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.

摘要 老年性听力损失(ARHL)或老年性耳聋是最常见的感觉障碍，随着 预期寿命，预计将对我们社会的福祉产生巨大影响。事实上，试镜和 沟通是我们人类互动的本质。这一纲领性提案的总体框架 只有通过对弱势人群的研究，才有可能全面了解急性淋巴细胞性白血病 内耳的突触和神经结构，但也检查发生在 对螺旋神经节神经元突起变化的反应。我们召集了专业人士 从遗传学到细胞生物学和生理学(Tempel、Yamoah、Ricci和Gratton)。这些调查人员已经 已经以高度协同和富有成效的方式共同工作。 有三个项目(P)由三个核心(行政、老鼠遗传和结构分析)提供服务 核心)，以检验中央假设，老化的听觉感觉上皮经历结构变化， 允许高K+内淋巴渗入外淋巴，触发HC和SGN去极化，增加 细胞内Ca~(2+)([Ca~(2+)]i)和随后的“无声”突触和神经元变性(P2，P3)。我们预测 结构的变化是由老化的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两种已鉴定的TJ蛋白的遗传操作 表达水平显著下降的感觉上皮细胞将作为原型与 另外三个ARHL模型来验证我们的假设(P1-3，核心B-C)。我们认为神经和突触 外周(P2、P3)的变化将介导细胞变化，从而导致听觉上的长期变化 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、测试和提出急性淋巴细胞性白血病的治疗目标，从而转变和转移 从主流范式转向机械化和平移化的平台。