Mechanisms of hypersensitivity to sound-induced cochlear damage
对声音引起的耳蜗损伤过敏的机制
基本信息
- 批准号:9914229
- 负责人:
- 金额:$ 58.93万
- 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:2013-03-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsAcousticsAddressAge-MonthsAgingAndrogensAttentionBiochemicalBiological FactorsCa(2+)-Transporting ATPaseCastrationCochleaCochlear NerveComplexConfocal MicroscopyDataEndoplasmic ReticulumEnvironmentEstradiolEstrogen ReceptorsEstrogensExhibitsFemaleFiberFrequenciesGlutamate ReceptorGlutamatesGonadal HormonesGonadal Steroid HormonesHearingHormonesHourHumanHypersensitivityImmunohistochemistryInner Hair CellsIschemiaKnock-outKnockout MiceLabyrinthLeadLinkMeasuresMediatingMolecularMusNeuronsNoiseOvarianOvarian hormonePathogenesisPhosphorylationPositioning AttributeProcessPublishingPumpQuantitative Reverse Transcriptase PCRRoleSensorySex DifferencesSignal TransductionStructureSurfaceSwellingSynapsesSynaptic TransmissionSystemTestingWestern Blottingauditory pathwaybasechildhood hearing lossexcitotoxicityhearing impairmentmalemutantnerve supplyneurotoxicitypostsynapticprotective effectreceptorreceptor functionribbon synapsesexual dimorphismsoundspiral gangliontraffickingtransmission process
项目摘要
Project Summary
All information about the acoustic environment is carried from the inner ear to the CNS by the afferent fibers of
the cochlear nerve. Rapidly gating AMPA glutamate receptors (AMPAR; GluA2, GluA3 and GluA4 subunits)
mediate synaptic transmission at the mature synapse between the inner hair cells (IHC) and the afferent fibers
of the cochlear nerve (IHC synapse). However, the contribution of each type of AMPAR subunit to overall
glutamatergic receptor function and afferent transmission/sensitivity in the cochlea is poorly understood.
Understanding this process is important because glutamate excitotoxicity through AMPAR has been implicated
in the pathogenesis of hearing loss caused by noise, ischemia and aging. Sex differences in the vulnerability to
hearing loss occur in humans. We therefore began investigating the contribution of AMPAR subunits to
transmission at the IHC synapse and whether there are sex-specific differences in AMPAR subunits that
contribute to sound-induced cochlear damage and hearing loss. Based on functional and ultrastructural
preliminary data, we now hypothesize that “GluA3 AMPAR subunits have a critical role in the sexually
dimorphic vulnerability to hearing loss”. To define mechanistically how GluA3 contributes to the structural and
molecular components of IHC synapses and to sex differences that underlie the hypersensitivity to sound-
induced cochlear damage, we will use a powerful combination of functional (ABRs, DPOAEs),
immunocytochemical (confocal microscopy), biochemical, qRT-PCR, and ultrastructural approaches to test the
following hypotheses. In Aim 1, we will determine whether GluA3 promotes the abundance of GluA2 at IHC
synapses. In Aim 2, we will determine whether GluA3 at IHC synapses protects mice from sound-induced
cochlear damage. Aim 3, based on published data and our preliminary findings, we propose the hypothesis
that in the absence of GluA3, ovarian hormones facilitate the hypersensitivity to sound-induced cochlear
damage, while androgens have protective effects. These proposed studies are the first to address the
important question of how changes in AMPAR subunit composition lead to sex differences in hearing loss.
