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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

基本信息

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
项目类别：
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

项目摘要

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