Auditory Nerve Degeneration and Repair

描述（由申请人提供）：螺旋神经节神经元（sgn）变性导致永久性感音神经性听力损失（SNHL），并且是不可逆的。外源性神经干细胞（NSCs）移植为治疗包括SNHL在内的多种神经退行性疾病提供了一种有希望的治疗策略。然而，各种神经退行性疾病动物模型的研究表明，损伤后成功移植NSCs的时间窗口很窄，NSCs的长期存活和功能整合受到限制，特别是在慢性退化的宿主环境中。尽管假设移植后NSCs的存活和适当分化需要良好的微环境，但很少有人关注宿主微环境究竟如何影响移植的NSCs的行为。为了解决这一差距，我们使用了一种具有良好特征的瓦巴因诱导的急性SGN损伤动物模型，证明了移植的NSCs在受损听神经中在损伤后早期的存活率明显高于损伤后后期的存活率。最近，我们已经证明急性SGN损伤诱导Sox2的上调，Sox2是一种转录因子，在发育和成人神经发生和胶质瘤发生期间在未分化神经细胞中高度表达。这种上调，以及Sox2+神经胶质细胞在损伤的成人听神经中的增殖，表明成熟的神经胶质细胞在急性SGN损伤时可以恢复到分化程度较低的表型，并重新进入细胞周期。基于这些新发现，我们假设SGN损伤刺激静止的胶质细胞进行表型转化，从而产生更有利于移植的NSCs存活和分化的微环境。这个项目的目标是确定的作用

DESCRIPTION (provided by applicant): Degeneration of spiral ganglion neurons (SGNs) results in permanent sensorineural hearing loss (SNHL) and is irreversible. Transplantation of exogenous neural stem cells (NSCs) offers a promising therapeutic strategy for the treatment of a variety of neural degenerative disorders including SNHL. However, studies of various animal models of neurodegenerative diseases indicate that the time window for the successful transplantation of NSCs after injury is narrow, and that long-term survival and functional integration of NSCs is limited, particularly, in the chronically degenerated host environment. Despite the assumption that a favorable microenvironment is required for the survival and appropriate differentiation of NSCs after transplantation, little attention has been paid to exactl how the host microenvironment affects the behavior of transplanted NSCs. To address this gap, we have documented that survival of transplanted NSCs is significantly greater in the injured auditory nerve at early post-injury intervals compared to later post-injury intervals using a well-characterized animal model of ouabain-induced acute SGN injury. More recently, we have shown that acute SGN injury induces up-regulation of Sox2, a transcription factor that is highly expressed in undifferentiated neural cells during development and adult neurogenesis and gliogenesis. This up-regulation, along with the proliferation of Sox2+ glial cells in the injured adult auditory nerve, suggests that mature glial cells can revert to a less differentiated phenotype and re-enter the cell cycle in response to acute SGN injury. Based on these new findings, we hypothesize that SGN injury stimulates the quiescent glial cells to undergo a phenotypic transformation resulting in a microenvironment more conducive to the survival and differentiation of transplanted NSCs. The objective of this project is to determine the role of the host microenvironment, with a focus on endogenous glial cells, in regulating the survival and differentiation of transplanted NSCs. We will characterize phenotypic changes of glial cells in response to acute SGN injury (Aim 1); determine the mechanisms whereby acute injury-induced glial phenotypic changes mediate NSC survival and differentiation in vitro (Aim 2); and determine the ability of de-differentiated glial cells to influence the survival, neuronal differentiation and morphological integration of transplanted NSCs in vivo (Aim 3). The proposed experiments will reveal 1) the key molecular factors associated with glial cell phenotypic changes in response to SGN injury and 2) the molecular mechanisms promoting the survival of transplanted NSCs by de-differentiated glial cells. Such data will provide answers to basic questions about glial cell biology and establish in vitro and in vivo models for studies of glial cells in the auditory system. In addition, information obtained will be of great public health interest for the design of therapeutic strategies for SNHL and other neurodegenerative disorders using glial cells as targets.