Prevention of Noise-Induced Acceleration of Age-Related Hearing Loss

预防噪声引起的年龄相关性听力损失加速

• 批准号: 10621690
• 负责人: Richard Altschuler
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621690
• 关键词: Acceleration; Acoustic Nerve; Age; Age-Months; Aging; Antioxidants; Ascorbic Acid; Auditory; Auditory system; Beta Carotene; Cells; Clinical; Clinical Trials; Cochlea; Complex; Copper; Data; Dementia; Detection; Development; Diet; Disease; Elderly; Electrodes; Employment Opportunities; Exposure to; FRAP1 gene; Fire - disasters; Future; Gene Expression; Genes; Goals; Gulf War; Hair Cells; Hearing Tests; Human; Immune response; Incidence; Inner Hair Cells; Intervention; Macular degeneration; Magnesium; Mental Depression; Military Personnel; Mission; Modeling; Mus; Neurons; Noise; Noise-Induced Hearing Loss; Outer Hair Cells; Oxidative Stress; Patient Care; Performance; Persons; Positioning Attribute; Presbycusis; Prevention; Quality of life; Rattus; Risk; SDZ RAD; Sensory; Services; Severities; Signal Pathway; Sirolimus; Synapses; Testing; Therapeutic Intervention; Translations; Trauma; Veterans; Vitamin A; Zinc; age related; arm; base; brain stem auditory evoked potentials; clinical application; clinically relevant; comparative efficacy; disability; early onset; efficacy testing; hearing impairment; improved; middle age; military veteran; mouse model; noise exposure; permanent hearing loss; prevent; response; service member; side effect; social integration; spiral ganglion; transcriptome sequencing; treatment effect; young adult

The proposed studies test mechanism-based, clinically relevant interventions to meet the challenges of aging in the Veteran population. The underlying hypothesis is that prior exposure to noise, such as that which occurs to service members, contributes to the burden of later age-related hearing loss (ARHL) resulting in an earlier onset and a greater hearing impairment. Studies use the UM-HET4 model and test a small arms fire (SAF)-like impulse noise, chosen for military relevance and a 8-16 kHz 100 dB noise, chosen because it has already been shown to accelerate a component of ARHL in the mouse model. Noise (or sham) is given at 4 months of age to model noise during service as a young adult. Four distinct components of ARHL are assessed: 1) loss of sensory cells (hair cells) and associated threshold shifts in auditory brain stem response (ABR), 2) loss of synaptic connections of the auditory nerve (AN) to inner hair cells (IHCs) and associated changes in ABR dynamic range, 3) loss of AN cell bodies, and 4) a temporal processing deficit evidenced by reduced Gap Detection. These are tested at 6, 12, 18 and 24 months of age in Aim 1, comparing mice with and without either of the noise exposures. Aim 1: Assess the progression of ARHL in mice receiving noise exposure at 4 months of age compared to age-matched littermates without noise overstimulation. Our goal is to identify mechanism-based treatments to prevent or reduce ARHL and any acceleration and enhancement from prior noise exposure. Treatments tested can be started in mid-life (9 mos. old in mice) to model treatment to Veterans. One treatment targets oxidative stress, using a combination of anti-oxidants (vitamins A, C, E plus magnesium) already shown to reduce noise-induced hearing loss. A second treatment, rapamycin, has been shown in our preliminary studies to reduce age-related loss of cochlear sensory cells (outer hair cells). Both rapamycin and ACEMg are already in clinical application or trails for other purposes. Side-effects of prolonged rapamycin could limit application in veterans. Aims 2b and c therefore test a potentially safer rapalog and a potentially safer application period, respectively, to see if they retain efficacy. Aim 2a: Determine if ACEMg or rapamycin added to diet at 9 mos. of age will decrease ARHL and/or reduce noise acceleration / enhancement of ARHL (tested using Aim 1 metrics); Aim 2b: Determine if use of everolimus, a more mTORC1 specific rapalog or Aim 2c: a later (14 mos.) intermittent (every 2 weeks) application of rapamycin retains efficacy in reducing ARHL. Aim 3 uses RNA-Seq to identify the functional signaling pathway targets of the rapamycin effect in reducing ARHL towards the goal of providing a basis for identification or development of safer rapalogs Aim 3: Identify age-related changes in cochlear gene expression and the influence of rapamycin on ARHL related functional signaling pathways.

