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Trophic Interactions in Developing and Adult Inner Ear

发育中和成人内耳的营养相互作用

基本信息

批准号：
7713536
负责人：
Gabriel Corfas
金额：
$ 45.93万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-15 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7713536
关键词：
Ablation Adult Afferent Neurons Affinity Aftercare Age Animals Auditory Axon Back Biological Models Birth Brain-Derived Neurotrophic Factor Cells Cochlea Dependence Diet Dominant-Negative Mutation Down-Regulation Ear Embryonic Development Epithelium Equilibrium ErbB4 gene Functional disorder Genes Genetic Models Genetic Recombination Glial Fibrillary Acidic Protein Glutamate Receptor Grant Hair Cells Health Hearing Image In Situ Hybridization Incidence Inner Hair Cells Knock-out Knockout Mice Labyrinth LacZ Genes Maintenance Modeling Molecular Mus Nerve Nerve Degeneration Nerve Growth Factor Receptors Neuregulin 1 Neuroglia Neurons Neuropathy Neurotrophin 3 Noise Organ Organ of Corti Pathogenesis Pattern Peripheral Pharmaceutical Preparations Phenotype Play Predisposition Prevalence Process Receptor Signaling Relative (related person)Reverse Transcriptase Polymerase Chain Reaction Role Sensorineural Hearing Loss Sensory Sensory Ganglia Signal Pathway Signal Transduction Source Structure Supporting Cell Synapses System Technology Testing Thiamine Time Tissues Transgenic Mice Transgenic Organisms Work base deprivation equilibration disorder ganglion cell genetic manipulation hearing impairment insight morphometry mouse model mutant nerve supply neuron loss neuronal survival neurotrophic factor overexpression postnatal promoter receptor recombinase research study response ribbon synapse spiral ganglion

项目摘要

DESCRIPTION (provided by applicant): The cellular and molecular mechanisms underlying long-term neuronal survival in the inner ear remain poorly understood. Histopathological correlations have suggested that hair cells are a critical source of survival signals for the VIIIth nerve. However, our work indicates that supporting cells in both cochlear and vestibular epithelia play key roles in neuronal maintenance via the neuregulin 1-erbB receptor and neurotrophin-Trk signaling pathways. Postnatal loss of erbB signaling in supporting cells leads to neuronal degeneration, preceded by a specific loss of NT3 in the cochlea and BDNF in the vestibular organs, at a time when these neurotrophins (NTs) are expressed primarily by supporting cells. Since erbB receptor signaling induces NT expression in other non-neuronal cells, and since inner ear sensory neurons express NRG1, we hypothesize that: NRG1, produced by cochlear and vestibular sensory neurons, induces supporting cells to express NTs, NT3 in the organ of Corti and BDNF in the vestibular epithelia. These NTs, acting back on the neurons, maintain their synaptic contacts with hair cells, induce their survival and preserve their function. We will test this hypothesis using genetically modified mice. In Aim 1, inducible cell-specific knockouts will test if elimination of either NT3 or BDNF in supporting cells or hair cells causes neuronal degeneration and inner ear dysfunction; and conditional cell-specific overexpression transgenics will test if the neuronal degeneration caused by loss of erbB signaling in supporting cells can be rescued by increasing NT expression. In Aim 2, we evaluate inner hair cell contributions to long-term neuronal maintenance using mice lacking the high-affinity thiamine transporter such that dietary thiamine restriction leads to widespread and selective loss of inner hair cells, without damage to supporting cells. Inner ear tissues will be quantitatively assessed over time by confocal morphometry of hair cell synapses and sensory ganglion cells, functional tests of evoked responses, and assessment of gene levels/patterns of expression of key trophic factors and their receptors using RT-PCR and in situ hybridization. Comparison of phenotypes obtained when controlling the up- or down-regulation of NT3 vs. BDNF in hair cells vs. supporting cells at different post-natal ages will provide insights into the specific roles of each neurotrophin, the cells involved in the signaling pathways, and the age-dependence of neuronal susceptibility to trophic factor deprivation. These experiments will provide important insights into the pathogenesis and potential treatment of sensorineural hearing loss and peripheral balance disorders. Progressive dysfunction of the inner ear is an important health issue. In spite of the high incidence of hearing and balance disorders, the cellular and molecular mechanisms that contribute to the long-term integrity of inner ear structure and function remain poorly understood. This project will investigate the cellular and molecular mechanisms involved in the long-term survival and function of inner ear sensory neurons using transgenic mouse models.

描述（由申请人提供）：内耳神经元长期存活的细胞和分子机制尚不清楚。组织病理学相关性表明，毛细胞是第八神经存活信号的重要来源。然而，我们的工作表明，耳蜗和前庭上皮中的支持细胞通过神经调节蛋白1-erbB受体和神经营养因子- trk信号通路在神经元维持中发挥关键作用。出生后支持细胞中erbB信号的丢失导致神经元变性，在此之前耳蜗中NT3和前庭器官中BDNF的特异性丢失，此时这些神经营养因子（NTs）主要由支持细胞表达。由于erbB受体信号在其他非神经元细胞中诱导NT表达，内耳感觉神经元表达NRG1，我们假设：耳蜗和前庭感觉神经元产生的NRG1诱导支持细胞在Corti器官中表达NT、NT3，在前庭上皮中表达BDNF。这些NTs作用于神经元，维持它们与毛细胞的突触接触，诱导毛细胞存活并保持其功能。我们将用转基因老鼠来验证这一假设。在Aim 1中，诱导细胞特异性敲除将测试支持细胞或毛细胞中NT3或BDNF的消除是否会导致神经元变性和内耳功能障碍；和条件细胞特异性过表达转基因将测试是否可以通过增加NT表达来挽救支持细胞中erbB信号缺失引起的神经元变性。在Aim 2中，我们使用缺乏高亲和力硫胺素转运体的小鼠，评估了内毛细胞对长期神经元维持的贡献，因此饮食硫胺素限制导致内毛细胞广泛和选择性的损失，而不会损害支持细胞。随着时间的推移，内耳组织将通过毛细胞突触和感觉神经节细胞的共聚焦形态测量、诱发反应的功能测试、关键营养因子及其受体的基因水平/表达模式的评估（使用RT-PCR和原位杂交）进行定量评估。通过比较不同出生年龄毛细胞和支持细胞中NT3和BDNF的上调或下调调控所获得的表型，可以深入了解每种神经营养因子的具体作用、参与信号通路的细胞以及神经元对营养因子剥夺易感性的年龄依赖性。这些实验将为感音神经性听力损失和外周平衡障碍的发病机制和潜在治疗提供重要的见解。进行性内耳功能障碍是一个重要的健康问题。尽管听力和平衡障碍的发病率很高，但对内耳结构和功能长期完整性的细胞和分子机制仍知之甚少。本项目将利用转基因小鼠模型研究内耳感觉神经元长期存活和功能的细胞和分子机制。