Mechanisms of Sensory Regeneration

感觉再生的机制

• 批准号: 7039249
• 负责人: Mark Warchol
• 金额: $ 33.99万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039249
• 关键词: JUN kinase; afferent nerve; biological signal transduction; cadherins; cell cell interaction; cell growth regulation; cell proliferation; chickens; ear hair cell; enzyme activity; nervous system regeneration; neuronal guidance; organ culture; tissue /cell culture; transcription factor; vestibular apparatus

DESCRIPTION (provided by applicant): The loss of sensory hair cells from the human inner ear is a leading cause of hearing and balance deficits. The potential for sensory regeneration in the human ear is very limited, but hair cells in the ears of many no mammalian vertebrates can quickly regenerate after injury. A complete understanding of the basic biology of this regenerative process should suggest methods for promoting similar forms of regeneration in the human ear. The overall goals of this study are to identify the molecular signaling pathways that regulate the regeneration of hair cells and their sensory neurons. Our recent work has suggested that cell-cell interactions mediated by the adhesion molecule N-cadherin are a key regulator of sensory regeneration. Experiments proposed here will examine two specific signaling pathways that are known to be activated by N-cadherin interactions. Present data suggest that N-cadherin may regulate either (1) the cellular translocation of Beta-catenin from cell-cell junctions to cell nuclei, and/or (2) activation of the c-Jun kinase (JNK) signaling pathway. We suspect that both of these pathways might act in parallel to regulate the regenerative proliferation of inner ear supporting cells. Other experiments will examine the possible involvement of Sonic Hedgehog (SHH) signaling in the regenerative process. Our pilot data have demonstrated that most of the molecular constituents of the SHH pathway are present in the avian vestibular organs during the early stages of regeneration. We hypothesize that SHH may act as an endogenously produced mitogen in the avian ear during regeneration. A related project will focus on the regeneration of sensory neurons in the vestibular organs. In order to restore sensory function, regenerated hair cells need to establish precise synaptic contacts with afferent neurons. We hypothesize that a signaling molecule that inhibits neuronal growth is produced within the reversal zone of the striola in the utricle. Significantly, we have identified a transcription factor that is uniquely expressed in this region throughout the regenerative process. We propose a series of experiments that are aimed at identification of guidance cues that afferent neurons use to navigate to replacement hair cells during the regenerative process. Knowledge of how afferent neurons are guided to their targets may suggest new methods for enhancing the neural interface of auditory and vestibular prostheses.

描述（由申请人提供）：人类内耳感觉毛细胞的丧失是听力和平衡缺陷的主要原因。人耳的感觉再生潜力非常有限，但许多非哺乳动物脊椎动物耳朵中的毛细胞在受伤后可以快速再生。对这种再生过程的基本生物学的全面了解应该会提出促进人耳类似形式再生的方法。这项研究的总体目标是确定调节毛细胞及其感觉神经元再生的分子信号传导途径。 我们最近的工作表明，粘附分子 N-钙粘蛋白介导的细胞间相互作用是感觉再生的关键调节因子。这里提出的实验将检查已知由 N-钙粘蛋白相互作用激活的两种特定信号传导途径。目前的数据表明，N-钙粘蛋白可能调节 (1) β-连环蛋白从细胞-细胞连接到细胞核的细胞易位，和/或 (2) c-Jun 激酶 (JNK) 信号通路的激活。我们怀疑这两条途径可能并行作用来调节内耳支持细胞的再生增殖。 其他实验将研究 Sonic Hedgehog (SHH) 信号在再生过程中的可能参与。我们的试验数据表明，SHH 通路的大部分分子成分存在于再生早期阶段的禽类前庭器官中。我们假设 SHH 可能作为禽耳再生过程中内源产生的有丝分裂原。 一个相关项目将重点关注前庭器官中感觉神经元的再生。为了恢复感觉功能，再生的毛细胞需要与传入神经元建立精确的突触接触。我们假设抑制神经元生长的信号分子是在椭圆囊纹状体的反转区内产生的。值得注意的是，我们已经确定了在整个再生过程中该区域独特表达的转录因子。我们提出了一系列实验，旨在识别传入神经元在再生过程中用于导航到替代毛细胞的引导线索。了解传入神经元如何引导至目标可能会提出增强听觉和前庭假体神经接口的新方法。