Project 3: Pathophysiology of human age-related hearing loss

项目总结/摘要-项目3 确定与年龄相关的听力损失所涉及的病理机制和部位， 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 发病率和复杂的遗传因素。这些个体差异可能会导致 老年人的听力曲线和阈上听觉功能。在我们的中心， 代谢和感觉性老年性聋表型是基于将特定耳蜗缺陷与 听力概况，并导致四个耳蜗为基础的表型。项目3将完善这些 通过开发和验证预测耳蜗和听神经的生理指标， 老年人的病理学目的3.1验证外毛细胞和耳蜗外侧壁缺陷的假说 不同地贡献于感觉性与代谢性老年性聋。Aim 3.1中的实验采用了度量标准 与外毛细胞和血管纹功能相关，以预测耳蜗病变部位并确定 病理模式与感觉和代谢性听力损失的估计一致的程度。目的 3.2检查听神经的结构和功能，以检验听神经的变化 活动导致老年人听觉功能的独特和累加效应。通过使用类似的生理 评估，项目1和项目2的实验将提供一种方法来验证项目3的结果， 机制和解剖病理学明确的小鼠模型。的显著进步 在表征潜在的耳蜗和神经病变的老年性聋是至关重要的发展 并在新的治疗方法可用时进行测试，通过适当地分配临床试验的参与者， 以及决定对个人的最佳干预方案。此外，个体差异 在项目3中确定的病理生理学假设对皮质表征有不同的影响 的言语和阈上听觉处理，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.