Synaptic mechanisms underlying noise-induced and age-related hearing loss
噪音引起的和与年龄相关的听力损失的突触机制
基本信息
- 批准号:8677875
- 负责人:
- 金额:$ 2.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-01 至 2014-08-20
- 项目状态:已结题
- 来源:
- 关键词:Acoustic NerveAffectAgeAuditory systemBiological Neural NetworksBrainBuffersCalciumCalcium ChannelCalmodulinCell physiologyCellsClinical TreatmentDataDefectDevelopmentEgtazic AcidFrequenciesFunctional disorderFutureGoalsHair CellsHearingHomeostasisInbred CBA MiceIndividualModificationMusNeuraxisNeurophysiology - biologic functionNoiseNoise-Induced Hearing LossOutcome StudyOutcomes ResearchPathway interactionsPeripheralPopulationPre-Clinical ModelPresbycusisPresynaptic TerminalsProcessPropertyQuality of lifeResearchResearch Project GrantsRyanodine ReceptorsShapesSignal PathwaySignal Transduction PathwaySliceSourceStagingStructureSynapsesSynaptic TransmissionTestingTraumaagedauditory nucleihearing impairmentpostsynapticpresynapticpublic health relevancereceptorrestorationsignal processingsoundsynaptic functionvoltage
项目摘要
DESCRIPTION (provided by applicant): Noise-induced hearing loss (NIHL) and age-related hearing loss (AHL) are two major hearing impairments, and affected individuals often show compromised ability in processing fine temporal structures of sound. While most studies of NIHL and AHL focus on the peripheral defects, much less is known about accompanying alterations in the central auditory system. This proposal will explore the changes of synaptic transmission and the underlying cellular mechanisms following NIHL and AHL at the endbulb of Held synapses. These synapses are the first synaptic connection of the central auditory system and are well known to be important in fine temporal processing. Preliminary data shows that synaptic transmission at mouse endbulbs of Held is compromised with NIHL and AHL, likely due to impaired calcium homeostasis in the endbulb terminals. The first aim of this proposal will test the hypothesis that elevation of calcium concentration at the presynaptic terminal underlines the aberrant synaptic release during sustained activity following NIHL. Synaptic transmission will be evaluated in both normal and NIHL mice utilizing manipulations that modify calcium buffering in the microdomain and nanodomains near the active zone. The source of the calcium elevation will be identified by assessing synaptic transmission while disrupting specific pathways including external calcium influx via voltage-gated calcium channels, Ca-calmodulin dependent calcium channel inactivation, and calcium induced calcium release from internal calcium stores via ryanodine receptors and IP3 receptors. The second aim of this proposal will explore the functional impact of the changes in synaptic transmission following NIHL by examining the firing properties of postsynaptic bushy cells. This aim will test the hypothesis that increase in asynchronous release in NIHL mice leads to decreased synaptic efficacy and compromised temporal precision. Particularly, the study will also explore manipulations that can acutely restore the normal firing properties of bushy cells in slice. The third aim of this proposal will tst the hypothesis that impaired synaptic transmission at the endbulbs during AHL share the same impaired calcium homeostasis mechanisms as observed in NIHL. As in Aims 1 and 2, Aim 3 will examine the synaptic transmission and test the signaling pathways in aged mice with AHL. The long-term goal of this study is to identify the common cellular mechanisms that underlie synaptic modifications of the central auditory system following NIHL and AHL, and to identify manipulations that can acutely rescue normal synaptic function in a preclinical model. Ultimately, these studies could suggest approaches for future clinical treatments of NIHL and AHL.
