Molecular genetics of human age-related hearing loss

人类年龄相关性听力损失的分子遗传学

• 批准号: 10637870
• 负责人: Nicolas Grillet
• 金额: $ 57.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637870
• 关键词: Acceleration; Address; Adult; Affect; Age Months; Aging; Alleles; Animals; Antibodies; Auditory; Biochemistry; Biological Assay; Cell membrane; Cells; Co-Immunoprecipitations; Cochlea; Cochlear Implants; Communication; Complementary DNA; Complex; Data; Defect; Dementia; Development; Disease; Ear; Elderly; Environmental Impact; Environmental Risk Factor; Etiology; European; Exhibits; Exposure to; Future; Genes; Genetic; Genetic Epistasis; Genetic Transcription; Genetic Variation; Genotype; Goals; Hair Cells; Hearing; Hearing Aids; Homeostasis; Human; Human Genetics; Hybrids; Impaired cognition; Impairment; Knock-in; Knock-in Mouse; Labyrinth; Libraries; Link; Lipoxygenase; Mammals; Modeling; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; Mutate; Noise; Organelles; Pathogenicity; Pathology; Pathway interactions; Phenotype; Population; Predisposition; Presbycusis; Process; Proteins; Recovery; Recovery of Function; Reporting; Research; Sensory; Severities; Temporary Threshold Shift; Testing; Variant; Work; Yeasts; auditory pathway; deafness; gene conservation; genetic variant; genome wide association study; hearing impairment; hearing restoration; hereditary hearing loss; humanized mouse; loss of function; mechanotransduction; mouse model; mutant; neurosensory; next generation sequencing; normal hearing; prevent; programs; response; social exclusion; sound; transcriptomics

SUMMARY The gradual loss of hearing is a common manifestation of aging, ultimately affecting communication and leading to social exclusion and cognitive decline in the elderly population. Our long-term research goal is to understand the elusive molecular pathways that are responsible for age-related hearing loss (ARHL) in humans, to promote our understanding of, delay or prevent this condition. Our approach will be to mine and dissect the list of 51 variants associated with human ARHL identified previously in two European populations, which represent the largest genome-wide association study (GWAS) conducted to date. Our central hypothesis is that the ARHL variants and associated genes can be grouped into functional networks. Here, we propose to identify one of these functional networks starting from one variant that affects a gene for which we have expertise, termed LOXHD1. LOXHD1 is expressed in hair cells, which are sensory cells of the inner ear that are capable of transforming the force induced by sound into an electric current, a process that is called mechanotransduction. We found that LOXHD1 is required for the mechanotransduction process itself in mature hair cells. Because of the strong evolutionary conservation of the genes and mechanisms involved in hearing among mammals, we hypothesize that the ARHL missense variant LOXHD1R1090Q can be modeled in mice, to facilitate our understanding of the pathogenicity of its human orthologue. In Specific Aim 1, we will determine the auditory phenotype of the aging mouse mutant Loxhd1R1064Q, which mimics the human ARHL variant, and determine the localization of the LOXHD1 protein together with the mechanotransduction channel in cochlear hair cells. By completing this aim, we expect to define the manner in which LOXHD1R1090Q increases the susceptibility to ARHL in humans. In Specific Aim 2, we will determine whether the ARHL LOXHD1 variant increases the susceptibility of the animals to environmental insults, such as noise, and whether it accelerates the aging process in the ear. We will determine the transcriptional program of hair cells during noise damage recovery in the presence of the wild-type form or the ARHL variant. In Specific Aim 3, we will use biochemistry to validate direct LOXHD1 putative interactors that also correspond to ARHL genes. We will test if their localization is affected by LOXHD1 deficiency using antibodies and tagged knock-in mice. Overall, we expect to connect the first subset of human ARHL genes in a functional network. Our future work will aim to define other subsets of genes to obtain the full picture of ARHL in European populations, and then extend this approach to other populations.

摘要 听力的逐渐丧失是衰老的常见表现，最终影响沟通和 导致老年人口的社会排斥和认知能力下降。我们的长期研究目标是 了解导致老年性耳聋(ARHL)的难以捉摸的分子通路 人类，以促进我们对这种情况的理解，延迟或预防这种情况。我们的方法将是我的和 剖析了之前在两个欧洲人群中发现的与人类ARHL相关的51个变异体的列表， 这是迄今为止进行的最大规模的全基因组关联研究。我们的中心假设 ARHL变异体和相关基因可以组成功能网络。在这里，我们 建议从一个影响基因的变体开始识别这些功能网络中的一个 我们有专业知识，称之为LOXHD1。LOXHD1在毛细胞中表达，毛细胞是 内耳能够将声音感应的力转化为电流，这是一个过程 这被称为机械转导。我们发现LOXHD1在机械转导过程中是必需的 在成熟的毛细胞中。因为基因和机制的进化保守性很强 参与哺乳动物的听力，我们假设ARHL错义变体LOXHD1R1090Q可以 在小鼠身上建立模型，以帮助我们了解其人类同源基因的致病性。 在特定的目标1中，我们将确定老化小鼠突变体Loxhd1R1064Q的听觉表型，该突变体 模拟人类ARHL变异体，并与LOXHD1蛋白一起确定LOXHD1蛋白的定位 耳蜗毛细胞中的机械转导通道。通过完成这一目标，我们期望在以下方面定义方式 哪种LOXHD1R1090Q增加了人类对ARHL的易感性。 在特定的目标2中，我们将确定ARHL LOXHD1变体是否增加了 动物对环境的侮辱，如噪音，以及它是否会加速耳朵的衰老过程。我们 将决定毛细胞在噪声损伤恢复过程中的转录程序 野生型或ARHL变种。 在特定的目标3中，我们将使用生物化学来验证直接的LOXHD1假定的相互作用，也 与ARHL基因相对应。我们将使用抗体来测试它们的定位是否受到LOXHD1缺乏的影响 并标记了敲入鼠。 总体而言，我们希望将人类ARHL基因的第一个子集连接到一个功能网络中。我们未来的工作 将致力于定义其他基因亚集，以获得欧洲人群中ARHL的全貌，然后 将这种方法推广到其他人群。