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

• 批准号: 9340057
• 负责人: EBENEZER N YAMOAH
• 金额: $ 162万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340057
• 关键词: Achievement; Affect; Age; Aging; Animal Model; Apical; Auditory; Auditory Brainstem Responses; Auditory Threshold; Auditory system; Biochemical; Biology; Cell physiology; Cells; Cellular biology; Characteristics; Cochlea; Cochlear duct; Communication; DNA Sequence Alteration; Data; Disease; Endolymph; Epithelium; Etiology; Exhibits; Frequencies; Functional Imaging; Gene Deletion; Genes; Genetic; Genetic Models; Genetic Transcription; Goals; Hair Cells; Hearing; Human; Image; Imaging Techniques; Individual; Ions; Labyrinth; Lateral; Life Expectancy; Mechanics; Mediating; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Nervous system structure; Neurites; Neuronal Plasticity; Neurons; Neurotransmitters; Noise-Induced Hearing Loss; Pathology; Perilymph; Presbycusis; Proteins; Psychological Impact; Quality of life; Receptor Cell; Research; Research Personnel; Resources; Secondary to; Sensorineural Hearing Loss; Sensory; Societies; Specialist; Stimulus; Structure; Sum; Synapses; Testing; Therapeutic; Tight Junctions; Work; age related; base; cost; deafness; design; genetic manipulation; hearing impairment; insight; mouse model; new therapeutic target; occludin; outcome prediction; programs; protein expression; prototype; relating to nervous system; response; spiral ganglion

Abstract Age-related hearing loss (ARHL) or presbycusis is the most prevalent sensory deficit and with the increase in life expectancy, it is predicted to have vast impact in the well-being of our society. Indeed, audition and communication is the essence of our human interactions. The overall framework for this programmatic proposal is that a comprehensive understanding of ARHL is only possible through studies of not only the vulnerable synaptic and neural structures of the inner ear, but also examination of the neural plasticity that occurs in response to changes at the neurites of spiral ganglion neurons. We have brought together expert individuals from genetics to cell biology and physiology (Tempel, Yamoah, Ricci, and Gratton). These investigators have already worked together in a highly synergistic and productive manner. There are three projects (P) served by three Cores (Administrative, Mouse Genetics and Structural Analysis Cores) to test the Central Hypothesis that the aging auditory sensory epithelia undergo structural changes that allow the high K+ endolymph to leak into the perilymph, triggering HC and SGN depolarization, increased intracellular Ca2+ ([Ca2+]i) and subsequent “silent” synaptic and neuronal degeneration (P2, P3). We predict that structural changes are mediated by weakening tight junctions (TJs) in the aging cochlear sensory epithelium (P1, Core C). Genetic manipulation of Claudin 9 and Occludin, two identified TJ proteins in the sensory epithelium, that show robust reduction in expression levels, will be used as prototypes together with three additional ARHL models to test our hypothesis (P1-3, Cores B-C). We propose that neural and synaptic alterations at the periphery (P2, P3) will mediate cellular changes that confer long-lasting alterations auditory system. The proposed studies will reveal critical neural and synaptic mechanisms of ARHL. New therapeutic targets for the treatment of ARHL will be assessed, tested and proposed, thus, transforming and shifting the prevailing paradigm to mechanistic and translational platforms.

抽象的 年龄相关性听力损失（ARHL）或老年性耳聋是最普遍的感觉缺陷，并且随着年龄的增加 预期寿命，预计将对我们社会的福祉产生巨大影响。确实，试镜和 沟通是我们人类互动的本质。本方案提案的总体框架 是只有通过对弱势群体的研究才能全面了解 ARHL 内耳的突触和神经结构，还检查发生在的神经可塑性 对螺旋神经节神经元神经突变化的反应。我们汇集了专家 从遗传学到细胞生物学和生理学（Tempel、Yamoah、Ricci 和 Gratton）。这些调查人员有 已经以高度协同和富有成效的方式合作。 三个项目 (P) 由三个核心服务（管理、小鼠遗传学和结构分析） 核心）来测试中心假设，即老化的听觉感觉上皮经历结构变化， 允许高 K+ 内淋巴漏入外淋巴，触发 HC 和 SGN 去极化，增加 细胞内 Ca2+ ([Ca2+]i) 和随后的“沉默”突触和神经元变性 (P2、P3)。我们预测 结构变化是由老化耳蜗感觉中的紧密连接（TJ）减弱所介导的 上皮（P1，核心 C）。 Claudin 9 和 Occludin 的基因操作，这两种在 感觉上皮表现出表达水平的大幅降低，将与 三个额外的 ARHL 模型来检验我们的假设（P1-3，核心 B-C）。我们建议神经和突触 外围（P2、P3）的变化将介导细胞变化，从而带来持久的听觉变化 系统。拟议的研究将揭示 ARHL 的关键神经和突触机制。新疗法 将评估、测试和提出 ARHL 治疗的目标，从而改变和转变 机械和转化平台的流行范式。