Auditory Nerve Degeneration and Repair

听觉神经退化与修复

基本信息

批准号：
9211519
负责人：
Hainan Lang
金额：
$ 4.76万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-10 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211519
关键词：
Acoustic Nerve Acute Address Adult Affect Afferent Neurons Age Aging Animal Model Area Attention Auditory Auditory system Behavior Biological Assay Brain CBA/CaJ Mouse Cell Cycle Cell Differentiation process Cell Separation Cell Survival Cellular biology Cessation of life Characteristics Coculture Techniques DNA Sequence Alteration Data Development Environment Gene Expression Gene Proteins Genes Genetic Transcription Hair Cells Human In Vitro Injury Knowledge Labyrinth Mediating Microarray Analysis Molecular Molecular Profiling Mus Natural regeneration Nerve Degeneration Nerve Tissue Neurodegenerative Disorders Neuroglia Neuronal Differentiation Neuronal Injury Neurons Noise Ouabain Outcome Pharmaceutical Preparations Phenotype Play Proteins Proteomics Public Health Reporter Genes Role Sensorineural Hearing Loss Sensory Hair Stem cell transplant Surface Testing Therapeutic Time Transplantation Undifferentiated Up-Regulation adult neurogenesis aged base cell behavior design gliogenesis in vivo in vivo Model injured interest mouse model nerve stem cell neurogenesis protein expression protein profiling relating to nervous system repaired research study response spiral ganglion transcription factor transcriptomics treatment strategy

项目摘要

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.

描述（由申请人提供）：螺旋神经节神经元（SGN）的退化导致永久性感音神经性听力损失（SNHL）并且是不可逆的。外源神经干细胞（NSC）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前途的治疗策略。然而，对各种神经退行性疾病动物模型的研究表明，损伤后NSCs成功移植的时间窗口很窄，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 NSC 的存活和适当分化需要有利的微环境，但很少有人关注宿主微环境如何影响移植 NSC 的行为。为了解决这一差距，我们使用哇巴因诱导的急性 SGN 损伤的良好表征的动物模型记录了，与损伤后较晚的时间间隔相比，受伤后早期的听神经中移植的 NSC 的存活率明显更高。最近，我们发现急性 SGN 损伤会诱导 Sox2 上调，Sox2 是一种转录因子，在发育和成体神经发生和胶质细胞生成过程中的未分化神经细胞中高度表达。这种上调以及受损成人听神经中 Sox2+ 神经胶质细胞的增殖表明，成熟的神经胶质细胞可以恢复到分化程度较低的表型，并重新进入细胞周期，以响应急性 SGN 损伤。基于这些新发现，我们假设 SGN 损伤刺激静止神经胶质细胞发生表型转变，从而形成更有利于移植 NSC 存活和分化的微环境。该项目的目标是确定宿主微环境，重点是内源性神经胶质细胞，调节移植的神经干细胞的存活和分化。我们将表征神经胶质细胞响应急性 SGN 损伤的表型变化（目标 1）；确定急性损伤诱导的神经胶质表型变化介导体外 NSC 存活和分化的机制（目标 2）；并确定去分化的神经胶质细胞影响体内移植 NSC 的存活、神经元分化和形态整合的能力（目标 3）。拟议的实验将揭示 1) 与神经胶质细胞响应 SGN 损伤而发生表型变化相关的关键分子因素，以及 2) 去分化神经胶质细胞促进移植 NSC 存活的分子机制。这些数据将为神经胶质细胞生物学的基本问题提供答案，并建立用于听觉系统神经胶质细胞研究的体外和体内模型。此外，所获得的信息对于设计以神经胶质细胞为靶点的 SNHL 和其他神经退行性疾病的治疗策略具有重大的公共健康意义。