High-Resolution Mapping of Susceptibility Genes for NIHL

NIHL 易感基因的高分辨率图谱

基本信息

批准号：
8725407
负责人：
Rick A Friedman
金额：
$ 44.26万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725407
关键词：
Accounting Biological Biological Models Blast Cell Breeding Candidate Disease Gene Cardiovascular system Cataloging Catalogs Chromosome Mapping Chronic Cochlea Complex Computer Simulation Congenic Mice Coupled Data Databases Development Diagnostic Disease Dissection Exposure to Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Risk Genome Genomics Genotype Hearing problem Heritability Human Hybrids Inbred Strain Inbred Strains Mice Knockout Mice Laboratories Labyrinth Lead Link Maps Metabolic Methodology Methods Modeling Molecular Mus National Institute for Occupational Safety and Health Noise Noise-Induced Hearing Loss Pathway interactions Phenotype Population Predisposition Presbycusis Prevention Quantitative Trait Loci RNA Research Personnel Resolution Resources Susceptibility Gene System Systems Biology Techniques Testing Thinking Time Tinnitus Tissues Transcript Transgenic Organisms Twin Studies United States Validation Variant Workplace base cohort congenic density gene discovery genetic analysis genetic association genetic variant hearing impairment indexing mouse genome mouse model novel research study trait

项目摘要

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.

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/国家职业安全与健康研究所/）。慢性脉冲噪声（亚音速）或突然的爆炸暴露（超音速）对耳蜗造成的损害会导致永久性听力损失和耳鸣。迫切需要暴露前诊断和靶向治疗的开发。人类双胞胎研究的估计表明，噪声性听力损失 (NIHL) 的遗传力约为 36%，尽管已经进行了几项 NIHL 候选基因关联研究；由于很难找到足够规模、特征明确的群体，因此每个人都缺乏力量。小鼠和人类内耳在解剖学和遗传学上的相似性，加上已知的表型应变变异，使小鼠成为基因发现的理想模型。在本申请中，我们提出了两个具体目标来识别导致 NIHL 易感性的基因和途径。我们最重要的假设是，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全面定义导致这种变异的基因座（目标 1a），使用混合小鼠多样性面板（目标 1b）对相同和其他基因座进行高分辨率作图，并将其与耳蜗转录水平相结合以模拟生物网络并识别因果变异（目标 1c 和 2）。本申请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。