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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.

总结