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Basic Mechanisms on Hearing Loss of Cochlear Origin

Basic Mechanisms on Hearing Loss of Cochlear Origin
耳蜗源性听力损失的基本机制
批准号:
10554258
负责人:
Allen F. Ryan
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-10-01 至 2024-12-31

项目摘要

项目成果

Allen F. Ryan的其他基金

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中文摘要
翻译
目的:感音神经性听力损失(SNHL)与军事的许多方面密切相关
英文摘要
Objectives: Sensorineural hearing loss (SNHL) is strongly associated with many aspects of military service including blast injury. The overall objectives of this proposal are to improve the prevention and treatment of SNHL in Veterans. Research Design: We previously used in vitro screening to identify novel compounds that can protect hair cells (HCs) from ototoxic damage. We tested them in vivo against noise-induced hearing loss (NIHL) and found partial protection. We also used high-resolution proteomics to identify additional processes involved in NIHL. Overall, our results suggest that many cellular processes contribute to HC damage. In this application we propose to screen compound combinations targeting diverse HC damage and survival processes, to identify the most effective combinations. This will allow us to identify optimal strategies for further development as pharmacological interventions in humans, using compound combinations and/or multi-acting compounds. Methodology: Studies will be performed in vitro using aminoglycoside damage or in vivo using noise damage to the cochlea. For in vivo studies, intracochlear or intratympanic delivery of HC protectants will begin immediately after exposure. We will use a well-established mouse model of noise damage, chronic delivery of compounds to cochlear perilymph or the round window with osmotic minipumps, serial auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) audiometry, and morphological evaluation of cochlear HCs and afferent nerve endings. Progress over the past period of funding: During the past period of funding, using the mammalian organ of Corti, the only tissue containing the damage-sensitive mammalian outer HCs, we screened several compound libraries. We identified a broad range of compounds targeting different cellular processes, that were effective in protecting HCs. We then transferred selected compounds to an in vivo model of noise-induced hearing loss (NIHL), where we also noted protection. We also completed the first-ever high-resolution proteomics study of NIHL, which identified many proteins and processes not previously known to be involved in noise damage, and which are potential targets for pharmacotherapy. We also performed the first high-resolution proteomic study of isolated HCs. In addition, we completed studies of gene regulation relevant to HC regeneration, and found that gene therapy with espin1 dramatically enhanced stereocilia formation on regenerating HCs. We discovered a novel protective HC pathway mediated by ATP receptors that reduce activity in HCs at high stimulus levels, protecting them from noise damage. Our studies resulted in 18 peer-reviewed publications to date. Clinical Relationship: The prevention and treatment of SNHL is of great importance to Veterans and the VA. The effects of SNHL on Veterans’ quality of life are substantial. SNHL and tinnitus also account for more disability compensation in the VA than any other disorder, and rehabilitation costs are high. The proposed research is targeted at developing new and improved therapies for prevention and treatment of this important health problem.
期刊论文(200)
专著(0)
科研奖励(0)
会议论文
Ventral cochlear nucleus neural discharge characteristics in the absence of outer hair cells.
在没有外毛细胞的情况下,腹侧耳蜗核神经放电特征。
DOI: 10.1016/0006-8993(85)91119-9
发表时间: 1985
期刊: Brain research
影响因子: 2.9
作者: [Woolf,NK, Ryan,AF]
通讯作者: Ryan,AF
The relationship of local cerebral glucose utilization to optical density ratios.
局部脑葡萄糖利用率与光密度比的关系。
DOI: 10.1016/0006-8993(83)91204-0
发表时间: 1983
期刊: Brain research
影响因子: 2.9
作者: [Sharp,FR, Kilduff,TS, Bzorgchami,S, Heller,HC, Ryan,AF]
通讯作者: Ryan,AF
DOI: 10.1007/s12035-016-0060-7
发表时间: 2017-09
期刊: Molecular neurobiology
影响因子: 5.1
作者: [Masuda M, Li Y, Pak K, Chavez E, Mullen L, Ryan AF]
通讯作者: Ryan AF
Mechanisms of sensorineural cell damage, death and survival in the cochlea.
耳蜗中感觉神经细胞损伤、死亡和存活的机制。
DOI: 10.3389/fnagi.2015.00058
发表时间: 2015
期刊: Frontiers in aging neuroscience
影响因子: 4.8
作者: [Wong AC, Ryan AF]
通讯作者: Ryan AF
共 117 条
    Genome-wide association study of tinnitus in the Million Veterans Program with emphasis on traumatic brain injury
    • 批准号:
      10247446
    • 项目类别:
    • 资助金额:
      $0.0万
    • 财政年份:
      2019
    • 负责人:
      Allen F. Ryan
    • 依托单位:
    Genome-wide association study of tinnitus in the Million Veterans Program with emphasis on traumatic brain injury
    • 批准号:
      9483218
    • 项目类别:
    • 资助金额:
      $0.0万
    • 财政年份:
      2019
    • 负责人:
      Allen F. Ryan
    • 依托单位:
    Genome-wide association study of tinnitus in the Million Veterans Program with emphasis on traumatic brain injury
    • 批准号:
      10383146
    • 项目类别:
    • 资助金额:
      $0.0万
    • 财政年份:
      2019
    • 负责人:
      Allen F. Ryan
    • 依托单位:
    A Biological Interface for Auditory Rehabilitation with a Cochlear Implant
    • 批准号:
      8594549
    • 项目类别:
    • 资助金额:
      $0.0万
    • 财政年份:
      2013
    • 负责人:
      Allen F. Ryan
    • 依托单位:
    海外基金