Genetic Modulation of Noise Injury to the Cochlear Lateral Wall

我们和其他人已经确定了几个促进小鼠耳蜗噪声损伤的基因， 同源物可促进人类的类似损伤。我们现在有证据表明， 在小鼠中的一个性状基因座（QTL），它不影响噪声损伤的程度，而是影响噪声损伤的细胞分布。 噪音伤害在中度噪声暴露（4-45 kHz，110 dB SPL，2小时）后数小时，CBA/J小鼠显示出 耳蜗内电位（EP）降低，以及血管纹、螺旋纹 韧带和螺旋利姆布斯。虽然EP随时间恢复，但对纹和利姆布斯的损伤是永久性的。 相比之下，C57 BL/6 J（B6）小鼠没有显示出显著的急性EP降低，并且显示出最小的急性或永久性EP降低。 细胞病理学B6/CBA F1杂交小鼠以与CBA亲本品系相似的方式对噪声作出反应， 表明一个或几个显性基因座控制损伤表型的所有方面。N2回交小鼠 显示出相同的噪音病理学星座，并表明噪音表型与该地区的联系 含有小鼠2号染色体上的agglutinase基因座。我们假设链接间隔包括 一种参与通过侧纹（基底细胞和中间细胞）和利姆布斯的离子运输的基因。基因 可能编码一种离子通道，其电导率被缺氧或氧化应激下调。 我们的研究结果指出，新的遗传调制的耳蜗离子稳态在噪声压力。的 相关基因和过程可能影响耳蜗噪声损伤的长期稳定性， 表现为老年性耳聋的损伤累积。我们的具体目标是1）确定细胞 CBA小鼠噪声暴露后EP降低的基础; 2）检测噪声相关的 构成CBA表型的纹、螺旋韧带和利姆布斯的细胞病理学，以及3）鉴定 候选基因是CBA与B6菌株在噪声影响方面差异的基础。 与公共卫生的相关性：耳蜗包含许多功能未知的细胞类型， 但可能有助于维持适当的离子环境，使感觉细胞能够存活并作出反应， 对声音敏感。我们的工作指向一个或多个基因，深刻影响噪音的分布 非感觉细胞损伤。该基因及其参与的过程可能会影响长期的 耳蜗损伤的稳定性，以及可诊断为老年性耳聋的损伤的累积。

We and others have identified several genes that promote cochlear noise injury in mice, and whose homologues may promote similar injury in humans. We now have evidence for a major effect quantitative trait locus (QTL) in mice that influences not the extent of noise injury, but rather the cellular distribution of noise injury. Hours after a moderate noise exposure (4-45 kHz, 110 dB SPL, 2 hrs), CBA/J mice show a reduction in the endocochlear potential (EP), as well as characteristic pathology within stria vascularis, spiral ligament, and spiral limbus. Although the EP recovers over time, the injury to stria and limbus is permanent. C57BL/6J (B6) mice, by contrast, show no significant acute EP reduction, and minimal acute or permanent cellular pathology. B6/CBA F1 hybrid mice respond to noise in a manner similar to the CBA parent strain, suggesting that one or a few dominant loci govern all facets of the injury phenotype. N2 backcross mice show the same constellation of noise pathology, and suggest linkage of the noise phenotype to the region containing the agouti locus on mouse chromosome 2. We HYPOTHESIZE that the linkage interval includes a gene involved in ion transport through the lateral stria (basal and intermediate cells) and limbus. The gene may code for an ion channel whose conductance is down-regulated by hypoxia or oxidative stress. Our findings point to novel genetic modulation of cochlear ion homeostasis during noise stress. The gene(s) and processes involved may impact the long term stability of cochlear noise injury and the accumulation of injury that presents as presbycusis. Our SPECIFIC AIMS are 1) To determine the cellular basis of EP reduction after noise exposure in CBA mice, 2) To examine the correlation of noise-related cellular pathologies of stria, spiral ligament, and limbus that comprise the CBA phenotype, and 3) To identify candidate gene(s) underlying CBA versus B6 strain differences in the effects of noise. RELEVANCE TO PUBLIC HEALTH: The cochlea contains many cell types whose functions are not known, but probably help maintain an appropriate ionic environment so that sensory cells can survive and respond sensitively to sound. Our work points to one or more genes that profoundy impact the distribution of noise injury in non-sensory cells. The gene, and the processes in which it is involved, may affect the long-term stability of cochlear injury, and the accumulation of injury that may be diagnosed as presbycusis.