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: 10471926
• 负责人: Royce Ellen Clifford
• 金额: $ 80.11万
• 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/10471926
• 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; gene network; 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.

老年人中与跌倒有关的伤害死亡率为20%，是第六大主要原因 在这群人中的死亡。前庭重力感受器的增龄性功能障碍 系统与这些老年跌倒高度相关，显著的与年龄相关的退行性变 几乎与所有类型的前庭细胞有关。这项研究的总体目标是分析 前庭特异的人和小鼠全基因组关联研究 基因组表达，以及前庭系统特定位置的单细胞测序，然后 测试确定了实验室中的基因和相关途径。我们的目标是描述基因组学 与年龄相关的失衡，为今后的预防和治疗提供参考。中心假设是 通过这种分析，我们可以确定与平衡系统相关的解剖和生理位置 这对两个物种来说都是共同的。我们的理由是，通过这种分析，我们可以更好地专注于 实验室检测和最终治疗干预的相关基因和途径。建立在 人DCC和PTK2基因在同一途径中的相关性 正如DCC在杂交小鼠多样性小组(HMDP)GWAS中确定的那样，我们的具体目标将是： 1)a.在一项大型临床试验的荟萃分析中，根据头晕/跌倒的表型，对人类进行GWA 数据集；b.基于小鼠的行为和重力传感器功能表型的GWARs HMDP；2)a.对小鼠和人类外科手术的前庭组织进行RNA测序 样本；b.单个组织上的单细胞RNA-Seq；c.比较已鉴定的基因和 通过计算方法评估从老鼠到人类的通路的翻译 平衡系统；以及3)使用以下工具对目标2中定义的顶级候选对象执行功能测试 敲除/敲入老鼠。该项目的多项创新包括：1)第一个重力地球空间分析 老年小鼠和老年人类的受体功能，2)全面的基因目录 以及通过物种间比较参与前庭功能变异的途径，作为 公平(可发现、可访问、可互操作、可重复使用)依从性，3)小鼠体内验证 模型和对现有人类队列中这些候选对象的分析，以及4)未来的潜力 进行靶向治疗。我们的结果是平衡系统的第一个可比较的GWA 动物模型和人类之间的关系。这项工作的影响将是为 开发有针对性的平衡系统治疗，以减少老年人跌倒。