High-Resolution Mapping of Susceptibility Genes for NIHL

描述（由申请人提供）：在美国，大约10%的总人口每天在工作场所暴露在危险水平的噪音中（国家职业安全与健康研究所，//www.cdc.gov/NIOSH/）。慢性脉冲噪声（亚音速）或突然爆炸（超音速）对耳蜗造成的损害导致永久性和衰弱性听力丧失和耳鸣。迫切需要暴露前诊断和开发靶向治疗。来自人类双胞胎研究的估计表明噪音性听力损失（NIHL）的遗传率约为36%，尽管已经进行了一些NIHL的候选基因关联研究，但是；由于难以找到足够规模的特征明确的队列，每种方法都缺乏有效性。小鼠和人类内耳在解剖学和遗传学上的相似性，加上已知的表型变异，使小鼠成为基因发现的理想模型。在这个应用程序中，我们提出了两个特定的目标，以确定基因和途径赋予NIHL的易感性。我们最重要的假设是，在近交系小鼠中存在与NIHL易感性的分子机制和途径相关的遗传变异。本研究的主要目的是使用基因组标记小鼠（Aims 1a）全面定义导致这种变异的基因座，使用杂交小鼠多样性面板（aim 1b）对相同和额外的基因座进行高分辨率定位，并将其与耳蜗转录物水平相结合，以模拟生物网络并识别因果变异（Aims 1c和2）。本应用程序中描述的实验结果将构成在人群中进行测试的假设的基础。

DESCRIPTION (provided by applicant): In the United States, roughly 10% of the total population is exposed to hazardous levels of noise in the workplace on a daily basis (National Institute for Occupational Safety and Health, //www.cdc.gov/NIOSH/). The damage sustained by the cochlea from chronic impulse noise (subsonic) or sudden blast exposure (supersonic) leads to permanent and debilitating hearing loss and tinnitus. Pre-exposure diagnostics and the development of targeted therapies are sorely needed. Estimates from human twin studies suggest heritability for noise induced hearing loss (NIHL) of approximately 36% and although several candidate gene association studies for NIHL have been conducted, however; each lacks power due to the difficulties in finding well-characterized cohorts of sufficient size. The similarities, both anatomically and genetically, between the mouse and human inner ears, coupled with the known strain variation in phenotypes, makes the mouse an ideal model for gene discovery. In this application we propose two specific aims to identify genes and pathways that confer susceptibility to NIHL. Our overriding hypothesis is that among inbred strains of mice there are genetic variants relevant to the molecular mechanisms and pathways underlying susceptibility to NIHL. The primary aim of this study is to comprehensively define loci that contribute to this variation using Genome-Tagged Mice (Aims 1a), to perform high-resolution mapping of the same and additional loci using a Hybrid Mouse Diversity Panel (Aim 1b) and to integrate this with cochlear transcript levels to model biologic networks and identify causal variants (Aims 1c and 2). The findings from the experiments described in this application will form the basis for hypotheses to be tested in human populations.