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: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554258
• 关键词: ATP Receptors; Address; Affect; Aging; Aminoglycosides; Antibiotics; Auditory Brainstem Responses; Blast Injuries; Cell Survival; Cell physiology; Cells; Cellular biology; Chronic; Clinical; Cochlea; Cochlear Hearing Loss; Compensation; Complex; Cytoprotection; Data; Development; Disease; Ear; Environment; Etiology; Evaluation; Exposure to; Funding; Future; Gene Expression Regulation; Genetic; Goals; Hair Cells; Health; Hearing; Hearing Aids; Hearing Tests; Hearing problem; Human; In Vitro; Individual; Intervention; Isotopes; Libraries; Mediating; Methodology; Methods; Microprocessor; Middle East; Military Personnel; Morphology; Nature; Nerve Endings; Noise; Noise-Induced Hearing Loss; Organ of Corti; Outcome; Outer Hair Cells; Pathology; Pathway interactions; Peer Review; Perilymph; Pharmacotherapy; Prevention; Prevention therapy; Probability; Process; Progress Reports; Proteins; Proteomics; Publications; Quality of life; Rehabilitation therapy; Research; Research Design; Resolution; Risk; Sensorineural Hearing Loss; Signal Transduction; Source; Stimulus; Temporary Threshold Shift; Testing; Therapeutic Intervention; Tinnitus; Tissues; Veterans; afferent nerve; cell injury; combat zone; cost; disability; disability payment; gene therapy; hair cell regeneration; hearing impairment; hearing loss risk; high risk; improved; in vivo; in vivo Model; knockout animal; knockout gene; military service; mouse model; noise exposure; novel; osmotic minipump; otoacoustic emission; ototoxicity; pharmacologic; prevent; prevent hearing loss; psychologic; round window; screening; sound; targeted treatment

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.

目的：感官听力损失（SNHL）与军事的许多方面密切相关 服务包括爆炸损伤。该提案的总体目标是改善预防 和在退伍军人中对SNHL的处理。 研究设计：我们以前在体外筛查中识别可以保护的新型化合物 耳毒性损伤受到毛细胞（HC）。我们在体内测试了它们针对噪声引起的听力损失的测试 （NIHL）并找到了部分保护。我们还使用高分辨率蛋白质组学来识别其他 NIHL涉及的过程。总体而言，我们的结果表明许多细胞过程有助于HC 损害。在此应用中，我们建议筛选针对潜水员HC的化合物组合 损坏和生存过程，以确定最有效的组合。这将使我们能够 确定进一步发展的最佳策略作为人类的药物干预措施 化合物组合和/或多作用化合物。 方法：研究将在体外使用氨基糖苷损伤或在体内使用噪声进行研究 对耳蜗的损害。对于体内研究，HC保护剂的核内或肌内递送 曝光后将立即开始。我们将使用完善的鼠标损坏鼠标模型， 长期将化合物递送到人工耳蜗或带有渗透微型机的圆形窗户， 串行听觉脑干响应（ABR）和失真产物耳声发射（DPOAE） 人工耳蜗HC和传入神经末尾的听力学和形态学评估。 在过去的资金期间进展：在过去的资金期间，使用哺乳动物 Corti的器官，是唯一包含对损伤敏感哺乳动物外部HCS的组织，我们筛选了 几个复合库。我们确定了针对不同细胞的广泛化合物 有效保护HCS的过程。然后，我们将选定的化合物转移到 噪声引起的听力损失（NIHL）的体内模型，我们还指出了保护。我们也是 完成了NIHL的第一个高分辨率蛋白质组学研究，该研究鉴定了许多蛋白质 以及以前未知参与噪声损害的过程，它们是潜在目标 用于药物治疗。我们还对分离的HC进行了首次高分辨率蛋白质组学研究。 此外，我们完成了与HC再生相关的基因调节的研究，发现 ESPIN1的基因疗法在再生HCS上显着增强了立体膜形成。我们 发现了一种由ATP接收器介导的新型受保护的HC途径，该途径降低了HCS的活性 高刺激水平，保护它们免受噪声伤害。我们的研究导致了18个同行评审 迄今为止的出版物。 临床关系：SNHL的预防和治疗对退伍军人非常重要 和VA。 SNHL对退伍军人生活质量的影响很大。 snhl和耳鸣 在VA中，造成比任何其他疾病的残疾补偿要多，康复费用 很高。拟议的研究旨在开发新的和改进的疗法 预防和治疗这一重要健康问题。

项目成果

Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro.

• DOI: 10.1186/1471-2202-12-114
• 发表时间: 2011-11-14
• 期刊: BMC neuroscience
• 影响因子: 2.4
• 作者: Brand Y;Setz C;Levano S;Listyo A;Chavez E;Pak K;Sung M;Radojevic V;Ryan AF;Bodmer D
• 通讯作者: Bodmer D

The Promoter and Multiple Enhancers of the pou4f3 Gene Regulate Expression in Inner Ear Hair Cells.

• 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

Genetic architecture distinguishes tinnitus from hearing loss.

• DOI: 10.1038/s41467-024-44842-x
• 发表时间: 2024-01-19
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Clifford, Royce E.;Maihofer, Adam X.;Chatzinakos, Chris;Coleman, Jonathan R. I.;Daskalakis, Nikolaos P.;Gasperi, Marianna;Hogan, Kelleigh;Mikita, Elizabeth A.;Stein, Murray B.;Tcheandjieu, Catherine;Telese, Francesca;Zuo, Yanning;Ryan, Allen F.;Nievergelt, Caroline M.
• 通讯作者: Nievergelt, Caroline M.

Regional differences of brain glucose metabolic compensation after unilateral labyrinthectomy in rats: a [14C]2-deoxyglucose study.

大鼠单侧迷路切除术后脑葡萄糖代谢代偿的区域差异：[14C]2-脱氧葡萄糖研究。

• DOI: 10.1016/0006-8993(86)90316-1
• 发表时间: 1986
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Luyten,WH;Sharp,FR;Ryan,AF
• 通讯作者: Ryan,AF

The spatial representation of frequency in the rat dorsal cochlear nucleus and inferior colliculus.

大鼠耳蜗背核和下丘频率的空间表示。

• DOI: 10.1016/0378-5955(88)90060-3
• 发表时间: 1988
• 期刊: Hearing research
• 影响因子: 2.8
• 作者: Ryan,AF;Furlow,Z;Woolf,NK;Keithley,EM
• 通讯作者: Keithley,EM