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

Mechanisms of protection from noise-induced hearing loss

噪音引起的听力损失的保护机制

基本信息

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
项目类别：
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

项目摘要

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