COCHLEAR VULNERABILITY/REACTIVE OXYGEN SPECIES

获得性听力损失代表了基因和环境的复杂相互作用。虽然有很多人支持存在影响耳蜗易受噪音和耳毒素影响的基因，但几乎没有确定的候选基因或过程。一个候选过程涉及活性氧物种(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都与ROS升高有关，抗氧化酶的缺乏增加了对损伤的易感性。我们假设，一些使人们易患获得性听力损失的基因缺陷涉及ROS调节机制的损害，使耳蜗更容易受到伤害。我们将使用易听力损失和耐受的小鼠模型(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“基因敲除”小鼠，仔细考虑年龄，以达到以下特定目的：(1)将噪声暴露后耳蜗ROS产生的动态与特定的耳蜗损伤相关联。我们将通过听觉脑干反应、光镜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产生的大小和时间进程之间的关系。(2)确定ROS产生与噪声性耳蜗病关系的遗传影响。我们将确定听力和ROS调节的遗传缺陷对耳蜗ROS产生和噪声性耳蜗性损伤之间关系的影响。(3)揭示了遗传和年龄对抗氧化剂疗效影响的基础。我们将确定年龄和听力遗传缺陷对外源抗氧化剂能力的影响，以减轻ROS的产生和噪声诱导的耳蜗损伤。我们的实验将确定ROS产生的动力学如何很好地预测耳蜗损伤，以及进行性耳聋基因是否可能损害耳蜗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.