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Determinants of age-induced hearing loss and reversal strategies

年龄引起的听力损失的决定因素和逆转策略

基本信息

批准号：
10496280
负责人：
EBENEZER N YAMOAH
金额：
$ 238.49万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10496280
关键词：
3-Dimensional Ablation Address Age Aging Analytical Chemistry Anatomy Animal Model Animal Sources Animals Auditory Auditory Brainstem Responses Auditory area Axon Behavioral Biochemical Biological Markers Biology Brain Brain Stem Calcium Cell Nucleus Chronology Clinical Cochlear nucleus Code Complex Demyelinations Dimensions Electrophysiology (science)Ensure Equilibrium Etiology Event Exhibits Functional disorder Genetic Genetic Models Hair Cells Human Image Imaging Techniques Individual Joints Knock-in Label Labyrinth Lead Life Expectancy Medial Mental Depression Modeling Molecular Myelin Nature Neurons Noise-Induced Hearing Loss Organelles Outcome Pathology Personal Satisfaction Pharmacogenetics Phenotype Physiology Presbycusis Productivity Proteome Proteomics Psychological Impact Public Health Pyramidal Tracts Research Personnel Resources Sampling Sensorineural Hearing Loss Sensory Social isolation Societies Sum Synapses Synaptic plasticity Testing Time Work age related aged aging auditory system auditory pathway clinically relevant design effective therapy functional plasticity hearing impairment in vivo insight mouse model neural neural network neuron loss optogenetics programs signal processing sound spiral ganglion stem tool trapezoid body treatment strategy

项目摘要

Abstract Presbycusis or age-related hearing loss (ARHL) represents the most prevalent sensory deficit. It begets social isolation and depression. We hypothesize that aging auditory neurons undergo cellular, and structural changes, resulting in demyelination and selective neuronal subtypes loss. The ensuing plasticity produces profound neural network re-wiring and aberrant functional plasticity along the auditory pathway. These predicted changes' progressive nature requires systematic analyses of the ARHL mechanism at different auditory pathway hubs, which can only be achieved through a joint collaborative effort. Motivated by this public health challenge, we have designed a collaborative multiscale study that addresses the aging auditory system's successive mechanisms. The clinical and translational outcomes of our findings promise to be vast. The overarching hypotheses are tested in three Projects, using resources and tools from four Cores. The investigative team consists of experts from genetic to physiology and imaging and analytical chemistry. Three projects (P1-3) are served by four Cores (A-D). Core A is for administrative oversight and organization of the Cores and Projects. The team includes Drs. Yamoah (Project 1), Xie (Project 2), Maria-Rubio/Williamson (Project 3), Yamoah (Core A), Yamoah/Lee (Core B), Fritzsch/Perkins (Core C), and Zhu (Core D). Together, they will determine the mechanisms of ARHL of sensory and neural etiology. The team has worked together synergistically and productively. The projects focus on critical centers of the auditory pathways recognized for the coding and processing of sound information. They include the primary auditory neurons (AN; P1), cochlear nuclei (CN; P2-3), superior olivary complex (SOC; P2-3), and auditory cortex (ACtx, P3). We use genetic, optogenetics, and pharmacogenetic mouse models (Core B). We employ structural analyses (Core C) and differential proteomic analyses of young-and aged-auditory neurons to uncover biomarkers (Core D). Integration of the program ensures outcomes that are overwhelmingly greater than the sum of the individual components. Identification of ARHL biomarkers is likely to pave the way for effective treatment strategies.

摘要老年性耳聋或年龄相关性听力损失(ARHL)是最常见的感觉障碍。它催生了社交与世隔绝和抑郁。我们假设老化的听觉神经元经历了细胞和结构的变化，导致脱髓鞘和选择性神经元亚型丢失。随之而来的可塑性产生了深刻的神经沿听觉通路的网络重新布线和异常的功能可塑性。这些预测的变化渐进性要求对不同听觉通路中枢的ARHL机制进行系统分析，只有通过共同的合作努力才能实现这一目标。在这一公共卫生挑战的激励下，我们我设计了一项合作的多尺度研究，以解决老化的听觉系统连续机制。我们发现的临床和翻译结果将是巨大的。最重要的是利用四个核心的资源和工具，在三个项目中对假设进行了测试。研究团队由从遗传学到生理学、成像和分析化学的专家组成。三个项目(P1-3)由四个核心(A-D)提供服务。核心A用于行政监督和组织核心和项目。该团队包括Yamoah博士(项目1)、谢博士(项目2)、Maria-Rubio/Williamson (项目3)、Yamoah(核心A)、Yamoah/Lee(核心B)、Fritzsch/Perkins(核心C)和朱(核心D)。一起，他们将确定ARHL的感官和神经病因学机制。这个团队一直在一起工作协同和富有成效的。这些项目集中在公认的听觉通路的关键中心声音信息的编码和处理。它们包括初级听神经元(An；P1)、耳蜗区核团(Cn；P2-3)、上橄榄复合体(SOC；P2-3)和听皮质(ACTx，P3)。我们使用的是基因，光遗传学和药物遗传学小鼠模型(核心B)。我们采用结构分析(核心C)和对年轻和老年听神经元进行差异蛋白质组学分析以揭示生物标记物(核心D)。计划的整合确保了结果远远大于个人的总和组件。ARHL生物标志物的识别可能为有效的治疗策略铺平道路。