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
噪声性听力损失的保护机制
摘要
噪声性听力损失(NIHL)是听力损失的第二大原因,
迄今为止,全球范围内的听力损失尚未被理解,这对风险预测、预防和
最终治疗这种使人衰弱的疾病。1.1 10亿年轻人(年龄在12-35岁之间)
由于在娱乐场所暴露于噪音而导致听力损失的风险。在运营服务人员中
持久的自由和伊拉克的自由,NIHL及其相关的耳鸣是前两名的诊断,
未解决的听力损失每年造成全球7500亿美元的损失。噪音衰减和听力
艾滋病目前分别是唯一的保护和治疗措施。现在很清楚,耳蜗
在低-中等噪声暴露(非爆炸性)下,突触损失先于毛细胞损失,有效地沉默受影响的
神经元我们的实验室和其他人已经阐明了改变小鼠对NIHL敏感性的遗传机制
还有人类通过小鼠GWAS,我们已经确定了一个关键基因,Prkag 2编码的g2亚基的基因。
AMPK复合物。我们发现,破坏性的噪音导致核AMPK活性,特别是在内毛细胞,
Prkag 2缺陷小鼠由于内毛细胞突触前带的更大不稳定性而易患NIHL。
迫切需要确定旨在预防和/或修复耳蜗损伤的定向疗法
从噪声暴露,其中的基本机制的理解是一个必要的先决条件。朝向
开发用于预防和/或纠正噪声引起的
突触病,我们现在试图破译的途径和机制,连接核AMPK活动在内毛
细胞为NIHL。根据我们的初步数据,我们的中心假设是AMPK被激活,
在噪声暴露后,通过核内磷酸化作用被困在内毛细胞而不是外毛细胞的核中,
随后调节下游靶点的表达,这些靶点影响突触前神经元的数量和体积。
丝带利用遗传学、生理学、细胞生物学、生物化学和结构生物学的结合,我们
提出以下三个目标:识别与NIHL易感性相关的细胞因子(目的
1),AMPK核质穿梭的分子基础(目的2),以及其他因子的鉴定
AMPK通路导致NIHL易感性(目的3)。由于AMPK通路是细胞生长的基础,
生存、新陈代谢、基因调节和听力,并且是有针对性的,这些目标的完成具有
有可能导致对这种衰弱状况的有意义的干预。
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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