High-Resolution Mapping of Susceptibility Genes for NIHL

描述(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)或突然冲击波暴露(超音速)对耳蜗所造成的损害会导致永久性和衰弱的听力损失和耳鸣。暴露前的诊断和靶向治疗的发展是迫切需要的。来自人类双胞胎研究的估计表明，噪声性听力损失(NIHL)的遗传率约为36%，尽管已经进行了几项与NIHL相关的候选基因研究，但由于难以找到足够大小的特征良好的队列，每一项研究都缺乏力量。小鼠和人类内耳在解剖学和遗传学上的相似性，加上已知的菌株表型差异，使小鼠成为基因发现的理想模型。在这项申请中，我们提出了两个特定的目标，以确定赋予NIHL易感性的基因和途径。我们压倒一切的假设是，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。这项研究的主要目的是利用基因组标记的小鼠(目标1a)全面定义导致这种变异的基因座，使用杂交小鼠多样性小组(目标1b)对相同和额外的基因座进行高分辨率定位，并将其与耳蜗转录水平结合起来，以建立生物网络模型并确定因果变异(目标1c和2)。本申请中描述的实验结果将为假设在人类群体中进行测试奠定基础。

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.