Genetics of Noise Resistance in the Aging Ear

描述（由申请人提供）：听力损失，随着慢性 暴露于高强度噪声（噪声性听力损失; NIHL）和年龄 老年性听力损失（阿勒或老年性耳聋）是主要的健康问题。他们 是普遍的，其后果是永久性的，其对人类的影响 沟通和生活质量至关重要。了重要进展 在表征耳朵的结构变化，基础上NIHL 然而，这些变化背后的机制仍然很差 明白 在人群中，继发于噪声暴露的听力损失以及 归因于衰老的是个体之间的高度可变：有些人有'坚韧' 耳朵，而其他人有“温柔”的耳朵。与此相反， 在一个近交系内，NIHL和/或阿勒的变异性显著降低 菌株，而菌株之间有显着差异。我们的长期目标 是利用小鼠模型中的这些品系差异来研究 影响NIHL和阿勒易感性的因素，以及 他们 我们的近期目标集中在近交系中对NIHL的显著抗性 小鼠品系l29 S6/SvEvTac（129 S6），最近由Liberman报道 实验室一旦达到临界暴露水平，NIHL通常会迅速增长 达到，129 S6中的NIHL在很宽的范围内增长慢10倍。 曝光能量Kujawa实验室的初步结果表明， 129 S6还显示了一种阿勒类型，表明阿勒脆弱性不需要 与NIHL易感性相关，因为它们似乎在C57 BL/6小鼠中。进一步 Kujawa/Tempel合作的初步结果表明， 129 S6的NIHL抗性为隐性遗传。与此 在此基础上，我们建议：1）更好地表征阿勒和 阿勒对129 S6的NIHL抗性的影响 组织病理学测量，2）提供主要的染色体定位 使用成熟的技术在129 S6中影响噪声抗性的基因 3）使用相同的遗传技术，确定是否 129 S6中的阿勒由与129 S6中的阿勒相关的相同基因座介导。 C57 BL/6菌株。 影响阿勒易感性的基因的最终特征， NIHL将为细胞和分子过程提供基本的见解 潜在的耳蜗退化，这反过来将是设计 保护人类听力的有效策略。

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.