Genetics of Noise Resistance

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， 问题它们是常见的，其后果是永久性的，其对人类的影响 沟通和生活质量很重要。尽管在这方面取得了重要进展， 表征与NIHL或阿勒相关的耳结构变化， 对这些变化的根本原因知之甚少。 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： 有些人的耳朵很“坚韧”，有些人的耳朵很“软”。与人类相比，实验室小鼠表现出显著的 近交系内个体间NIHL变异性较小，而NIHL差异显著 不同自交系之间的敏感性。我们的长期目标是利用小鼠的这些品系差异， 研究影响NIHL抗性和易感性的遗传因素的模型 在这里，我们建议把重点放在显着的NIHL抗性观察近交系小鼠品系 12986/SvEvTac（129S6）。我们将讨论以下具体目标：SA 1。优化并确认我们的 初步构建了129 S6的NIHL抗性QTL图谱。开发第二个NIHL- 在不同小鼠品系MOLF/Ei中的抗性QTL图谱用于比较。SA 2：生成同源菌株 利用表型驱动的NIHL抗性选择和基因型驱动的标记辅助选择 QTL区域。将测试分离的QTL区域的上位相互作用。SA 3.确定候选NIHL- 利用DNA微阵列研究噪声暴露后基因表达的变化。基因 在两个菌株中，将对菌株之间的差异调节和QTL区域内的定位进行测序 并比较变化。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NIHL抗性QTL在功能上相互作用。基因中的核苷酸差异被怀疑 将使用基因靶向敲入技术测试QTL的解释，以确定它们是否足以 将NIHL抗性转移到另一个菌株。 影响NIHL抗性的基因的表征将提供对细胞免疫的基本见解。 以及噪音引起的耳蜗损伤的分子过程。反过来，这些见解将是关键， 制定有效的策略来保护人类的听力。

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.