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: 10576822
• 负责人: Rick A Friedman
• 金额: $ 72.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10576822
• 关键词: Adult; Affect; Binding; Biochemical; Biochemistry; Biological Assay; Biology; Candidate Disease Gene; Cell Nucleus; Cell Survival; Cells; Cellular biology; Cochlea; Complex; Cryoelectron Microscopy; Cytoplasm; Data; Development; Diagnosis; Disease; Exposure to; Freedom; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Goals; Hair Cells; Hearing; Hearing Aids; Human; Individual; Inner Hair Cells; Intervention; Karyopherins; Knowledge; Laboratories; Link; Measures; Metabolism; Molecular; Mus; Neurons; Noise; Noise-Induced Hearing Loss; Nuclear; Nuclear Export; Nuclear Import; Nucleoplasm; Outcome; PRKAG2 gene; Pathway interactions; Persons; Phosphorylation; Physiological; Physiology; Populations at Risk; Predisposition; Prevention; Prevention therapy; Recreation; Research; Role; Structure; Synapses; Testing; Tinnitus; X-Ray Crystallography; aged; attenuation; base; candidate identification; cost; genetic approach; genome wide association study; hearing impairment; hearing loss risk; noise exposure; novel; novel therapeutics; nucleocytoplasmic transport; operation; presynaptic; prevent; protective pathway; repaired; response; ribbon synapse; risk prediction; service member; structural biology; targeted treatment; trafficking

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 噪音引起的听力损失的保护机制 抽象的 噪音性听力损失 (NIHL) 的细胞和分子基础，噪音性听力损失是听力损失的第二个主要原因 迄今为止，全球范围内的听力损失尚不清楚，这给风险预测、预防和治疗带来了障碍 最终治疗这种使人衰弱的疾病。 11亿年轻人（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。在行动的服务成员中 持久自由和伊拉克自由、NIHL 及其相关耳鸣是最常见的两种诊断 未得到解决的听力损失每年给全球造成 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。现在已经明确的是，人工耳蜗 在低中度噪音暴露（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实验室已经阐明了改变小鼠对 NIHL 敏感性的遗传机制 和人类。通过小鼠 GWAS，我们鉴定了一个关键基因 Prkag2，编码 AMPK 复合物。我们发现，破坏性噪音会导致核 AMPK 活性，特别是在内毛细胞中， Prkag2 缺陷的小鼠由于内毛细胞突触前带的不稳定性更大而容易患 NIHL。 迫切需要确定旨在预防和/或修复耳蜗损伤的定向疗法 免受噪声暴露的影响，了解其基本机制是必要的先决条件。走向 开发预防和/或纠正噪声引起的靶向治疗的长期目标 突触病，我们现在寻求破译与内毛中核 AMPK 活性相关的途径和机制 细胞至 NIHL。根据我们的初步数据，我们的中心假设是 AMPK 被激活并 噪音暴露后，通过核内磷酸化被困在内毛细胞的核中，但不是外毛细胞 随后调节影响突触前数量和体积的下游靶标的表达 丝带。结合遗传学、生理学、细胞生物学、生物化学和结构生物学，我们 提出以下三个目标： 鉴定与 NIHL 易感性相关的细胞因子（Aim 1)、AMPK 核质穿梭的分子基础（目标 2），以及其他因素的鉴定 AMPK 途径导致 NIHL 易感性（目标 3）。由于 AMPK 途径是细胞的基础 生存、新陈代谢、基因调控和听力，并且是有针对性的，这些目标的完成具有 有可能对这种令人衰弱的状况进行有意义的干预。