The genetics of functional decline in the aging vestibular system: A GWAS and gene expression analysis in aging mice and humans

衰老前庭系统功能衰退的遗传学：衰老小鼠和人类的 GWAS 和基因表达分析

• 批准号: 10275996
• 负责人: Royce Ellen Clifford
• 金额: $ 82.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10275996
• 关键词: Acceleration; Adult; Affect; Age; Aging; American; Anatomy; Animal Disease Models; Animal Model; Atherosclerosis Risk in Communities; Atlases; Behavioral; Biology; Candidate Disease Gene; Catalogs; Cause of Death; Cells; Cerebellum; Cessation of life; Complex; Computational Biology; Computing Methodologies; DCC gene; Data; Data Scientist; Data Set; Development; Discipline; Dizziness; Elderly; Equilibrium; Evoked Potentials; FAIR principles; Force of Gravity; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomics; Goals; Hair Cells; Head; Heritability; Human; Human Genetics; Human Genome; Hybrids; Incidence; Individual; Intervention; Knock-in Mouse; Knock-out; Knowledge; Literature; Measures; Mediating; Meta-Analysis; Methodology; Motion; Mus; Muscle; National Institute on Deafness and Other Communication Disorders; Nerve Fibers; Neurons; Operative Surgical Procedures; Organ; Otolaryngologist; Outcome; PTK2 gene; Pathway Analysis; Pathway interactions; Performance; Pharmacologic Substance; Phenotype; Physiological; Population; Prevention; Prevention therapy; Process; Publications; Purkinje Cells; Quantitative Trait Loci; Reporting; Resources; Rodent Model; Saccule and Utricle; Sensory; Site; Specimen; System; Testing; Therapeutic Intervention; Tissues; Transcriptional Regulation; Translations; Validation; Variant; Vestibular ganglion; Vestibular nucleus structure; Veterans; Women' s Health; Work; age related; aged; base; biobank; cell type; cohort; comparative; effective therapy; fall injury; falls; functional decline; ganglion cell; genetic analysis; genetic architecture; genome wide association study; genomic locus; hereditary hearing loss; human model; human old age (65+); human subject; in vivo; innovation; large datasets; mortality; mouse genome; mouse model; multidisciplinary; programs; receptor; receptor function; response; sensor; single cell sequencing; single-cell RNA sequencing; targeted treatment; trait; transcriptome sequencing; transcriptomics

Fall-related injury in the elderly carries a 20% mortality rate, and is the sixth leading cause of death in this population. Age-related dysfunction of gravity receptors within the vestibular system is highly correlated with these elderly falls, and significant age-related degeneration is associated with nearly all types of vestibular cells. The overarching goal of this study is to analyze human and mice genome-wide association studies (GWAS), vestibular-specific human and mice genomic expression, and single-cell sequencing of specific sites in the vestibular system, then test identified genes and related pathways in the lab. Our objective is to characterize the genomics related to age-related imbalance for future prevention and treatment. The central hypothesis is that by this analysis, we can identify anatomic and physiologic sites relevant to the balance system that is common to both species. Our rationale is that by this analysis, we can better focus on relevant genes and pathways for lab testing and ultimate therapeutic intervention. Building upon a small GWAS on elderly falls that correlated human DCC and PTK2 genes in the same pathway as Dcc identified in the Hybrid Mouse Diversity Panel (HMDP) GWAS, our specific aims will be: 1) a. Perform GWAS in humans based on a dizziness/falls phenotype in a meta-analysis of large datasets; b. GWAS in mice based on a behavioral and gravity sensor function phenotype in the HMDP; 2) a. Perform RNA-Sequencing on vestibular tissues from mice and human surgical specimens; b. Single-cell RNA-Seq on individual tissues; c. Compare identified genes and pathways via computational methods to assess translation of pathways from the mouse to human balance system; and 3) Perform functional testing for the top candidates defined in Aim 2 using knock-out/knock-in mice. Multiple innovations of this project include: 1) the first GWAS of gravity receptor function in aged mice and in elderly humans, 2) a comprehensive catalogue of genes and pathways involved in vestibular functional variation with inter-species comparison, as part of FAIR (findable, accessible, interoperable, reusable) Compliance, 3) in vivo validation in mouse models and an analysis of these candidates in available human cohorts, and 4) future potential for targeted therapies. Our outcome is the first comparative GWAS of the balance system between animal models and humans. The impact of this work will be to lay a firm foundation for development of targeted treatment of the balance system to diminish falls in the elderly.

老年人跌倒相关伤害的死亡率为20%，是第六大原因