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 噪声性听力损失的保护机制 摘要 噪声性听力损失(NIHL)的细胞和分子基础 全球范围内的听力损失，到目前为止还不清楚，这给风险的预测、预防和 最终治疗这种令人衰弱的疾病。11亿年轻人(年龄在12岁至35岁之间) 在娱乐场所暴露在噪音中导致听力损失的风险。在行动的服役人员中 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和 未解决的听力损失每年造成全球7500亿美元的损失。噪声衰减和听力 艾滋病目前分别是预防和治疗的唯一措施。现在很清楚的是，人工耳蜗 在中低噪声暴露(非爆炸性)下，突触丢失先于毛细胞丢失，有效地沉默受影响 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，我们已经确定了一个关键基因Prkag2，它编码的是G2亚基。 AMPK复合体。我们发现，破坏性的噪音会导致核AMPK活性，特别是在内毛细胞和 Prkag2基因缺陷的小鼠由于内毛细胞突触前带的更大的不稳定性而易患NIHL。 迫切需要确定旨在预防和/或修复耳蜗病的定向疗法。 避免接触噪音，对其基本机制的了解是一个必要的先决条件。冲向 为预防和/或纠正噪声引起的疾病开发有针对性的治疗的长期目标 突触作用，我们现在试图破译内毛中与核AMPK活性有关的途径和机制 细胞到NIHL。根据我们的初步数据，我们的中心假设是AMPK被激活并 噪声暴露后被核内磷酸化而不是外毛细胞核所困 随后调节下游靶标的表达，从而影响突触前的数量和体积 丝带。我们结合了遗传学、生理学、细胞生物学、生物化学和结构生物学， 提出以下三个目标：确定与NIHL易感性相关的细胞因素(AIM 1)，AMPK核质穿梭的分子基础(目标2)，以及附加因子的鉴定 在导致对NIHL易感性的AMPK途径中(目标3)。因为AMPK通路是细胞的基础 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 有可能导致对这一衰弱状况采取有意义的干预措施。