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

基本信息

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
项目类别：
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

项目摘要

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常见表现，最终影响沟通和交流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性听力损失 (ARHL) 的难以捉摸的分子途径人类，以促进我们对这种情况的了解、延迟或预防。我们的方法将是开采和剖析先前在两个欧洲人群中发现的与人类 ARHL 相关的 51 个变异列表，这是迄今为止进行的最大的全基因组关联研究（GWAS）。我们的中心假设 ARHL 变体和相关基因可以分为功能网络。在这里，我们建议从影响基因的一种变体开始识别这些功能网络之一我们拥有专业知识，称为 LOXHD1。 LOXHD1 在毛细胞中表达，毛细胞是感觉细胞内耳能够将声音引起的力转化为电流，这是一个过程这就是所谓的机械传导。我们发现 LOXHD1 是机械传导过程所必需的本身位于成熟的毛细胞中。由于基因和机制具有很强的进化保守性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，以促进我们了解其人类直系同源物的致病性。在具体目标 1 中，我们将确定衰老小鼠突变体 Loxhd1R1064Q 的听觉表型，其中模拟人类 ARHL 变体，并确定 LOXHD1 蛋白与耳蜗毛细胞中的机械传导通道。通过完成这一目标，我们期望定义以下方式：其中 LOXHD1R1090Q 会增加人类对 ARHL 的易感性。在具体目标 2 中，我们将确定 ARHL LOXHD1 变异是否会增加动物对环境侵害的影响，例如噪音，以及它是否会加速耳朵的老化过程。我们将确定在存在噪声损伤恢复期间毛细胞的转录程序野生型或 ARHL 变体。在具体目标 3 中，我们将使用生物化学来验证直接的 LOXHD1 假定相互作用因子，该相互作用因子也对应于 ARHL 基因。我们将使用抗体测试它们的定位是否受到 LOXHD1 缺陷的影响并标记敲入小鼠。总的来说，我们期望将人类 ARHL 基因的第一个子集连接到一个功能网络中。我们未来的工作将旨在定义其他基因子集，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。