Genetics of Noise Resistance

描述(申请人提供)：噪声性听力损失(NIHL)和年龄相关性听力损失(AHL或老年性耳聋)是主要的健康问题。它们是常见的，它们的后果是永久性的，它们对人类交流和生活质量的影响是巨大的。虽然在描述与NIHL或AHL相关的耳朵结构变化方面取得了重要进展，但这些变化背后的机制尚不清楚。在人类中，暴露在噪音中的继发性听力损失在不同的人之间存在很大的差异：一些人的耳朵很“硬”，而另一些人的耳朵“柔软”。与人类相比，实验室小鼠在同一近交系内的个体间NIHL的变异性明显较小，而不同近交系之间的NIHL敏感性存在显著差异。我们的长期目标是利用小鼠模型中这些品系的差异来研究影响耐药率和易感性的遗传因素。在这里，我们建议重点关注在近交系小鼠12986/SvEvTac(129S6)中观察到的显着的耐药率。我们将解决以下具体目标：SA 1.完善和确认我们初步的129S6抗性数量性状基因座(QTL)图谱。在不同的小鼠品系Molf/Ei中开发第二个NIHL抗性QTL图谱以进行比较。SA 2：使用针对NIHL抗性的表型驱动选择和针对QTL区域的基因驱动、标记辅助选择来产生同源菌株。将对分离的QTL区域进行上位性互作测试。利用DNA微阵列研究噪声暴露后基因表达的变化，寻找NIHL抗性候选基因。两个菌株之间差异调控和QTL区域内定位的基因将被测序，并比较变异情况。强候选基因将在遗传杂交中进行测试，以确定它们是否与抗NIHL的QTL在功能上相互作用。将使用基因打靶敲入技术测试疑似解释QTL的基因的核苷酸差异，以确定它们是否足以将NIHL耐药性转移到另一种菌株。对影响NIHL抗性的基因的表征将为深入了解噪声诱导的耳蜗损伤的细胞和分子过程提供基础。反过来，这些洞察力将是设计有效策略以保护人类群体听力的关键。

DESCRIPTION (provided by applicant): Noise-induced hearing loss (NIHL) and age-related hearing loss (AHL or presbycusis) are major health problems. They are common, their consequences are permanent, and their impacts on human communication and quality of life are significant. Although important advances have been made in characterizing the structural changes in the ear that are associated with NIHL or AHL, the mechanisms underlying these changes are poorly understood. In humans, hearing loss secondary to noise exposure is highly variable between individuals: some people have "tough" ears, while others have "tender" ears. In contrast to humans, laboratory mice show significantly less variability in NIHL among individuals within an inbred strain while there are striking differences in NIHL sensitivity between different inbred strains. Our long-term goal is to exploit these strain differences in mouse models to study the genetic factors influencing resistance and susceptibility to NIHL Here we propose to focus on the remarkable NIHL resistance observed in the inbred mouse strain 12986/SvEvTac (129S6). We will address the following Specific Aims: SA 1. Refine and confirm our preliminary Quantitative Trait Locus (QTL) map for NIHL resistance in 129S6. Develop a second NIHL-resistance QTL map in a different mouse strain, MOLF/Ei for comparison. SA 2: Generate congenic strains using both phenotype-driven selection for NIHL resistance and genotype-driven, marker-assisted selection for QTL regions. Isolated QTL regions will be tested for epistatic interactions. SA 3. Identify candidate NIHL resistance genes using DNA microarrays to study changes in gene expression after noise exposure. Genes differentially regulated between strains and mapping within QTL regions will be sequenced in both strains and compared for variations. SA 4. Strong candidate genes will be tested in genetic crosses to determine whether they interact functionally with the NIHL-resistant QTL. Nucleotide differences in genes suspected to account for the QTL will be tested using gene targeting knock-in techniques to see if they are sufficient to transfer NIHL resistance to another strain. The characterization of genes influencing NIHL resistance will provide fundamental insight into the cellular and molecular processes underlying noise-induced cochlear damage. In turn, these insights will be key to devising effective strategies to preserve hearing in human populations.