Genetics of Noise Resistance

描述（由申请人提供）：噪音性听力损失（NIHL）和年龄相关性听力损失（AHL或老年性听力损失）是主要的健康问题。它们很常见，其后果是永久性的，它们对人类交流和生活质量的影响是重大的。尽管在描述与NIHL或AHL相关的耳部结构变化方面取得了重要进展，但这些变化的机制尚不清楚。在人类中，噪音引起的听力损失因人而异：有些人的耳朵“坚硬”，而另一些人的耳朵“柔软”。与人类相比，实验室小鼠在近交系内的NIHL个体之间的变异性显着降低，而不同近交系之间NIHL敏感性存在显着差异。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抗性和易感性的遗传因素。在这里，我们建议重点研究在近交系小鼠12986/SvEvTac （129S6）中观察到的显著的NIHL抗性。我们将解决以下具体目标：SA 1。完善并确认初步的129S6 NIHL抗性QTL图谱。在不同的小鼠品系MOLF/Ei中建立第二个nihl抗性QTL图谱进行比较。SA 2：利用表型驱动的NIHL抗性选择和基因型驱动的QTL区域标记辅助选择产生同源菌株。将对分离的QTL区域进行上位性相互作用测试。SA) 3。利用DNA微阵列技术鉴定候选NIHL抗性基因，研究噪声暴露后基因表达的变化。菌株之间的基因差异调控和QTL区域内的定位将在两个菌株中测序并比较差异。SA) 4。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 QTL在功能上相互作用。将使用基因靶向敲入技术检测被怀疑导致QTL的基因的核苷酸差异，看看它们是否足以将NIHL抗性转移到另一个菌株上。影响NIHL抗性的基因特征将为噪声诱导耳蜗损伤的细胞和分子过程提供基本的见解。反过来，这些见解将是设计有效策略以保护人类听力的关键。

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.