Genetic Modulation of Noise Injury to the Cochlear Lateral Wall

噪声对耳蜗外侧壁损伤的基因调控

• 批准号: 7262707
• 负责人: KEVIN K. OHLEMILLER
• 金额: $ 22.33万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-20 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7262707
• 关键词: Genetic; Modulation; Noise; Injury; Cochlear

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.

描述（由申请人提供）：我们和其他人已经鉴定了几种促进小鼠耳蜗噪声损伤的基因，其同源物可能促进人类的类似损伤。我们现在有证据表明，小鼠中的一个主要效应数量性状位点（QTL）不影响噪声损伤的程度，而是影响噪声损伤的细胞分布。中度噪声暴露（4-45 kHz，110 dB SPL，2 小时）后数小时，CBA/J 小鼠表现出耳蜗电位 (EP) 降低，以及血管纹、螺旋韧带和螺旋缘内的特征性病理。尽管 EP 随着时间的推移会恢复，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，并且急性或永久性细胞病理也很少。 B6/CBA F1 杂交小鼠对噪音的反应方式与 CBA 亲本品系相似，表明一个或几个显性基因座控制损伤表型的所有方面。 N2 回交小鼠表现出相同的噪声病理学，并表明噪声表型与小鼠 2 号染色体上包含刺鼠基因座的区域存在连锁。我们假设连锁区间包括参与通过侧纹（基底细胞和中间细胞）和角膜缘的离子运输的基因。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。我们的研究结果指出了噪音应激期间耳蜗离子稳态的新基因调节。所涉及的基因和过程可能会影响耳蜗噪声损伤的长期稳定性以及表现为老年性耳聋的损伤累积。我们的具体目标是 1) 确定 CBA 小鼠噪声暴露后 EP 减少的细胞基础，2) 检查构成 CBA 表型的纹状体、螺旋韧带和角膜缘的噪声相关细胞病理学的相关性，以及 3) 确定 CBA 与 B6 品系在噪声影响方面差异的潜在候选基因。与公众健康的相关性：耳蜗含有许多细胞类型，其功能尚不清楚，但可能有助于维持适当的离子环境，以便感觉细胞能够生存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非感觉细胞中噪音损伤的分布有深远的影响。该基因及其所涉及的过程可能会影响耳蜗损伤的长期稳定性，以及可能被诊断为老年性耳聋的损伤累积。