Mechanisms of protection from noise-induced hearing loss
噪音引起的听力损失的保护机制
基本信息
- 批准号:10576822
- 负责人:
- 金额:$ 72.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-18 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectBindingBiochemicalBiochemistryBiological AssayBiologyCandidate Disease GeneCell NucleusCell SurvivalCellsCellular biologyCochleaComplexCryoelectron MicroscopyCytoplasmDataDevelopmentDiagnosisDiseaseExposure toFreedomGene Expression ProfilingGene Expression RegulationGenesGeneticGoalsHair CellsHearingHearing AidsHumanIndividualInner Hair CellsInterventionKaryopherinsKnowledgeLaboratoriesLinkMeasuresMetabolismMolecularMusNeuronsNoiseNoise-Induced Hearing LossNuclearNuclear ExportNuclear ImportNucleoplasmOutcomePRKAG2 genePathway interactionsPersonsPhosphorylationPhysiologicalPhysiologyPopulations at RiskPredispositionPreventionPrevention therapyRecreationResearchRoleStructureSynapsesTestingTinnitusX-Ray Crystallographyagedattenuationbasecandidate identificationcostgenetic approachgenome wide association studyhearing impairmenthearing loss risknoise exposurenovelnovel therapeuticsnucleocytoplasmic transportoperationpresynapticpreventprotective pathwayrepairedresponseribbon synapserisk predictionservice memberstructural biologytargeted treatmenttrafficking
项目摘要
TITLE
Mechanisms of protection from noise-induced hearing loss
ABSTRACT
The cellular and molecular bases underlying noise-induced hearing loss (NIHL), the second leading cause of
hearing loss globally, are to date, not understood presenting a barrier to the prediction of risk, the prevention, and
ultimately the treatment of this debilitating disease. 1.1 billion young people (aged between 12-35 years) are at
risk of hearing loss due to exposure to noise in recreational settings. Among Service Members of Operation
Enduring Freedom and Iraqi Freedom, NIHL and its associated tinnitus are the top two diagnoses and
unaddressed hearing loss poses an annual global cost of $750 billion US dollars. Noise attenuation and hearing
aids currently represent the only measures for protection and treatment, respectively. It is now clear that cochlear
synaptic loss precedes hair cell loss at low-moderate noise exposures (nonexplosive) effectively silencing affected
neurons. Our laboratory and others have illuminated genetic mechanisms that modify sensitivity to NIHL in mice
and humans. Through mouse GWAS we have identified a critical gene, Prkag2 encoding the g2 subunit of the
AMPK complex. We find that damaging noise leads to nuclear AMPK activity specifically in inner hair cells and
that Prkag2 deficient mice are susceptible to NIHL due to greater instability of the inner hair cell presynaptic ribbon.
There is an urgent need to identify directed therapies aimed at the prevention and/or repair of cochlear damage
from noise exposure, for which an understanding of the underlying mechanisms is an obligate prerequisite. Toward
the long-term goal of developing targeted therapies for the prevention and/or correction of noise-induced
synaptopathy, we now seek to decipher the pathways and mechanisms linking nuclear AMPK activity in inner hair
cells to NIHL. Based upon our preliminary data, our central hypothesis is that AMPK becomes activated and
trapped in the nucleus of inner but not outer hair cells by intranuclear phosphorylation after noise exposure and
subsequently regulates the expression of downstream targets that impact the number and volume of presynaptic
ribbons. Using a combination of genetics, physiology, cell biology, biochemistry, and structural biology, we
propose the following three aims: the identification of cellular factors associated with susceptibility to NIHL (Aim
1), the molecular basis of nucleocytoplasmic shuttling of AMPK (Aim 2), and the identification of additional factors
in the AMPK pathway leading to susceptibility to NIHL (Aim 3). As the AMPK pathway is fundamental to cell
survival, metabolism, gene regulation, and hearing, and is targetable, the completion of these aims has the
potential to lead to meaningful interventions for this debilitating condition.
标题
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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Rick A Friedman其他文献
Preserving hearing after sudden loss in acoustic neuroma
- DOI:
10.1016/s0194-5998(99)80288-5 - 发表时间:
1999-08-01 - 期刊:
- 影响因子:
- 作者:
Bradley W Kesser;Rick A Friedman;Derald E Brackmann;William E Hitselberger - 通讯作者:
William E Hitselberger
Rick A Friedman的其他文献
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{{ truncateString('Rick A Friedman', 18)}}的其他基金
Otolaryngology Training in Immunology, Virology and Molecular Biology
免疫学、病毒学和分子生物学的耳鼻喉科培训
- 批准号:
10426896 - 财政年份:2022
- 资助金额:
$ 72.65万 - 项目类别:
Otolaryngology Training in Immunology, Virology and Molecular Biology
免疫学、病毒学和分子生物学的耳鼻喉科培训
- 批准号:
10599353 - 财政年份:2022
- 资助金额:
$ 72.65万 - 项目类别:
Mechanisms of protection from noise-induced hearing loss
噪音引起的听力损失的保护机制
- 批准号:
10365558 - 财政年份:2022
- 资助金额:
$ 72.65万 - 项目类别:
The genetic basis for age-related hearing loss in outbred mice
远交小鼠年龄相关性听力损失的遗传基础
- 批准号:
10266167 - 财政年份:2020
- 资助金额:
$ 72.65万 - 项目类别:
The genetic basis for age-related hearing loss in outbred mice
远交小鼠年龄相关性听力损失的遗传基础
- 批准号:
10468839 - 财政年份:2020
- 资助金额:
$ 72.65万 - 项目类别:
The genetic basis for age-related hearing loss in outbred mice
远交小鼠年龄相关性听力损失的遗传基础
- 批准号:
10685625 - 财政年份:2020
- 资助金额:
$ 72.65万 - 项目类别:
High-Resolution Mapping of Susceptibility Genes for NIHL
NIHL 易感基因的高分辨率图谱
- 批准号:
8602516 - 财政年份:2011
- 资助金额:
$ 72.65万 - 项目类别:
High-Resolution Mapping of Susceptibility Genes for NIHL
NIHL 易感基因的高分辨率图谱
- 批准号:
8725407 - 财政年份:2011
- 资助金额:
$ 72.65万 - 项目类别:
High-Resolution Mapping of Susceptibility Genes for NIHL
NIHL 易感基因的高分辨率图谱
- 批准号:
8215868 - 财政年份:2011
- 资助金额:
$ 72.65万 - 项目类别:
High-Resolution Mapping of Susceptibility Genes for NIHL
NIHL 易感基因的高分辨率图谱
- 批准号:
8793777 - 财政年份:2011
- 资助金额:
$ 72.65万 - 项目类别:
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