Project 3: Pathophysiology of human age-related hearing loss

项目摘要/摘要 – 项目 3 确定与年龄相关的听力损失相关的病理机制和部位 具有挑战性，因为它们可能反映了一生的环境暴露、易感性和共同的差异 发病率和复杂的遗传因素。这些个体差异可能会造成巨大的差异 老年人的听力特征和阈上听觉功能。在我们的中心，分类 代谢性和感觉性老年性耳聋表型基于动物模型，将特定的耳蜗缺陷与 听力特征，并产生了四种基于耳蜗的表型。项目3将完善这些 通过开发和验证预测耳蜗和听觉神经的生理测量来确定表型 老年人的病理学。目标 3.1 检验外毛细胞和耳蜗侧壁缺陷的假设 对感觉性老年性耳聋和代谢性老年性耳聋的影响不同。 Aim 3.1 中的实验纳入了指标 与外毛细胞和血管纹功能相关，可预测耳蜗病理部位并确定 病理模式与感觉和代谢性听力损失的估计一致的程度。目标 3.2 检查听神经结构和功能，检验听神经变化的假设 活动会对老年人的听觉功能产生独特的累加效应。通过使用类似的生理学 项目 1 和项目 2 中的评估、实验将提供验证项目 3 结果的方法 机制和解剖病理学明确的小鼠模型。重大进步 老年性耳聋的潜在耳蜗和神经病理学特征对于发展至关重要 并通过适当分配临床试验参与者来测试新的治疗方法， 并确定个人的最佳干预方案。而且，个体差异 项目 3 中确定的病理生理学被假设对皮质表征有不同的影响 言语和阈上听觉处理的能力，在项目 4 中评估。

PROJECT SUMMARY/ABSTRACT – PROJECT 3 Determining the mechanisms and site(s) of pathologies involved in age-related hearing loss is challenging as they likely reflect a lifetime of environmental exposures, differences in susceptibility and co- morbidities, and complex genetic factors. These individual differences may contribute to the large variation in audiometric profiles and suprathreshold auditory function seen in older adults. In our Center, classification of metabolic and sensory presbyacusis phenotypes is based on animal models linking specific cochlear deficits to audiometric profiles, and has resulted in four cochlear-based phenotypes. Project 3 will refine these phenotypes by developing and validating physiologic measures that predict cochlear and auditory nerve pathology in older adults. Aim 3.1 tests the hypothesis that outer hair cell and cochlear lateral wall deficits differentially contribute to sensory versus metabolic presbyacusis. Experiments in Aim 3.1 incorporate metrics related to outer hair cell and stria vascularis function to predict cochlear pathologic site(s) and determine the extent to which patterns of pathology are consistent with estimates of sensory and metabolic hearing loss. Aim 3.2 examines auditory nerve structure and function to test the hypothesis that changes in auditory nerve activity result in unique and additive effects in auditory function of older adults. By using similar physiologic assessments, experiments in Project 1 and Project 2 will provide a means to validate Project 3 results in mouse models where the mechanisms and anatomical pathology are well defined. A significant advancement in the characterization of underlying cochlear and neural pathologies of presbyacusis is crucial in developing and testing new treatments as they become available, by appropriately assigning participants in clinical trials, and in determining the best course of intervention for an individual. Moreover, individual differences in pathophysiology identified in Project 3 are hypothesized to have differential effects on cortical representation of speech and suprathreshold auditory processing, assessed in Project 4.