Regeneration in the vestibular system

前庭系统的再生

基本信息

批准号：
8048077
负责人：
Olivia Mary Bermingham-McDonogh
金额：
$ 24.1万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8048077
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

项目摘要

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）：在美国，平衡障碍和眩晕是一个重大的健康问题，是老年人受伤的主要原因。尽管有许多因素导致平衡疾病，但前庭意义上的病理器官被认为是主要因素。在半圆形管的cristae和人的黄斑中，毛细胞数量逐渐损失。功能测试表明，周围前庭功能随着年龄的增长的类似下降。目前尚无有效的治疗方法来恢复外围前庭功能。在过去的20年中，有几份报道表明可以在前庭感觉上皮中产生新的毛细胞。一些更有希望的数据来自对Cristae的研究，特别是在龙猫中。但是，尚无确切的证据，表明在成年哺乳动物cristae中可以产生新的毛细胞。基本问题是，可用于研究诸如龙猫等物种的毛细胞再生的工具相当有限。这些研究中的大多数是通过传统的形态分析进行的，该分析无法充分评估来自耳毒性药物的任何恢复是由于从头毛细胞再生，现有支持细胞的转分解或修复受损的毛细胞所致。在最近对小鼠内耳中的Notch信号传导的研究中，我们发现，尽管这种发育信号通路不再活跃在成熟的耳蜗中，但它似乎在Cristae的支持细胞中活跃。我们认为，如果Notch途径在成熟的小鼠Cristae中仍然活跃，我们可以通过转分化刺激毛细胞替换。在初步研究中，使用Notch途径的药理学调节剂，我们发现了证据表明，支持细胞可以将成熟小鼠Cristae中的毛细胞转变为毛细胞。我们建议使用鼠标中可用的广泛的遗传工具对这些新发现进行跟进，以确定（1）Notch信号在成熟的哺乳动物cristae（2）支持细胞中是否保持活跃，可以诱导细胞通过抑制Notch途径（3）成熟的哺乳动物Cristae的毛发细胞，从而将毛细胞延伸到毛细胞中。我们进一步建议通过操纵Notch途径刺激体内成熟小鼠Cristae的毛细胞替代，并进行功能分析以确定是否有任何形态学证据证明毛细胞替代的任何形态学证据是否与功能恢复相关。目前，由于衰老损失，目前尚无可行的方法来恢复前庭上皮细胞的毛细胞。如果我们发现可以在Notch途径中使用药理学操作刺激该系统中的恢复，那么这可能会为数百万个老年人提供好处，以改善其生活质量并降低受伤的风险。公共卫生相关性：在美国，平衡障碍和眩晕是一个重大的健康问题，是老年人受伤的主要原因。尽管有许多因素导致平衡疾病，但前庭意义上的病理器官被认为是主要因素。如果我们发现可以在Notch途径中使用药理学操作刺激该系统中的恢复，那么这可能会为数百万个老年人提供好处，以改善其生活质量并降低受伤的风险。