Determinants of age-induced hearing loss and reversal strategies
年龄引起的听力损失的决定因素和逆转策略
基本信息
- 批准号:9340057
- 负责人:
- 金额:$ 162万
- 依托单位:
- 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 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:AchievementAffectAgeAgingAnimal ModelApicalAuditoryAuditory Brainstem ResponsesAuditory ThresholdAuditory systemBiochemicalBiologyCell physiologyCellsCellular biologyCharacteristicsCochleaCochlear ductCommunicationDNA Sequence AlterationDataDiseaseEndolymphEpitheliumEtiologyExhibitsFrequenciesFunctional ImagingGene DeletionGenesGeneticGenetic ModelsGenetic TranscriptionGoalsHair CellsHearingHumanImageImaging TechniquesIndividualIonsLabyrinthLateralLife ExpectancyMechanicsMediatingModelingMolecularMusMutationNerve DegenerationNervous system structureNeuritesNeuronal PlasticityNeuronsNeurotransmittersNoise-Induced Hearing LossPathologyPerilymphPresbycusisProteinsPsychological ImpactQuality of lifeReceptor CellResearchResearch PersonnelResourcesSecondary toSensorineural Hearing LossSensorySocietiesSpecialistStimulusStructureSumSynapsesTestingTherapeuticTight JunctionsWorkage relatedbasecostdeafnessdesigngenetic manipulationhearing impairmentinsightmouse modelnew therapeutic targetoccludinoutcome predictionprogramsprotein expressionprototyperelating to nervous systemresponsespiral ganglion
项目摘要
Abstract
Age-related hearing loss (ARHL) or presbycusis is the most prevalent sensory deficit and with the increase in
life expectancy, it is predicted to have vast impact in the well-being of our society. Indeed, audition and
communication is the essence of our human interactions. The overall framework for this programmatic proposal
is that a comprehensive understanding of ARHL is only possible through studies of not only the vulnerable
synaptic and neural structures of the inner ear, but also examination of the neural plasticity that occurs in
response to changes at the neurites of spiral ganglion neurons. We have brought together expert individuals
from genetics to cell biology and physiology (Tempel, Yamoah, Ricci, and Gratton). These investigators have
already worked together in a highly synergistic and productive manner.
There are three projects (P) served by three Cores (Administrative, Mouse Genetics and Structural Analysis
Cores) to test the Central Hypothesis that the aging auditory sensory epithelia undergo structural changes that
allow the high K+ endolymph to leak into the perilymph, triggering HC and SGN depolarization, increased
intracellular Ca2+ ([Ca2+]i) and subsequent “silent” synaptic and neuronal degeneration (P2, P3). We predict
that structural changes are mediated by weakening tight junctions (TJs) in the aging cochlear sensory
epithelium (P1, Core C). Genetic manipulation of Claudin 9 and Occludin, two identified TJ proteins in the
sensory epithelium, that show robust reduction in expression levels, will be used as prototypes together with
three additional ARHL models to test our hypothesis (P1-3, Cores B-C). We propose that neural and synaptic
alterations at the periphery (P2, P3) will mediate cellular changes that confer long-lasting alterations auditory
system. The proposed studies will reveal critical neural and synaptic mechanisms of ARHL. New therapeutic
targets for the treatment of ARHL will be assessed, tested and proposed, thus, transforming and shifting the
prevailing paradigm to mechanistic and translational platforms.
抽象的
年龄相关性听力损失(ARHL)或老年性耳聋是最普遍的感觉缺陷,并且随着年龄的增加
预期寿命,预计将对我们社会的福祉产生巨大影响。确实,试镜和
沟通是我们人类互动的本质。本方案提案的总体框架
是只有通过对弱势群体的研究才能全面了解 ARHL
内耳的突触和神经结构,还检查发生在的神经可塑性
对螺旋神经节神经元神经突变化的反应。我们汇集了专家
从遗传学到细胞生物学和生理学(Tempel、Yamoah、Ricci 和 Gratton)。这些调查人员有
已经以高度协同和富有成效的方式合作。
三个项目 (P) 由三个核心服务(管理、小鼠遗传学和结构分析)
核心)来测试中心假设,即老化的听觉感觉上皮经历结构变化,
允许高 K+ 内淋巴漏入外淋巴,触发 HC 和 SGN 去极化,增加
细胞内 Ca2+ ([Ca2+]i) 和随后的“沉默”突触和神经元变性 (P2、P3)。我们预测
结构变化是由老化耳蜗感觉中的紧密连接(TJ)减弱所介导的
上皮(P1,核心 C)。 Claudin 9 和 Occludin 的基因操作,这两种在
感觉上皮表现出表达水平的大幅降低,将与
三个额外的 ARHL 模型来检验我们的假设(P1-3,核心 B-C)。我们建议神经和突触
外围(P2、P3)的变化将介导细胞变化,从而带来持久的听觉变化
系统。拟议的研究将揭示 ARHL 的关键神经和突触机制。新疗法
将评估、测试和提出 ARHL 治疗的目标,从而改变和转变
机械和转化平台的流行范式。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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EBENEZER N YAMOAH其他文献
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{{ truncateString('EBENEZER N YAMOAH', 18)}}的其他基金
Determinants of age-induced hearing loss and reversal strategies
年龄引起的听力损失的决定因素和逆转策略
- 批准号:
10496280 - 财政年份:2023
- 资助金额:
$ 162万 - 项目类别:
Molecular and Functional Mechanisms of the aging auditory neuron
衰老听觉神经元的分子和功能机制
- 批准号:
10496285 - 财政年份:2023
- 资助金额:
$ 162万 - 项目类别:
Inner ear ion channels in healthy and diseased conditions
健康和患病条件下的内耳离子通道
- 批准号:
10745190 - 财政年份:2017
- 资助金额:
$ 162万 - 项目类别:
Inner ear ion channels in healthy and diseased conditions
健康和患病条件下的内耳离子通道
- 批准号:
9976492 - 财政年份:2017
- 资助金额:
$ 162万 - 项目类别:
Inner ear ion channels in healthy and diseased conditions
健康和患病条件下的内耳离子通道
- 批准号:
10194449 - 财政年份:2017
- 资助金额:
$ 162万 - 项目类别:
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