COCHLEAR VULNERABILITY/REACTIVE OXYGEN SPECIES

获得性听力损失是基因和环境的复杂相互作用。 虽然有很多支持存在的基因，影响耳蜗的脆弱性，噪音和耳毒素，很少有候选基因或过程已被确定。 一个候选过程涉及活性氧（ROS）的产生和调节。 慢性神经退行性疾病和急性CNS损伤都涉及ROS升高，并且抗氧化酶的缺乏促进对损伤的脆弱性。 我们假设，一些遗传缺陷，使人们获得性听力损失涉及ROS调节机制的损害，使耳蜗更容易受到伤害。 我们将应用听力损失倾向和抗性小鼠模型（C57BL/6、BALB/c、CBA/Ca）和抗氧化酶（超氧化物歧化酶和谷胱甘肽过氧化物酶）缺陷的"敲除"小鼠，仔细考虑年龄，以实现以下具体目标：（1）将噪声暴露后耳蜗ROS产生的动态与特定耳蜗损伤相关联。 我们将通过听觉脑干反应、光学和电子显微镜以及毛细胞计数来确定急性噪声暴露和耳蜗损伤后耳蜗ROS产生的幅度和时间过程之间的关系。(2)确定遗传因素对ROS产生和噪声诱导的耳蜗损伤之间关系的影响。 我们将确定听力遗传缺陷和ROS调节对耳蜗ROS产生和噪声诱导的耳蜗损伤之间关系的影响。 (3)揭示遗传和年龄影响抗氧化剂功效的基础。 我们将确定年龄和听力遗传缺陷对外源性抗氧化剂减弱ROS产生和噪声诱导的耳蜗损伤的能力的影响。 我们的实验将确定ROS产生的动力学如何预测耳蜗损伤，以及进行性耳聋基因是否会损害耳蜗ROS调节。

Acquired hearing loss represents a complex interplay of genes and environment. Although there is much support for the existence of genes that influence the vulnerability of the cochlea to noise and ototoxins, few candidate genes or processes have been identified. One candidate process involves the generation and regulation of reactive oxygen species (ROS). Both chronic neurodegenerative disease and acute CNS injury involve elevated ROS, and deficiency of antioxidant enzymes promotes vulnerability to injury. We hypothesize that some genetic defects that predispose people to acquired hearing loss involve impairment of ROS regulatory mechanisms, rendering the cochlea more vulnerable to injury. We will apply hearing loss-prone and -resistant mouse models (C57BL/6, BALB/c, CBA/Ca), and 'knockout' mice deficient in antioxidant enzymes (superoxide dismutase and glutathione peroxidase), of carefully considered ages to the following Specific Aims: (1) Correlating the dynamics of cochlear ROS production following noise exposure with specific cochlear injury. We will establish the relation between the magnitude and time course of cochlear ROS production following acute noise exposure and cochlear injury, as measured by auditory brainstem responses, light and electron microscopy, and hair cell counts. (2) Identifying genetic influences on the relation between ROS production and noise-induced cochlear injury. We will determine the impact of genetic defects of hearing and ROS regulation on the relation between cochlear ROS production and noise-induced cochlear injury. (3) Uncovering the basis of genetic and age influences on the efficacy of antioxidants. We will determine the impact of age and genetic defects of hearing on the ability of exogenous antioxidants to attenuate both ROS production and noise-induced cochlear injury. Our experiments will establish how well the dynamics of ROS production predict cochlear injury, and whether progressive deafness genes may impair cochlear ROS regulation.