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

基本信息

批准号：
9976494
负责人：
Stefan Heller
金额：
$ 66.89万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976494
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

项目摘要

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.

项目摘要 /摘要小鼠耳蜗只有800个内毛细胞，大约三倍的外毛细胞。这个低细胞的数量在研究内耳细胞的分子生物学研究中特异性阻碍了进步。单毛细胞基因表达分析的使用有可能将这种劣势转化为主要优势是因为它可以通过产生高分辨率定量基因来过采样器官 Corti器官的数千个内部和外毛细胞的表达图，这是第一个目的授予申请。预计这些地图基于单个单元RNA-seq数据将很少错过当与其他感觉系统（例如视网膜）进行比较时，信息的信息时几千个光感受器细胞将占感觉细胞群的<0.05％。预计这些地图将揭示基因表达的梯度如何有助于内部和外发的功能性吨位细胞。此外，生成的地图将用作识别耳蜗明显变化的基线噪声引起的暂时阈值移位后的细胞。在这里，预计分析将揭示功能共同调节的头发束基因以及候选基因调节网络的模块，以易感性噪声引起的听力损失。第二系列实验旨在通过哪些非创伤声音暴露会暂时降低对永久噪声诱发阈值的敏感性转移。这项研究具有阐明与噪声敏感性有关的基因和机制。最后，建议在内毛细胞的分子水平补偿性变化下进行研究为了响应人工耳蜗整合的持续变化，例如缺乏功能传入或影响外毛细胞与tecorial膜之间的神经或缺乏联系。除了识别例如，共同调节的基因组，例如参与人工耳蜗的扩增，预计这项研究将会揭示毛细胞如何受到不会触发立即毛细胞损失的病理情况的影响。