Auditory Nerve Degeneration and Repair

听觉神经退化与修复

• 批准号: 8370280
• 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/8370280
• 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; Degenerative Disorder; 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. PUBLIC HEALTH RELEVANCE: The proposed studies will provide new knowledge of how changes in the microenvironment of the inner ear influence the outcome of stem cell transplantation. In particular, we will establish the critical roles glial cells play in regulatingthe survival and development of the transplanted stem cells. Such knowledge will impact the design of efficient therapies for sensorineural hearing loss 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）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前途的治疗策略。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的时间窗很窄，并且NSC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。尽管假设移植后神经干细胞的存活和适当分化需要有利的微环境，但很少注意宿主微环境如何影响移植的神经干细胞的行为。为了解决这一差距，我们已经证明，移植的神经干细胞的存活率显着更大的损伤后的早期损伤后的时间间隔相比，损伤后的时间间隔使用哇巴因诱导的急性SGN损伤的动物模型。最近，我们已经表明，急性SGN损伤诱导Sox 2的上调，Sox 2是一种在发育和成体神经发生和胶质细胞发生过程中在未分化神经细胞中高度表达的转录因子。这种上调，沿着Sox 2+神经胶质细胞在损伤的成年听神经中的增殖，表明成熟的神经胶质细胞可以回复到分化程度较低的表型，并响应于急性SGN损伤重新进入细胞周期。基于这些新的发现，我们假设SGN损伤刺激静止的神经胶质细胞进行表型转化，从而产生更有利于移植的NSC的存活和分化的微环境。本项目的目标是确定 宿主微环境，重点是内源性胶质细胞，在调节移植的神经干细胞的存活和分化。我们将描述神经胶质细胞对急性SGN损伤的表型变化（目标1）;确定急性损伤诱导的神经胶质细胞表型变化介导体外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的神经干细胞的存活、神经元分化和形态整合的能力（目标3）。所提出的实验将揭示1）与响应SGN损伤的神经胶质细胞表型变化相关的关键分子因子和2）通过去分化神经胶质细胞促进移植的NSC存活的分子机制。这些数据将提供有关神经胶质细胞生物学的基本问题的答案，并建立在体外和体内模型的神经胶质细胞在听觉系统的研究。此外，获得的信息将是巨大的公共卫生利益的SNHL和其他神经退行性疾病的治疗策略的设计使用神经胶质细胞作为目标。 公共卫生相关性：拟议的研究将为内耳微环境的变化如何影响干细胞移植的结果提供新的知识。特别是，我们将建立神经胶质细胞在调节移植干细胞的存活和发育中的关键作用。这些知识将影响使用神经胶质细胞作为靶点的感音神经性听力损失和其他神经退行性疾病的有效疗法的设计。