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COCHLEAR NERVE DEVELOPMENT

耳蜗神经发育

基本信息

批准号：
6379274
负责人：
STEPHEN M ECHTELER
金额：
$ 26.86万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-03-01 至 2005-06-30
项目状态：
已结题

项目摘要

The major aim of this research is to learn about the cellular, and ultimately the molecular, interactions that produce an ordered set of neuronal connections within the mammalian auditory periphery. Mammals possess two classes of auditory receptors, termed inner and outer hair cells, that project to the brain through separate neural components of the auditory nerve. Within the cochlea, auditory neurons innervate hair cells with astonishing accuracy; most form a single punctate synapse with only one receptor. Past work has shown that, during cochlear development, this neural specificity arises through extensive structural remodeling of individual cochlear neuron arbors, most of which form transient, supernumerary connections with outer hair cell receptors. During this process, up to 30% of all cochlear neurons die within the neonatal ear. This application, for renewal of a project in its 6th year, proposes to continue investigations into the formation of cochlear innervation by examining the cellular interactions between developing auditory neurons and hair cells, in-vivo, within the developing gerbil and, in vitro, within developing organotypic cultures of gerbil cochlea. Three sets of experiments are proposed: 1) The timecourse and spatial distribution of programmed auditory neuron death will be determined within the developing ear, by DNA labeling of apoptotic cells and serial reconstruction of the developing spiral ganglion; 2) Factors affecting the survival and programmed death of auditory neurons within the developing ear will be investigated by examining, both in vivo and in vitro, the cellular expression patterns of two cochlear neurotrophic molecules (BDNF and NT-3) and their receptors (trk B and trkC) using in situ hybridization and immunocytochemistry. 3) The influence of these neurotrophic factors on the formation of neural connections to inner and outer hair cells will be assessed by examining the structural development of individual auditory neuron arbors, labeled with neural tracers and reconstructed by light and confocal microscopy, within organotypic cultures that have been enriched for NT-3 and/or BDNF or depleted of these neurotrophins by the addition of trkB-IgG and trkC-IgG fusion proteins. Eighty-percent of all significant hearing impairment in the U.S is caused by the permanent loss of auditory neurons and receptors. It is crucial to understand the cellular interactions that form and maintain these sensorineural elements if effective biological strategies are to be devised for their protection or repair.

这项研究的主要目的是了解细胞，最终，分子间的相互作用产生了一系列有序的哺乳动物听觉周边的神经元连接。哺乳动物有两类听觉感受器，称为内毛和外毛细胞，通过独立的神经成分投射到大脑。听神经。在耳蜗内，听觉神经元支配毛细胞以惊人的准确性;大多数形成一个单一的点状突触，一个受体。过去的研究表明，在耳蜗发育过程中，神经特异性通过广泛的结构重塑产生，单个耳蜗神经元轴，其中大部分形成瞬时的，与外毛细胞受体的额外连接。在此在这个过程中，高达30%的耳蜗神经元在新生儿耳内死亡。本申请是一个项目在第六年的续期申请，建议继续研究耳蜗神经支配的形成，检查发育中的听觉神经元之间的细胞相互作用，毛细胞，在体内，在发育中的沙鼠和，在体外，发展沙鼠耳蜗的器官型培养。三套实验结果表明：1）时间进程和空间分布程序性听觉神经元死亡将在发育中的耳，通过凋亡细胞的DNA标记和连续重建，螺旋神经节的发育; 2）影响生存和发育中的耳朵内听觉神经元的程序性死亡将是研究通过检查，在体内和体外，细胞两种耳蜗神经营养分子（BDNF和NT-3）的表达模式及其受体（trk B和trk C），免疫细胞化学3)这些神经营养因子对神经细胞的影响与内毛细胞和外毛细胞的神经连接的形成将是通过检查个体听觉的结构发展来评估用神经示踪剂标记并通过光重建的神经元乔木，共聚焦显微镜，在器官型培养物中，对于NT-3和/或BDNF，或通过添加以下物质来耗尽这些神经营养因子： trkB-IgG和trkC-IgG融合蛋白。在美国，80%的严重听力损伤是由听觉神经元和感受器的永久性丧失。至关重要了解形成和维持这些的细胞相互作用如果要设计有效的生物学策略，保护或修复。