Mechanisms of Sensory Regeneration

描述（由申请人提供）：人内耳感觉毛细胞的丧失是听力和平衡缺陷的主要原因。人耳感觉再生的潜力非常有限，但许多哺乳类脊椎动物耳中的毛细胞在受伤后可以迅速再生。对这种再生过程的基础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。本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通路。 我们最近的工作表明，细胞间的相互作用介导的粘附分子N-钙粘蛋白是一个关键的调节器的感觉再生。这里提出的实验将检查两个特定的信号通路，已知被激活的N-钙粘蛋白的相互作用。目前的数据表明，N-钙粘蛋白可以调节（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。我们怀疑这两种途径可能平行地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。我们的试点数据表明，大多数的SHH途径的分子成分存在于鸟类前庭器官在早期阶段的再生。我们推测，SHH可能作为一种内源性产生的有丝分裂原在鸡耳再生过程中。 一个相关的项目将集中在前庭器官感觉神经元的再生。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。我们推测，一种抑制神经元生长的信号分子产生于胞囊内条纹的逆转区。值得注意的是，我们已经确定了一个转录因子，在整个再生过程中，在这个区域中唯一表达。我们提出了一系列的实验，旨在识别的指导线索，传入神经元用于导航到更换毛细胞在再生过程中。有关传入神经元如何被引导到其目标的知识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.