拟议的研究测试基于机制的、临床相关的干预措施，以应对以下挑战 退伍军人人口老龄化。基本假设是，之前接触过噪音，例如 发生在服役人员身上的这种情况会加重老年性听力损失（ARHL）的负担 导致更早发病和更严重的听力损伤。研究使用 UM-HET4 模型并测试 类似小型武器射击 (SAF) 的脉冲噪声，选择用于军事相关性和 8-16 kHz 100 dB 噪声， 之所以选择它，是因为它已被证明可以加速小鼠模型中 ARHL 的一个组成部分。噪音 （或假）在 4 个月大时给予，以模拟年轻成人服务期间的噪音。四种截然不同的 ARHL 的组成部分进行评估：1）感觉细胞（毛细胞）的损失和相关的阈值变化 听觉脑干反应 (ABR)，2) 听觉神经 (AN) 与内毛的突触连接丧失 细胞（IHC）和 ABR 动态范围的相关变化，3）AN 细胞体的损失，以及 4）时间 通过减少间隙检测来证明处理缺陷。这些在 6、12、18 和 24 个月时进行测试 目标 1 中的年龄，比较有和没有任何噪声暴露的小鼠。 目标 1：评估 4 个月大时接受噪音暴露的小鼠 ARHL 的进展情况 与没有噪音过度刺激的同龄同窝小鼠相比。 我们的目标是找到基于机制的治疗方法来预防或减少 ARHL 以及任何加速和 先前噪声暴露的增强。测试的治疗可以在中年开始（小鼠 9 岁） 退伍军人的模范待遇。一种治疗方法针对氧化应激，使用抗氧化剂的组合 （维生素 A、C、E 加镁）已被证明可以减少噪音引起的听力损失。第二次治疗， 我们的初步研究表明，雷帕霉素可以减少与年龄相关的耳蜗感觉细胞损失 （外毛细胞）。雷帕霉素和 ACEMg 均已进入临床应用或其他用途的试验。 长期使用雷帕霉素的副作用可能会限制其在退伍军人中的应用。因此目标 2b 和 c 测试 a 分别使用可能更安全的rapalog和可能更安全的应用期，以观察它们是否保留疗效。 目标 2a：确定是否在 9 个月时将 ACEMg 或雷帕霉素添加到饮食中。年龄的增长会降低 ARHL 和/或减少噪声加速/增强 ARHL（使用目标 1 指标进行测试）；目标 2b： 确定是否使用依维莫司（一种更具 mTORC1 特异性的 rapalog）或 Aim 2c：稍后（14 个月） 间歇性（每两周）应用雷帕霉素可保留减少 ARHL 的功效。 目标 3 使用 RNA-Seq 来识别雷帕霉素在减少 ARHL 的目标是为鉴定或开发更安全的 Rapalogs 提供基础 目标 3：确定耳蜗基因表达与年龄相关的变化以及雷帕霉素的影响 ARHL相关功能信号通路的研究

项目成果

Rapamycin Added to Diet in Late Mid-Life Delays Age-Related Hearing Loss in UMHET4 Mice.

在中年晚期饮食中添加雷帕霉素可延缓 UMHET4 小鼠与年龄相关的听力损失。

• 发表时间: 2021
• 作者: Altschuler, Richard A;Kabara, Lisa;Martin, Catherine;Kanicki, Ariane;Stewart, Courtney E;Kohrman, David C;Dolan, David F
• 通讯作者: Dolan, David F