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.

概括 听力逐渐丧失是衰老的普遍体现，最终影响了交流和 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 了解导致年龄相关听力损失（ARHL）的难以捉摸的分子途径 人类，以促进我们对理解，延迟或防止这种情况。我们的方法是矿山 剖析与以前在两个欧洲人群中确定的人类ARHL相关的51种变体的列表， 代表迄今为止进行的最大全基因组关联研究（GWAS）。我们的中心假设 是否可以将ARHL变体和相关基因分组到功能网络中。在这里，我们 提议从一个影响基因的变体开始，识别其中一个功能网络 我们拥有专业知识，称为loxhd1。 loxhd1在毛细胞中表达，这些细胞是 能够将声音诱导的力转换为电流的内耳，一个过程 这称为机械转导。我们发现机械转导过程需要LoxHD1 本身在成熟的毛细胞中。由于基因和机制的强烈进化保护 参与哺乳动物的听力，我们假设ARHL错义变体LOXHD1R1090Q可以 在小鼠中进行建模，以促进我们对其人类直系同源物的致病性的理解。 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，该表型 模仿人Arhl变体，并确定LoxHD1蛋白的定位以及 耳蜗细胞中的机械转导通道。通过完成此目标，我们希望定义 loxhd1r1090q提高了人类对ARHL的敏感性。 在特定目标2中，我们将确定ARHL LOXHD1变体是否增加了 动物会受到环境侮辱，例如噪声，以及它是否加速了耳朵的老化过程。我们 将在存在下确定毛细胞在噪声损伤恢复期间的转录程序 野生型形式或ARHL变体。 在特定的目标3中，我们将使用生物化学来验证直接的loxhd1推定交互作用者 对应于ARHL基因。我们将测试使用抗体的LOXHD1缺乏症影响其本地化是否受到影响 并标记为敲门鼠。 总体而言，我们希望将人类ARHL基因的第一个子集连接起来。我们未来的工作 旨在定义基因的其他子集，以获取欧洲人口中ARHL的全部图片，然后 将此方法扩展到其他人群。