权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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干预措施，以应对以下挑战：退伍军人中的老年人。潜在的假设是，先前暴露于噪音，如这发生在服务成员，有助于后期年龄相关性听力损失（ARHL）的负担导致更早的发病和更大的听力损伤。研究使用UM-HET 4模型和测试a 小型武器射击（SAF）样脉冲噪声，选择用于军事相关性和8-16 kHz 100 dB噪声，之所以选择它，是因为它已经被证明可以加速小鼠模型中ARHL的一个组成部分。噪声 (or Sham）在4个月大时给予，以模拟年轻成年人服役期间的噪音。四个不同评估ARHL的组成部分：1）感觉细胞（毛细胞）的损失和相关的阈值偏移，听性脑干反应（ABR），2）听神经（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细胞体的丢失，和4）时间由减少的间隙检测证明的处理缺陷。在6、12、18和24个月时进行测试目标1中的年龄，比较有和没有噪声暴露的小鼠。目的1：评估4月龄时接受噪声暴露的小鼠中ARHL的进展与年龄匹配的无噪声过度刺激的同窝仔相比。我们的目标是确定基于机制的治疗方法，以预防或减少ARHL和任何加速，从以前的噪音暴露的增强。测试的治疗可以在中年（9个月）开始。在小鼠中老化），为退伍军人提供模范待遇。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）已经证明可以减少噪音引起的听力损失。第二次治疗，雷帕霉素，已被证明在我们的初步研究，以减少年龄相关的损失耳蜗感觉细胞（外毛细胞）。雷帕霉素和ACEMg都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。目标2b和c因此测试a 可能更安全的快速给药期和可能更安全的应用期，以观察它们是否保持功效。目的2a：确定是否在9个月时将ACEMg或雷帕霉素添加到饮食中。年龄会降低ARHL 和/或减少噪声加速/增强ARHL（使用目标1度量进行测试）;目标2b：确定是否使用依维莫司，一种更具mTORC 1特异性的药物或Aim 2c：晚些时候（14个月）间歇（每2周）施用雷帕霉素保持了降低ARHL的功效。目的3：利用RNA-Seq鉴定雷帕霉素作用的功能性信号通路靶点， ARHL的目标是为鉴定或开发更安全的雷帕霉素类似物提供基础目的3：确定耳蜗基因表达的年龄相关变化和雷帕霉素的影响 ARHL相关的功能信号通路。