Genetics of Noise Resistance in the Aging Ear

描述(申请人提供)：随着慢性听力损失的累积 暴露于高强度声音(噪声性听力损失；NIHL)并随年龄增长 (年龄相关性听力损失；急性耳聋或老年性耳聋)是主要的健康问题。他们 是常见的，它们的后果是永久性的，它们对人类的影响 沟通和生活质量是重要的。重要的进展是 在描述两个NIHL所在的耳朵的结构变化时做出的 然而，这些变化背后的机制仍然很差 明白了。 在人类群体中，听力损失继发于噪声暴露和 被归因于衰老的人在不同的人之间有很大的差异：一些人有很强的 耳朵，而其他人的耳朵是“柔软的”。相比之下，与实验室小鼠打交道 在一个近交系中，NIHL和/或AHL的变异性明显较小 菌株之间存在显著差异。我们的长期目标 就是利用这些品系的差异在小鼠模型中研究遗传 影响NIHL和AHL易感性的因素及其相互作用 他们。 我们的近期目标集中在近交系对NIHL的显著抗性上 利伯曼最近报道的小鼠品系129S6/SvEvTac 实验室。而NIHL通常一旦达到临界暴露水平就会迅速增长 达到时，129S6中的NiHL在大范围内的增长速度要慢10倍 曝光能量。来自Kujawa实验室的初步结果表明 129S6还显示了一种AHL，表明AHL漏洞不需要 与NIHL脆弱性有关，因为它们似乎出现在C57BL/6小鼠身上。进一步 Kujawa/Tempel合作的初步结果表明，AHL和AHL 129S6的NIHL抗性为隐性遗传。有了这个 基础上，我们建议1)更好地描述AHL及其影响 AHL对129S6菌株NIHL抗性的影响 组织病理学措施，2)为主要的 利用成熟技术获得影响129S6抗噪性的基因(S 对于基因图谱，以及3)使用相同的基因技术，确定 129S6中的AHL是由与AHL相关的同一基因位点介导的 C57BL/6菌株。 影响AHL和AHL易感性基因的最终特征 NIHL将提供对细胞和分子过程的基本见解 潜在的耳蜗性变性，这反过来将是设计的关键 在人类群体中保护听力的有效策略。

DESCRIPTION (provided by applicant): Hearing losses that accumulate with chronic exposure to high-level sound (noise-induced hearing loss; NIHL) and with age (age-related hearing loss; AHL or presbycusis) are major health problems. They are common, their consequences are permanent, and their impact on human communication and quality of life is significant. Important advances have been made in characterizing the structural changes in the ear that underlie both NIHL and AHL, however, the mechanisms underlying these changes are still poorly understood. In human populations, hearing losses secondary to noise exposure and those attributed to aging are highly variable between individuals: some have 'tough' ears, while others have 'tender' ears. In contrast, work with laboratory mice has shown significantly less variability in NIHL and/or AHL within one inbred strain, while there are striking differences between strains. Our long-term goal is to exploit these strain differences in mouse models to study the genetic factors influencing susceptibility to NIHL and AHL, and interactions between them. Our immediate goals focus on the remarkable resistance to NIHL in the inbred mouse strain l29S6/SvEvTac (129S6), recently reported by the Liberman laboratory. Whereas NIHL typically grows rapidly once a critical exposure level is reached, NIHL in 129S6 grows 10 times more slowly over a wide range of exposure energy. Preliminary results from the Kujawa laboratory suggest that 129S6 also shows a type of AHL, demonstrating that AHL vulnerability need not be linked to NIHL vulnerability, as they appear to be in C57BL/6 mice. Further preliminary results from a Kujawa/Tempel collaboration suggest that both the AHL and the NIHL resistance in 129S6 are heritable as recessive traits. With this foundation, we propose to 1) better characterize the AHL and the influence of AHL on NIHL resistance in 129S6 using a number of physiological and histopathological measures, 2) provide a chromosomal localization for the major gene(s) influencing noise resistance in 129S6 using well-established techniques for genetic mapping, and 3) using the same genetic techniques, establish whether the AHL in 129S6 is mediated by the same gene locus associated with AHL in the C57BL/6 strain. The ultimate characterization of the genes influencing susceptibility to AHL and NIHL will provide fundamental insight into the cellular and molecular processes underlying cochlear degeneration, which, in turn, will be key to devising effective strategies to preserve hearing in human populations.