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声损伤的基因，并且它们的 同系物可能会促进人类遭受类似的伤害。我们现在有证据证明一种重要的量化效应 小鼠的性状基因座(QTL)不影响噪声损伤的程度，但影响细胞分布 噪音伤害。在中等噪声暴露(4-45 kHz，110dBSPL，2小时)后数小时，CBA/J小鼠表现出 蜗内电位(EP)降低，以及螺旋血管纹内的特征性病理 韧带和螺旋状角膜缘。虽然EP会随着时间的推移恢复，但纹状体和角膜缘的损伤是永久性的。 相比之下，C57BL/6J(B6)小鼠没有表现出明显的急性EP减少，急性或永久性的 细胞病理学。B6/CBA F1杂交小鼠对噪声的反应方式与CBA亲本相似， 这表明，一个或几个显性基因控制着伤害表型的各个方面。N2回交小鼠 显示了相同的噪声病理星座，并建议将噪声表型与该区域联系起来 包含小鼠2号染色体上的刺鼠基因。我们假设连锁区间包括 参与离子通过侧纹(基细胞和中间细胞)和角膜缘运输的基因。基因 可能编码一种离子通道，其电导因低氧或氧化应激而下调。 我们的发现指出了噪声应激对耳蜗离子动态平衡的新的遗传调节。这个 S基因及其参与的过程可能影响耳蜗声损伤的长期稳定性和 累积性损伤，表现为老年性耳聋。我们的具体目标是1)确定细胞 噪声暴露后CBA小鼠EP降低的基础，2)检验噪声相关因素的相关性 构成CBA表型的纹状体、螺旋韧带和角膜缘的细胞病理学，以及3)鉴定 候选基因(S)在噪声对CBA和B6菌株的影响上存在差异。 与公共健康的相关性：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，以便感觉细胞能够存活并做出反应 对声音敏感的。我们的工作指出了一个或多个基因对噪音的分布产生了深远的影响 非感觉性细胞的损伤。该基因及其参与的过程可能会影响长期的 耳蜗性损伤的稳定性和损伤的积累性，可诊断为老年性耳聋。

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.