Genetic Modulation of Noise Injury to the Cochlear Lateral Wall

描述(申请人提供)：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，它们的同源基因可能会促进人类的类似损伤。我们现在有证据表明，数量性状基因座(QTL)对小鼠的主效应不是影响噪声损伤的程度，而是影响噪声损伤的细胞分布。在中等噪声暴露(4-45 kHz，110dBSPL，2小时)数小时后，CBA/J小鼠表现出耳蜗内电位(EP)降低，以及血管纹、螺旋韧带和螺旋边缘的特征性病理。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，以及轻微的急性或永久性细胞病变。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所有方面。N_2回交小鼠表现出相同的噪声病理星座，并提示噪声表型与小鼠2号染色体上包含刺鼠基因座的区域连锁。我们假设连锁区间包括一个参与离子通过侧纹(基细胞和中间细胞)和边缘运输的基因。该基因可能编码一种离子通道，其电导因缺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。涉及的基因(S)和过程可能影响耳蜗声损伤的长期稳定性和表现为老年性耳聋的损伤的积累。我们的具体目标是：1)确定噪声暴露后CBA小鼠EP减少的细胞学基础；2)检测构成CBA表型的纹状体、螺旋韧带和角膜缘与噪声相关的细胞病理学之间的相关性；3)确定CBA和B6菌株在噪声影响下差异的候选基因(S)。与公共健康相关：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对声音做出敏感反应。我们的工作指出了一个或多个基因对噪音损伤在非感觉细胞中的分布产生了深远的影响。该基因及其参与的过程可能会影响耳蜗病的长期稳定性，以及可能被诊断为老年性耳聋的损伤的积累。

DESCRIPTION (provided by applicant): 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.