Response of cochlear hair cells to pathological changes in the auditory system

耳蜗毛细胞对听觉系统病理变化的反应

• 批准号: 9759909
• 负责人: Stefan Heller
• 金额: $ 66.89万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759909
• 关键词: Affect; Applications Grants; Auditory system; Biological Assay; Candidate Disease Gene; Cell physiology; Cells; Cochlea; Data; Defect; Disadvantaged; Disease Progression; Efferent Neurons; Environment; Exposure to; Financial compensation; Flow Cytometry; Gene Expression; Gene Expression Profiling; Gene Order; Genes; Genetic; Genetic Transcription; Global Change; Hair; Hair Cells; Human; In Situ Hybridization; Individual; Infrastructure; Inner Hair Cells; Intervention; Knock-out; Labyrinth; Maps; Measurable; Measurement; Measures; Metabolic; Methods; Molecular; Molecular Biology; Mus; Mutation; Neurotransmitters; Noise; Noise-Induced Hearing Loss; Organ; Organ of Corti; Outer Hair Cell of the Organ of the Corti; Outer Hair Cells; Pathologic; Photoreceptors; Physiology; Population; Predisposition; Process; Quantitative Reverse Transcriptase PCR; Recovery; Regulator Genes; Research; Resolution; Retina; Reverse Transcriptase Polymerase Chain Reaction; SLC17A8 gene; Sensory; Series; Shotgun Sequencing; Stress; Synapses; System; Technology; Temporary Threshold Shift; Time; Tissue-Specific Gene Expression; Trauma; afferent nerve; base; cell type; conditioning; experimental study; hearing impairment; immunocytochemistry; insight; mouse model; nerve supply; programs; protective effect; repaired; response; scaffold; sensory system; single-cell RNA sequencing; sound; tectorial membrane; therapy development; transcriptome; transcriptome sequencing

Project Summary / Abstract The mouse cochlea harbors only 800 inner hair cells and about three times as many outer hair cells. This low number of cells has hampered progress specifically in the study of the molecular biology of inner ear cells. The use of single hair cell gene expression profiling has the potential to turn this disadvantage into a major advantage because it allows for oversampling the organ by generating high resolution quantitative gene expression maps for thousands of inner and outer hair cells of the organ of Corti, which is the first Aim of this grant application. It is anticipated that these maps, based on single cell RNA-Seq data will miss little information when compared for example with other sensory systems such as the retina, where analysis of a few thousand photoreceptor cells would represent <0.05% of the sensory cell population. It is anticipated that the maps will reveal how gradients of gene expression contribute to functional tonotopy in inner and outer hair cells. Moreover, the generated maps will serve as base line for identifying distinct changes in cochlear hair cells after noise-induced temporary threshold shift. Here, it is anticipated that the analysis will reveal functional modules of co-regulated hair bundle genes as well as candidate gene regulatory networks for susceptibility to noise-induced hearing loss. A second series of experiments aims to identify the molecular mechanisms by which non-traumatic sound exposure temporarily reduces susceptibility for permanent noise induced threshold shift. This research has the potential of elucidating genes and mechanisms involved in susceptibility to noise. Finally, it is proposed to investigate at the molecular level compensatory changes in inner and outer hair cells in response to sustained changes in cochlear integration such as lack of functional afferent or efferent innervation or lack of connection between outer hair cells and the tectorial membrane. Beside identification of co-regulated gene groups for example involved in cochlear amplification, it is expected that this research will reveal how hair cells are affected by pathological situations that do not trigger immediate hair cell loss.

项目总结/摘要 小鼠耳蜗只有800个内毛细胞，外毛细胞的数量大约是其三倍。这种低 细胞数量的限制阻碍了内耳细胞分子生物学研究的进展。 单毛细胞基因表达谱的使用有可能将这一劣势转化为主要的 这是因为它允许通过产生高分辨率定量基因来对器官进行过采样 Corti器官的数千个内毛细胞和外毛细胞的表达图，这是本发明的第一个目的。 补助金申请预计这些基于单细胞RNA-Seq数据的图谱几乎不会丢失 当例如与诸如视网膜的其他感觉系统相比时， 几千个感光细胞将代表感觉细胞群的<0.05%。预计各国 这些图谱将揭示基因表达的梯度是如何影响内外毛的功能性色调的 细胞此外，生成的图将作为识别耳蜗毛的不同变化的基线 噪声诱导的暂时性阈值偏移后的细胞。在这里，预计分析将揭示功能性 共同调控的毛束基因模块以及易感性的候选基因调控网络， 噪音引起的听力损失第二个系列的实验旨在通过以下方式确定分子机制： 该非创伤性声音暴露暂时降低了对永久性噪声诱导阈值的敏感性 班这项研究有可能阐明与噪声易感性有关的基因和机制。 最后，建议在分子水平上研究内毛细胞和外毛细胞的代偿性变化 响应耳蜗整合的持续变化，例如功能性传入或传出的缺乏 外毛细胞和盖膜之间缺乏神经支配或连接。除了识别 例如，参与耳蜗放大的共调节基因组，预计这项研究将 揭示了毛细胞如何受到病理情况的影响，而这些病理情况不会立即引发毛细胞损失。