换。在初步研究中，通过Notch通路的药理学调节剂，我们发现了支持细胞可以在成熟小鼠嵴中转分化为毛细胞的证据。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 信号在成熟哺乳动物嵴中是否保持活跃 (2) 通过抑制Notch途径 (3) 成熟的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。我们进一步建议尝试通过操作Notch通路来刺激体内成熟小鼠嵴的毛细胞替换，并进行功能分析以确定毛细胞替换的任何形态学证据是否与功能恢复相关。目前，还没有可行的方法来恢复前庭上皮中的毛细胞，因为它们会随着衰老而丢失。如果我们发现可以通过 Notch 通路中的药理操作来刺激该系统的恢复，这可能会给数百万老年人带来好处，提高他们的生活质量并降低他们受伤的风险。 公共健康相关性：平衡障碍和眩晕是美国的一个重大健康问题，也是老年人跌倒受伤的主要原因。虽然导致平衡障碍的因素有很多，但前庭感觉器官的病理被认为是一个主要因素。如果我们发现可以通过 Notch 通路中的药理操作来刺激该系统的恢复，这可能会为数百万老年人带来好处，提高他们的生活质量并降低他们受伤的风险。