描述(由申请人提供):噪声引起的听力损失(NIHL)和与年龄相关的听力损失(AHL)是两个重大的听力障碍,受影响的个体经常表现出处理良好的声音时间结构的能力。尽管大多数对NIHL和AHL的研究都集中在外围缺陷上,但对中央听觉系统的变化的了解却少得多。该提案将探讨在持有突触的末端,在NIHL和AHL之后,突触传播的变化以及基本的细胞机制的变化。这些突触是中央听觉系统的第一个突触连接,众所周知在精细的时间处理中很重要。初步数据表明,在持有的小鼠末端的小鼠末端的突触传播被NIHL和AHL损害,这可能是由于末端骨末端中钙稳态受损所致。该提案的第一个目的是检验以下假设:突触前末端的钙浓度升高强调了NIHL持续活动期间的异常突触释放。将在正常和NIHL小鼠中评估突触传播,这些小鼠使用操纵,这些操纵修改了活动区附近微型域和纳米域中的钙缓冲。钙升高的来源将通过评估突触传播来确定,同时破坏特定的途径,包括通过电压门控钙通道,Ca-钙调蛋白依赖性钙通道失活以及钙诱导的钙从内部钙储存中释放的钙含量,通过Ryanodine受体和IP3受体从内部钙存储中释放钙。该提案的第二个目的将通过检查突触后浓密细胞的发射特性来探索突触传播变化的功能影响。该目标将检验以下假设,即NIHL小鼠中异步释放的增加导致突触效果降低并损害时间精度。特别是,该研究还将探索可以急性恢复切片中浓细胞的正常发射特性的操作。该提案的第三个目的是提出一个假设,即AHL期间末端的突触传播受损,其钙稳态机制与NIHL中观察到的相同的钙稳态机制受损。与AIMS 1和2中一样,AIM 3将检查突触传播并测试使用AHL老年小鼠的信号传导途径。这项研究的长期目标是确定NIHL和AHL后中央听觉系统的突触修饰的常见细胞机制,并确定可以在临时性模型中急剧挽救正常突触功能的操作。最终,这些研究可以提出对NIHL和AHL的未来临床治疗方法的方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Ruili Xie', 18)}}的其他基金
Age-dependent plasticity of central auditory synapses
中枢听觉突触的年龄依赖性可塑性
- 批准号:
10496286 - 财政年份:2023
- 资助金额:
$ 2.13万 - 项目类别:
Auditory nerve synaptopathy and the central mechanisms underlying noise-induced hearing loss
听神经突触病和噪声性听力损失的中枢机制
- 批准号:
10511106 - 财政年份:2022
- 资助金额:
$ 2.13万 - 项目类别:
Auditory nerve synaptopathy and the central mechanisms underlying noise-induced hearing loss
听神经突触病和噪声性听力损失的中枢机制
- 批准号:
10636895 - 财政年份:2022
- 资助金额:
$ 2.13万 - 项目类别:
Auditory nerve central synaptopathy during noise-induced hearing loss
噪声性听力损失期间的听觉神经中枢突触病
- 批准号:
10412432 - 财政年份:2021
- 资助金额:
$ 2.13万 - 项目类别:
Cellular mechanisms of age related hearing loss
年龄相关性听力损失的细胞机制
- 批准号:
9567464 - 财政年份:2017
- 资助金额:
$ 2.13万 - 项目类别:
Cellular mechanisms of age related hearing loss
年龄相关性听力损失的细胞机制
- 批准号:
9454682 - 财政年份:2017
- 资助金额:
$ 2.13万 - 项目类别:
Cellular mechanisms of age related hearing loss
年龄相关性听力损失的细胞机制
- 批准号:
10174904 - 财政年份:2017
- 资助金额:
$ 2.13万 - 项目类别:
Synaptic mechanisms underlying noise-induced and age-related hearing loss
噪音引起的和与年龄相关的听力损失的突触机制
- 批准号:
8576011 - 财政年份:2013
- 资助金额:
$ 2.13万 - 项目类别:
Synaptic mechanisms underlying noise-induced and age-related hearing loss
噪音引起的和与年龄相关的听力损失的突触机制
- 批准号:
8905035 - 财政年份:2013
- 资助金额:
$ 2.13万 - 项目类别:
Synaptic mechanisms underlying noise-induced and age-related hearing loss
噪音引起的和与年龄相关的听力损失的突触机制
- 批准号:
8874203 - 财政年份:2013
- 资助金额:
$ 2.13万 - 项目类别:
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