The genetic basis for age-related hearing loss in outbred mice

远交小鼠年龄相关性听力损失的遗传基础

• 批准号: 10685625
• 负责人: Rick A Friedman
• 金额: $ 36.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685625
• 关键词: 1 year old; Affect; Age; Age Years; Aging; Auditory; Auditory Brainstem Responses; Auditory system; Biological Models; Candidate Disease Gene; Chromatin; Chromosome Mapping; Cochlea; Cochlear Implants; Complex; Data; Dementia; Economic Burden; Elderly; Epithelial Cells; Epithelium; Expenditure; Family Study; Farm; Female; Follow-Up Studies; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genotype; Goals; Hearing; Hearing Aids; Heredity; Heritability; Homologous Gene; Housing; Human; Human Genome; Impaired cognition; Inbred Strains Mice; Investments; Labyrinth; Loneliness; Maps; Measures; Medical; Mental Depression; Molecular; Mus; Mutation; Nature; Organism; Pathway interactions; Patients; Persons; Phenotype; Physiology; Polygenic Traits; Population; Presbycusis; Prevention; Quantitative Trait Loci; Random Allocation; Research; Resolution; Resources; Risk; Severities; Single Nucleotide Polymorphism; Standardization; Structure; Therapeutic Intervention; Tissues; Twin Studies; Ultrafine; United States; Variant; XCL1 gene; candidate identification; cohort; cost; deafness; differential expression; drug development; experience; forward genetics; functional genomics; genetic analysis; genetic approach; genetic risk factor; genome wide association study; hearing impairment; hereditary hearing loss; human subject; improved; interest; male; model organism; mouse model; new therapeutic target; novel; otoacoustic emission; phenotypic data; prevent; progressive hearing loss; risk variant; targeted treatment; therapeutic development; trait; transcriptome sequencing

Project Summary / Abstract Age-related hearing impairment (ARHI) is the most common cause of hearing loss, is heritable, and is one of the most prevalent conditions affecting the elderly globally. Twin and family studies reveal 25-75% heritability for ARHI (Momi et al., 2015). Estimates suggest approximately two‐thirds of people over the age of 70 in the United States experience ARHI, and that by 2020, over half of all people in the United States with hearing loss will be over 70 years of age (Bainbridge and Wallhagen, 2014). ARHI has been shown to be independently associated with cognitive decline, dementia, depression, and loneliness and results in an estimated annual economic burden of over $3 billion (Deal et al., 2017; Deal et al., 2018; Lin and Albert, 2014). Our overarching hypothesis, supported by preliminary data in both mice and humans, is that ARHI is a complex trait with many likely genes associated (Fransen et al., 2015; Friedman et al., 2009; Kalra et al., 2019; Wells et al., 2019). Greater than 100 genes have been identified for monogenic deafness; however, a substantial fraction of patients with ARHI have no identifiable mutation in any known deafness gene suggesting that there remain additional genes to discover (Bowl and Dawson, 2018). Mice continue to be the predominant organism for hearing research. Similarities in the auditory structure and physiology between mice and humans, the close evolutionary relationship of genomes (most genes in mice have a human homologue), relatively low housing costs, genetic standardization and the available genetic toolkit make the mouse a crucial model system for the study of the functional genomics of the auditory system (Bowl and Dawson, 2015). We are proposing to identify candidate genes by performing the first complete genome-wide association study (GWAS) of ARHI in CFW mice and examining gene expression in the inner ear. Although several labs including ours have used human subjects for GWAS, to date there exist no comprehensively characterized cohorts with sufficient power and therefore there exist limited replication studies of candidate genes. In Aim 1, we will measure auditory brainstem response and distortion product otoacoustic emission thresholds in 2,000 one-year-old CFW mice equally divided among males and females. We will genotype each mouse at more than 1,000,000 single nucleotide polymorphism markers and in Aim 2 perform GWAS to identify quantitative trait loci (QTL). In Aim 3, we will use RNAseq to assess differences in gene expression in the inner ears of 100 randomly selected mice from the CFW cohort and define expressed QTLs (eQTLs).The genetic variation within CFW mice presents a unique opportunity to elucidate the molecular mechanisms that underlie ARHI providing novel targets for drug development and providing a means for identifying patients at risk.

项目摘要 /摘要 与年龄相关的听力障碍（ARHI）是最常见的听力损失原因，是可遗传的，是一个 最普遍的条件影响了上年的全球。双胞胎和家庭研究显示25-75％ Arhi的遗传力（Momi等，2015）。估计表明大约三分之二的人 70在美国体验了Arhi，到2020年，美国超过一半的人 听力损失将超过70岁（Bainbridge and Wallhagen，2014年）。 Arhi已被证明是 与认知能力下降，痴呆症，抑郁和孤独相关，并导致 估计年度经济燃烧超过30亿美元（Deal等，2017； Deal等，2018； Lin和Albert，2014）。 我们的总体假设在小鼠和人类的初步数据支持下，是Arhi是一个 具有许多可能相关基因的复杂性状（Fransen等，2015; Friedman等，2009; Kalra等，2019; Wells等，2019）。已经确定了100多个基因的单基因死亡。但是， ARHI患者的大部分部分在任何已知的耳聋基因中都没有鉴定突变表明 还有其他基因可以发现（Bowl and Dawson，2018）。 小鼠仍然是听力研究的主要生物。听觉结构的相似之处 小鼠与人之间的生理学，基因组的密切进化关系（大多数基因 小鼠具有人类同源物），相对较低的住房成本，遗传标准化和可用的 遗传工具包使小鼠成为研究听觉功能基因组学的关键模型系统 系统（Bowl and Dawson，2015年）。我们建议通过执行第一个来识别候选基因 CFW小鼠中ARHI的全基因组关联研究（GWAS）并检查基因表达 尽管包括我们在内的几个实验室已经使用了人类主题进行GWAS，但迄今为止没有 总体表征具有足够功率的人群，因此复制有限 候选基因的研究。在AIM 1中，我们将测量听觉的脑干响应和失真产品 2,000只一岁的CFW小鼠的耳声发射阈值在男性和女性之间平均分裂。 我们将以超过1,000,000个单核苷酸多态性标记和AIM 2的基因类型的基因型。 执行GWAS以识别定量性状位置（QTL）。在AIM 3中，我们将使用RNASEQ评估 从CFW队列中随机选择的100只小鼠的内耳中的基因表达并定义了表达 QTLS（EQTLS）。CFW小鼠内的遗传变异为阐明分子提供了独特的机会 Arhi为药物开发提供新颖的目标的机制，并提供了一种手段 确定有风险的患者。