Genetics of Noise Resistance

描述（由申请人提供）：噪声性听力损失（NIHL）和年龄相关性听力损失（阿勒或老年性耳聋）是主要的健康问题。它们是常见的，其后果是永久性的，对人类交流和生活质量的影响是巨大的。虽然在表征与NIHL或阿勒相关的耳结构变化方面取得了重要进展，但对这些变化的机制知之甚少。在人类中，继发于噪声暴露的听力损失在个体之间存在很大差异：有些人的耳朵“坚韧”，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个体之间NIHL的变异性显着降低，而不同近交系之间的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。在此，我们建议将重点放在近交系小鼠品系12986/SvEvTac（129 S6）中观察到的显著NIHL抗性上。我们将讨论以下具体目标：SA 1。优化并确认我们初步构建的129 S6 NIHL抗性QTL图谱。在不同的小鼠品系MOLF/Ei中开发第二个NIHL抗性QTL图谱用于比较。SA 2：使用NIHL抗性的表型驱动选择和QTL区域的基因型驱动、标记辅助选择生成同源菌株。将测试分离的QTL区域的上位相互作用。SA 3.使用DNA微阵列识别候选NIHL抗性基因，以研究噪声暴露后基因表达的变化。将对两种菌株中在菌株之间差异调节的基因和QTL区域内的定位进行测序，并比较变异。SA 4.将在遗传杂交中测试强候选基因，以确定它们是否与NIHL抗性QTL在功能上相互作用。将使用基因靶向敲入技术测试怀疑解释QTL的基因中的核苷酸差异，以查看它们是否足以将NIHL抗性转移到另一种菌株。影响NIHL抗性的基因的表征将为噪声诱导的耳蜗损伤的细胞和分子过程提供基本的见解。反过来，这些见解将是制定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.