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：
8602516
负责人：
Rick A Friedman
金额：
$ 39.64万
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/8602516
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 public health relevance 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. PUBLIC HEALTH RELEVANCE: There is evidence in both mice and humans that there is a heritable component to noise-induced hearing loss (NIHL). 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 the genetic analysis of strain variation using high-resolution mapping strategies. The primary aim of this study is to comprehensively define loci that contribute to this variation using novel and straight-forward methodologies. 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，总人口的大约10％每天暴露于工作场所中的危险水平（国家职业安全与健康研究所，///www.cdc.gov/niosh/）。慢性冲动噪声（亚音速）或突然的爆炸暴露（超音速）受到耳蜗造成的损害导致了永久性和使人衰弱的听力损失和耳鸣。急需暴露前诊断和靶向疗法的发展。人双胞胎研究的估计表明，噪声引起的听力丧失（NIHL）约为36％，尽管已经进行了几项NIHL的候选基因关联研究。由于难以找到足够大小的符合特征的人群，每个人都缺乏动力。在解剖学和遗传学上，小鼠和人内耳之间的相似性，以及表型中已知的应变变化，使小鼠成为基因发现的理想模型。在此应用中，我们提出了两个具体的目的，以识别具有对NIHL敏感的基因和途径。我们的压倒性假设是，在小鼠的近交菌株中，存在与分子机制和对NIHL敏感性的遗传变异。这项研究的主要目的是全面定义使用基因组标记的小鼠（目标1A）有助于这种变化的基因座，使用混合小鼠多样性面板（AIM 1B）对相同和附加基因群进行高分辨率映射（AIM 1B）（AIM 1B），并将其与共同的转录水平集成到模型和确定生物学网络和确定Causal veriants（AIMS 1C和2C）。本申请中描述的实验的发现将构成在人类种群中进行检验的假设的基础。公共卫生相关性：在小鼠和人类中都有证据表明，噪声引起的听力损失（NIHL）有一个可遗传的组成部分。在解剖学和遗传上，小鼠和人内耳之间的相似性，再加上表型中已知的应变变化，使小鼠成为理想的模型，使用高分辨率映射策略对应变变异的遗传分析。这项研究的主要目的是全面定义使用新颖和直率的方法来促进这种变化的基因座。本申请中描述的实验的发现将构成在人类种群中进行检验的假设的基础。