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Molecular Mechanisms in Noise-Induced Hearing Loss

噪声性听力损失的分子机制

基本信息

批准号：
9026293
负责人：
Su-Hua Sha
金额：
$ 31.77万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9026293
关键词：
Address Adult Affect Biochemical CBA/J Mouse Calcium Cell Death Cell Line Cells Clinical Data Deoxyglucose Developed Countries Dose Event Goals Hair Cells Health Care Costs Individual Knockout Mice Labyrinth Lead Leisure Activities Mediating Mental Depression Messenger RNA Mitochondria Modeling Molecular Molecular Genetics Mus Noise Noise-Induced Hearing Loss Oligomycins Organ of Corti Outcome Outer Hair Cells Pathology Pathway interactions Pharmaceutical Preparations Pilot Projects Preparation Presbycusis Prevention therapy Preventive Intervention Proteins Quality of life Reporting Research Sensory Hair Signal Pathway Signal Transduction Small Interfering RNA Sodium-Calcium Exchanger Surface Testing Therapeutic Intervention Western Blotting Work Workplace abstracting adeno-associated viral vector base calcium uniporter cell injury design disability gene therapy in vitro Model in vivo inhibitor/antagonist inner ear diseases innovation insight mutant novel prevent research study response ribbon synapse sensor stem success uptake

项目摘要

Abstract Noise-induced hearing loss (NIHL) is becoming increasingly common in industrialized countries, stemming from both workplace noise exposure and leisure activities. Corresponding with its functional deficit, loss of outer hair cells (OHCs) and synaptic ribbons are the primary inner ear pathology. Although a variety of biochemical and pathological events associated with OHC death have been reported, there is currently no established clinical therapy for the prevention or treatment of NIHL, owing largely to the lack of a comprehensive understanding of the precise molecular mechanisms and signaling pathways mediating OHC injury and loss of synaptic ribbons in response to noise exposure. The long-term goal of this research is to understand the molecular mechanisms that result in NIHL and to elucidate novel and rational pharmacological or molecular/genetic therapeutic interventions to ameliorate or prevent NIHL. We have previously reported that traumatic noise transiently depletes cellular energy reserves and increases levels of the energy sensor p- AMPKα in OHCs. Our exciting new preliminary results show an increased amount of mitochondrial calcium uniporter (MCU) and a decreased amount of the mitochondrial sodium calcium exchanger (NCLX) proteins in OHCs after noise exposure. The magnitude of these changes is positively correlated with noise intensity. Furthermore, such changes occur secondarily to noise-induced energy depletion and influx of calcium. Based on these data, the hypothesis is presented that the noise-induced increase of MCU moves calcium into mitochondria while the depression of NCLX reduces the extrusion of calcium out of mitochondria, actions that together create mitochondrial calcium overload. We will address this hypothesis using a comprehensive experimental approach employing both in-vivo studies with adult mice and a novel in-vitro model of energy depletion in an inner ear cell line model for testing specific aspects of the molecular mechanisms of NIHL. We also will use knockout mice, siRNA, gene therapy, and pharmacological compounds to block selected pathways that promote mitochondrial calcium overload in an attempt to achieve synergistic protection against NIHL. The results of this project will lead to new insights into mechanisms of NIHL and may direct the design of novel interventions for the prevention of NIHL benefiting the quality of life of individuals and reducing healthcare costs. In addition, the data generated in this proposal will make a significant contribution to our understanding of a broad range of inner ear disorders, since similarities have already been noted in the molecular events associated with noise-induced, drug-induced, and age-related hearing loss.

摘要