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: 10365558
• 负责人: Rick A Friedman
• 金额: $ 77.33万
• 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/10365558
• 关键词: Adult; Affect; Biochemical; Biochemistry; Biological Assay; Biology; Candidate Disease Gene; Cell Nucleus; Cell Survival; Cells; Cellular biology; Cochlea; Complex; Cryoelectron Microscopy; Cytoplasm; Cytoprotection; 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; Lead; Link; Measures; Metabolism; Molecular; Mus; Neurons; Noise; Noise-Induced Hearing Loss; Nuclear; Nuclear Export; Nuclear Import; Outcome; PRKAG2 gene; Pathway interactions; Persons; Phosphorylation; Physiological; Physiology; Predisposition; Prevention; Prevention therapy; Research; Role; Structure; Synapses; Testing; Tinnitus; X-Ray Crystallography; aged; attenuation; base; cost; genetic approach; genome wide association study; hearing impairment; hearing loss risk; noise exposure; novel; novel therapeutics; nucleocytoplasmic transport; operation; presynaptic; prevent; 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 免受噪声引起的听力损失的保护机制 抽象的 噪声引起的听力损失（NIHL）的细胞和分子碱基，第二个主要原因 全球听力损失是迄今为止的，尚不理解的，呈现出风险，预防和预测的障碍 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） 在休闲环境中因暴露于噪音而导致的听力损失的风险。在运营成员中 持久的自由和伊拉克自由，NIHL及其相关的耳鸣是前两个诊断， 未解决的听力损失年度全球成本为7500亿美元。噪音衰减和听力 目前，艾滋病分别是保护和治疗的唯一措施。现在很明显人耳蜗 突触损失先于低压噪声暴露（非平原）有效地沉默的毛细细胞损失。 神经元。我们的实验室和其他实验室具有照明遗传机制，可改变小鼠对NIHL的敏感性 和人类。通过小鼠GWAS，我们确定了一个关键基因，PRKAG2编码了G2亚基 AMPK复合物。我们发现，破坏性噪声会导致核AMPK活性，专门在内毛细胞中和 由于内毛细胞突触前色带的不稳定，该Prkag2缺乏的小鼠易受NIHL的影响。 迫切需要确定旨在预防和/或修复人工耳蜗损害的疗法 从噪声暴露中，对基本机制的理解是强制性的先决条件。走向 开发针对预防和/或校正噪声引起的靶向疗法的长期目标 突触病，我们现在寻求破译连接内发核AMPK活性的途径和机制 细胞到NIHL。基于我们的初步数据，我们的中心假设是AMPK被激活，并且 在噪声暴露和 随后调节影响突触前数量和体积的下游目标的表达 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 提出以下三个目的：鉴定与NIHL敏感性相关的细胞因素（AIM 1），AMPK的核质穿梭的分子基础（AIM 2），并鉴定了其他因素 在AMPK途径中，导致对NIHL的敏感性（AIM 3）。由于AMPK途径是细胞基础的 生存，新陈代谢，基因调节和听力，并且是针对性的，这些目标的完成具有 潜力导致这种令人衰弱的状况有意义的干预措施。