Project 3: Pathophysiology of human age-related hearing loss

项目摘要/摘要--项目3 确定年龄相关性听力损失的病理机制和部位(S)是 具有挑战性，因为它们可能反映了一生的环境暴露、易感性差异和共同 疾病和复杂的遗传因素。这些个体差异可能是导致 老年人的听力特征和阈值上的听觉功能。在我们的中心，分类 代谢性和感觉性老年性耳聋的表型是基于动物模型，将特定的耳蜗性缺陷与 听力特征，并产生了四种基于耳蜗型的表型。项目3将完善这些 开发和验证预测耳蜗神经和听神经的生理指标的表型 老年人的病理学。Aim 3.1测试外毛细胞和耳蜗侧壁缺陷的假说 感觉性耳聋与代谢性耳聋的差异。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预测耳蜗病理性部位(S) 病理模式与感觉性和代谢性听力损失的估计相符的程度。目标 3.2检查听神经结构和功能，以检验听神经变化的假设 运动对老年人的听觉功能有独特的和相加的影响。通过使用相似的生理学 项目1和项目2中的评估和实验将提供一种方法来验证项目3的结果 机制和解剖病理学已明确的小鼠模型。一个重大的进步 在描述老年性耳聋的基础耳蜗病和神经病理学方面，老年性耳聋的发展是至关重要的。 以及通过在临床试验中适当分配参与者来测试新的治疗方法， 以及确定对个人最好的干预方案。此外，个体差异在 项目3中确定的病理生理学假设对大脑皮层表现有不同的影响 在项目4中评估了语音和听阈上听觉处理的能力。

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.