Auditory Nerve Degeneration and Repair

听觉神经退化与修复

• 批准号: 8681418
• 负责人: Hainan Lang
• 金额: $ 36.88万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681418
• 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; Data; Development; Environment; Gene Expression; Gene Mutation; 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

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）：螺旋神经神经元（SGN）的变性会导致永久性的感官听力损失（SNHL），并且不可逆。外源神经干细胞（NSC）的移植提供了一种有希望的治疗策略，用于治疗包括SNHL在内的多种神经退行性疾病。然而，对神经退行性疾病的各种动物模型的研究表明，损伤后成功移植NSC的时间窗口狭窄，并且NSC的长期生存和功能整合受到限制，尤其是在长期退化的宿主环境中。尽管假设移植后的生存和适当的NSC的生存和适当的分化需要有利的微环境，但很少关注精确的宿主微环境如何影响移植的NSC的行为。为了解决这一差距，我们已经证明，与后来使用ouabain诱导的急性SGN损伤的动物模型相比，与后来的伤害后间隔相比，受伤后的听觉神经的移植NSC的存活明显更大。最近，我们表明急性SGN损伤诱导SOX2的上调，Sox2是一种转录因子，在发育，成人神经发生和神经胶质发生过程中，在未分化的神经细胞中高度表达。这种上调以及受伤的成年听觉神经中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较少分化的表型，并因急性SGN损伤而重新进入细胞周期。基于这些新发现，我们假设SGN损伤刺激了静止的神经胶质细胞进行表型转化，从而导致微环境更有利于移植NSC的存活和分化。该项目的目的是确定 宿主的微环境，侧重于内源性神经胶质细胞，以调节移植的NSC的存活和分化。我们将表征响应急性SGN损伤的神经胶质细胞的表型变化（AIM 1）；确定急性损伤引起的神经胶质表型变化的机制介导了NSC的存活和体外分化（AIM 2）；并确定去分化的神经胶质细胞影响体内移植NSC的生存，神经元分化和形态整合的能力（AIM 3）。提出的实验将揭示1）与SGN损伤有关的胶质细胞表型变化相关的关键分子因子以及2）促进通过去分化的神经胶质细胞促进移植NSC存活的分子机制。这样的数据将为有关神经胶质细胞生物学的基本问题提供答案，并建立在听觉系统中神经胶质细胞研究的体外和体内模型。此外，对于使用神经胶质细胞作为靶标的SNHL和其他神经退行性疾病的治疗策略设计，获得的信息将具有极大的公共卫生利益。