Mechanisms of Sensory Regeneration

描述(申请人提供)：人类内耳感觉毛细胞的丧失是听力和平衡障碍的主要原因。人类耳朵的感觉再生潜力非常有限，但许多非哺乳类脊椎动物耳朵中的毛细胞在受伤后可以迅速再生。如果完全了解这种再生过程的基本生物学原理，就应该提出一些方法来促进人类耳朵类似形式的再生。这项研究的总体目标是确定调控毛细胞及其感觉神经元再生的分子信号通路。 我们最近的工作表明，由黏附分子N-钙粘附素介导的细胞-细胞相互作用是感觉再生的关键调节因子。这里提出的实验将研究两个已知由N-钙粘附素相互作用激活的特定信号通路。目前的数据表明，N-钙粘附素可能调节(1)β-连环蛋白从细胞-细胞连接到细胞核的转位，和/或(2)c-jun激酶(JNK)信号通路的激活。我们怀疑这两条通路可能同时作用于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。我们的初步数据表明，在鸟类再生的早期阶段，SHH途径的大部分分子成分存在于鸟类的前庭器官中。我们推测，在鸟类再生过程中，SHH可能作为内源性的有丝分裂原在鸟类的耳朵中发挥作用。 一个相关的项目将专注于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联系。我们假设，在椭圆体中纹状体的反转区内产生了一个抑制神经元生长的信号分子。值得注意的是，我们已经确定了一个在整个再生过程中在该区域唯一表达的转录因子。我们提出了一系列实验，旨在识别在再生过程中传入神经元用来导航到替换毛细胞的指导线索。了解传入神经元是如何被引导到它们的目标的，可能会为增强听觉和前庭假体的神经接口提供新的方法。

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.