项目摘要
所有关于声环境的信息都是由内耳的传入纤维传递到中枢神经系统的。
耳蜗神经快速门控AMPA谷氨酸受体(AMPAR; GluA 2、GluA 3和GluA 4亚基)
在内毛细胞(IHC)和传入纤维之间的成熟突触处介导突触传递
耳蜗神经(IHC突触)。然而,每种类型的AMPAR亚基对整体的贡献是不同的。
耳蜗中的神经元能受体功能和传入传递/敏感性知之甚少。
了解这一过程是重要的,因为谷氨酸兴奋毒性通过AMPAR已牵连
在噪声、缺血和衰老引起的听力损失的发病机制中。在易受艾滋病毒/艾滋病感染方面的性别差异
听力损失发生在人类身上。因此,我们开始研究AMPAR亚基对
在免疫组化突触的传输,以及是否有性别特异性差异的AMPAR亚基,
导致声音引起的耳蜗损伤和听力损失。基于功能和超微结构
根据初步数据,我们现在假设“GluA 3 AMPAR亚基在性发育中起关键作用,
二态性听力损失”。为了从机制上定义GluA 3如何促进结构和功能,
IHC突触的分子成分和对声音敏感性的性别差异,
诱发耳蜗损伤,我们将使用功能(ABR,DPOAE),
免疫细胞化学(共聚焦显微镜),生物化学,qRT-PCR和超微结构方法来测试
根据假设。在目标1中,我们将确定GluA 3是否促进IHC中GluA 2的丰度
突触在目标2中,我们将确定IHC突触上的GluA 3是否保护小鼠免受声音诱导的损伤。
耳蜗损伤目的3,基于已发表的数据和我们的初步研究结果,我们提出了假设
在缺乏GluA 3的情况下,卵巢激素促进了对声音诱导的耳蜗的超敏反应。
损伤,而雄激素具有保护作用。这些拟议的研究是第一个解决
AMPAR亚基组成的变化如何导致听力损失的性别差异。
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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Maria Eulalia Rubio其他文献
Maria Eulalia Rubio的其他文献
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{{ truncateString('Maria Eulalia Rubio', 18)}}的其他基金
Alterations and mechanisms of auditory information processing in the aging auditory pathway
衰老听觉通路中听觉信息处理的改变和机制
- 批准号:
10496287 - 财政年份:2023
- 资助金额:
$ 58.93万 - 项目类别:
Mechanisms of hypersensitivity to sound-induced cochlear damage
对声音引起的耳蜗损伤过敏的机制
- 批准号:
10670814 - 财政年份:2013
- 资助金额:
$ 58.93万 - 项目类别:
Mechanisms of hypersensitivity to sound-induced cochlear damage
对声音引起的耳蜗损伤过敏的机制
- 批准号:
10442553 - 财政年份:2013
- 资助金额:
$ 58.93万 - 项目类别:
Anatomical and Functional Properties of Auditory Nerve Synapses
听神经突触的解剖和功能特性
- 批准号:
8620649 - 财政年份:2013
- 资助金额:
$ 58.93万 - 项目类别:
Anatomical and Functional Properties of Auditory Nerve Synapses
听神经突触的解剖和功能特性
- 批准号:
8804940 - 财政年份:2013
- 资助金额:
$ 58.93万 - 项目类别:
Anatomical and Functional Properties of Auditory Nerve Synapses
听神经突触的解剖和功能特性
- 批准号:
8477668 - 财政年份:2013
- 资助金额:
$ 58.93万 - 项目类别:
Anatomical and Functional Properties of Auditory Nerve Synapses
听神经突触的解剖和功能特性
- 批准号:
9207101 - 财政年份:2013
- 资助金额:
$ 58.93万 - 项目类别:
Mechanisms of hypersensitivity to sound-induced cochlear damage
对声音引起的耳蜗损伤过敏的机制
- 批准号:
10200747 - 财政年份:2013
- 资助金额:
$ 58.93万 - 项目类别:
Mechanisms of hypersensitivity to sound-induced cochlear damage
对声音引起的耳蜗损伤过敏的机制
- 批准号:
9764613 - 财政年份:2013
- 资助金额:
$ 58.93万 - 项目类别:
Anatomical and Functional Properties of Auditory Nerve Synapses
听神经突触的解剖和功能特性
- 批准号:
8810723 - 财政年份:2013
- 资助金额:
$ 58.93万 - 项目类别:
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