Functional Integrity of the Aging Auditory Synapse

摘要：年龄相关性听力损失(ARHL)对老年人的生活质量有重大影响 超过70%的70岁以上的人。这是一个日益严重的问题，具有重大意义 对社会经济的影响。急性淋巴细胞性白血病的病因很复杂，很可能同时涉及到 环境和遗传因素。与急性淋巴细胞性白血病相关的症状，特别是 在嘈杂的环境中最初丧失辨别声音的能力，后来发展到高 频率损失会随着时间的推移进一步发展到更低的频率，这表明 独立于初始触发器的常见漏洞。我们的假设是 ARHL的共同之处是最初毛细胞传入纤维突触的丢失。很像与 噪声引起的听力损失，我们假设是高阈值纤维的选择性损失。我们 将使用ARHL的多个遗传小鼠模型来验证这些假设。每个人都将是 使用包括听性脑干反应在内的全动物听觉测试进行监测 和失真产物耳声发射以记录发病的时间过程 各模型均为急性淋巴细胞性白血病。《特定目标2》将评估突触的维持和蛋白质 与突触前和突触后的元素相关联，以进一步表征颞叶 与听力损失相关的视窗。《特殊目标3》将使用电生理和 光学技术测量突触囊泡的释放和运输，监测钙 动态平衡和记录突触后特性突触电位以及电 属性。每个目标都与可用目标和技术很好地结合在一起 对这项提议的每一位其他调查人员，我们将共同确定一个全球 解决这一重要翻译问题的框架。

Abstract: Age related hearing loss (ARHL) has a major impact on quality of life of more than 70% of those over the age of 70. It is a growing problem with significant socioeconomic ramifications. The cause of ARHL is complex and likely involves both environmental and genetic factors. Symptoms associated with ARHL, specifically, the initial loss of ability to discriminate sound in a noisy environment that progress to high frequency loss that can further progress to lower frequencies over time, suggest a common vulnerability that is independent of the initial trigger. We are postulating that common to ARHL is an initial loss of hair cell afferent fiber synapses. Much as with noise induced hearing loss, we hypothesize a selective loss of high threshold fibers. We will test these hypotheses using multiple genetic mouse models of ARHL. Each will be monitored using whole animal auditory testing including auditory brainstem responses and distortion product otoacoustic emissions to document the time course of onset of ARHL in each model. Specific Aim 2 will evaluate synaptic maintenance and proteins associated with pre and postsynaptic elements to further characterize the temporal windows associated with hearing loss. Specific Aim 3 will use electrophysiological and optical technologies to measure synaptic vesicle release and trafficking, monitor calcium homeostasis and record postsynaptic properties synaptic potentials as well as electrical properties. Each aim is well integrated with the goals and techniques available from each of the other investigators on this proposal and together we shall identify a global framework in which to address this important translational problem.