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: 10468839
• 负责人: Rick A Friedman
• 金额: $ 38.3万
• 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/10468839
• 关键词: 1 year old; Affect; Age; Age-Years; Aging; Animal Model; Auditory; Auditory Brainstem Responses; Auditory system; Biological Models; Candidate Disease Gene; Chromatin; Chromosome Mapping; Cochlea; Cochlear Implants; Complex; Data; Dementia; Economic Burden; Elderly; Epithelial; Epithelial Cells; 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; Research; Resolution; Resources; Risk; Severities; Single Nucleotide Polymorphism; Standardization; Structure; Therapeutic Intervention; Tissues; Twin Studies; Ultrafine; United States; Variant; XCL1 gene; base; 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; 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.

项目概要/摘要 年龄相关性听力障碍 (ARHI) 是听力损失的最常见原因，具有遗传性，是听力损失之一 影响全球老年人的最普遍疾病。双胞胎和家庭研究显示 25-75% ARHI 的遗传力（Momi 等，2015）。据估计，大约三分之二的人年龄超过 美国有 70 人经历过 ARHI，到 2020 年，超过一半的美国人患有 ARHI 听力损失将在 70 岁以上发生（Bainbridge 和 Wallhagen，2014）。 ARHI 已被证明 与认知能力下降、痴呆、抑郁和孤独独立相关，并导致 估计年度经济负担超过 30 亿美元（Deal 等人，2017 年；Deal 等人，2018 年；Lin 和 Albert，2014 年）。 我们的总体假设是，ARHI 是一种由小鼠和人类的初步数据支持的假设。 与许多可能相关基因的复杂性状（Fransen 等人，2015；Friedman 等人，2009；Kalra 等人，2019； 威尔斯等人，2019）。已鉴定出超过 100 个与单基因耳聋相关的基因；然而，一个 相当一部分 ARHI 患者在任何已知的耳聋基因中都没有可识别的突变，这表明 仍有其他基因有待发现（Bowl 和 Dawson，2018）。 小鼠仍然是听力研究的主要生物体。听觉结构的相似之处 以及小鼠和人类之间的生理学，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重要模型系统 系统（Bowl 和 Dawson，2015）。我们建议通过执行第一个操作来识别候选基因 CFW 小鼠中 ARHI 的完整全基因组关联研究 (GWAS) 并检查基因表达 内耳。尽管包括我们在内的几个实验室已经使用人类受试者进行 GWAS，但迄今为止还没有 具有足够能力的全面特征队列，因此存在有限的复制 候选基因的研究。在目标 1 中，我们将测量听觉脑干反应和失真产物 2000 只一岁 CFW 小鼠的耳声发射阈值在雄性和雌性中均等。 我们将在目标 2 中对每只小鼠进行超过 1,000,000 个单核苷酸多态性标记的基因分型 执行 GWAS 来识别数量性状位点 (QTL)。在目标 3 中，我们将使用 RNAseq 来评估 从 CFW 队列中随机选择 100 只小鼠的内耳中的基因表达，并定义表达 QTL (eQTL)。CFW 小鼠内的遗传变异为阐明分子生物学提供了独特的机会。 ARHI 背后的机制为药物开发提供了新的靶标，并提供了一种手段 识别有风险的患者。