Roles of the Synapse in Hair-Cell Pathology
Roles of the Synapse in Hair-Cell Pathology
批准号:
10801270
负责人:
Lavinia Sheets
金额:
$50.58万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
未结题
起止时间:
2017-07-17 至 2028-05-31
关键词:
AMPA ReceptorsAcoustic NerveAddressAfferent NeuronsAgingAutomobile DrivingBiological AssayBiological ModelsCalciumCell physiologyCochleaDataDevelopmentEarExocytosisExposure toFishesFunctional ImagingFundingGlutamate ReceptorGlutamatesGoalsHair CellsHearingHourHumanImageImmunofluorescence ImmunologicImpairmentInflammationInflammatory ResponseInjuryInnate Immune SystemInner Hair CellsKnock-outLoudnessMacrophageMaintenanceMammalsMembrane PotentialsMetabolic stressMitochondriaModelingMolecularMorphologyN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNerve DegenerationNoiseOrganPathologyPermeabilityPhagocytesPharmacologyPlayRecoveryRecovery of FunctionResearchRoleSensory ReceptorsSignal PathwaySiteStimulusStudy modelsSynapsesSynaptic VesiclesTestingTimeTraumaVisualizationWorkZebrafishcholinergicdefined contributionexcitotoxicitygain of functiongenetic manipulationglutamatergic signalinghearing impairmentinjuredlateral linemechanotransductionmitochondrial metabolismnerve repairnerve supplynoise exposureorgan repairpharmacologicpostsynapticpresynapticpreventrecruitreinnervationrepairedribbon synapsesynaptic inhibitionsynaptogenesistherapeutic target
中文摘要
项目摘要
噪声暴露对耳蜗内毛细胞与听觉神经元突触联系的损伤
神经来自哺乳动物模型和人类的数据表明,一些内毛细胞突触的丢失可能是
永久性的,导致分离的听觉神经的缓慢退化。然而,最近的研究也支持了
哺乳动物耳蜗具有在噪声后进行毛细胞突触修复的内在能力
损害明确创伤性噪声后突触修复的细胞机制是研究神经元损伤的关键一步。
确定治疗靶点,以促进毛细胞突触接触的修复并防止听觉丧失,
神经
本研究的总体目标是了解毛细胞形态和功能的分子基础
器官修复和恢复后,噪音引起的损害。目前我们对毛细胞
创伤性噪音后的突触修复在很大程度上是由于我们无法定义细胞过程
在哺乳动物模型系统中促进突触修复。本项目将通过以下方式规避这些问题:
研究机械诱导的斑马鱼侧线毛细胞突触丢失和随后的修复,
一种由神经支配的毛细胞簇组成的机械感觉器官。斑马鱼侧线毛细胞
在分子和细胞水平上与哺乳动物毛细胞相当,包括共同的
创伤性过度刺激后毛细胞突触丧失和去神经支配。然而侧线毛细胞迅速
并在刺激引起的损伤后数小时内明确修复失去的突触连接。目标1
我们的建议将测试毛细胞活动支配突触修复的假设,而Aim 2将定义
炎症对突触恢复和神经再支配的贡献。我们每个目标的结果将提供
关于毛细胞突触连接如何在创伤性过度刺激后恢复的信息,
确定促进噪声暴露耳蜗内源性修复的策略,
听觉神经退化和听力损失。
英文摘要
Project Summary
Noise exposure damages synaptic connections between cochlear inner hair cells and innervating auditory
nerves. Data from mammalian models and humans indicate that loss of some inner hair cell synapses can be
permanent, leading to the slow degeneration of detached auditory nerves. Yet recent research also supports
that the mammalian cochlea possesses the intrinsic capacity for hair cell synaptic repair following noise
damage. Defining the cellular mechanisms of synapse repair following traumatic noise is a critical step toward
identifying therapeutic targets to promote repair of hair cell synaptic contacts and prevent loss of auditory
nerves.
The overall goal of this proposal is to understand the molecular basis of morphological and functional hair cell
organ repair and recovery following noise-induced damage. Current gaps in our understanding of how hair cell
synapses repair following traumatic noise are in large part due to our inability to define the cellular processes
that promote synaptic repair in mammalian model systems. This project will circumvent these issues by
investigating mechecaniclly induced hair-cell synapse loss and subsequent repair in the zebrafish lateral line—
a mechanosensory organ which is made up of clusters of innervated hair cells. Zebrafish lateral-line hair cells
are comparable to mammalian hair cells at the molecular and cellular level, including a shared mechanism of
hair cell synapse loss and de-innervation following traumatic overstimulation. Yet lateral line hair cells rapidly
and unambiguously repair lost synaptic connections within hours following stimulus-induced damage. Aim 1 of
our proposal will test the hypothesis that hair cell activity governs synaptic repair, while Aim 2 will define the
contribution of inflammation to synaptic recovery and reinnervation. The results of each of our Aims will provide
information on how hair cell synaptic connections are restored following traumatic overstimulation and will help
identify strategies to promote endogenous repair in noise exposed cochlea, thereby preventing subsequent
auditory nerve degeneration and hearing loss.
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DOI:
10.7554/elife.69264
发表时间:
2021-10-19
期刊:
eLife
影响因子:
7.7
作者:
[Holmgren M, Ravicz ME, Hancock KE, Strelkova O, Kallogjeri D, Indzhykulian AA, Warchol ME, Sheets L]
通讯作者:
Sheets L
DOI:
10.1038/s42003-023-04449-2
发表时间:
2023-01-21
期刊:
Communications biology
影响因子:
5.9
作者:
[]
通讯作者:
DOI:
10.3389/fcell.2020.628712
发表时间:
2020
期刊:
Frontiers in cell and developmental biology
影响因子:
5.5
作者:
[Holmgren M, Sheets L]
通讯作者:
Sheets L
DOI:
10.3389/fcell.2018.00114
发表时间:
2018
期刊:
Frontiers in cell and developmental biology
影响因子:
5.5
作者:
[Kindt KS, Sheets L]
通讯作者:
Sheets L
DOI:
10.3389/fncel.2021.693375
发表时间:
2021
期刊:
Frontiers in cellular neuroscience
影响因子:
5.3
作者:
[Holmgren M, Sheets L]
通讯作者:
Sheets L
共 6 条
Roles of the Synapse in Hair-Cell Pathology
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批准号:10187542
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项目类别:
-
资助金额:$32.41万
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财政年份:2017
-
负责人:Lavinia Sheets
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依托单位: