COCHLEAR VULNERABILITY/REACTIVE OXYGEN SPECIES

获得性听力损失是基因和环境复杂相互作用的结果。虽然有很多证据支持存在影响耳蜗对噪音和耳毒素易感性的基因，但很少有候选基因或过程被确定。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中枢神经系统损伤均涉及ROS升高，而抗氧化酶的缺乏促进了对损伤的易感性。我们假设一些遗传缺陷使人们易患获得性听力损失，涉及活性氧调节机制的损害，使耳蜗更容易受到损伤。我们将使用听力损失易感和抗性小鼠模型（C57BL/6, BALB/c, CBA/Ca），以及经过仔细考虑的年龄缺乏抗氧化酶（超氧化物歧化酶和谷胱甘肽过氧化物酶）的“敲除”小鼠，以达到以下具体目的：(1)将噪音暴露后耳蜗ROS产生的动态与特定耳蜗损伤相关联。我们将建立急性噪声暴露和耳蜗损伤后耳蜗活性氧产生的大小和时间过程之间的关系，通过听觉脑干反应、光学和电子显微镜以及毛细胞计数来测量。(2)确定ROS产生与噪声性耳蜗损伤之间关系的遗传影响。我们将确定听力遗传缺陷和活性氧调控对耳蜗活性氧产生与噪声性耳蜗损伤关系的影响。(3)揭示遗传和年龄对抗氧化剂功效影响的基础。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能力的影响。我们的实验将确定活性氧产生的动态预测耳蜗损伤的程度，以及进行性耳聋基因是否会损害耳蜗活性氧的调节。

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.