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

基本信息

批准号：
10633162
负责人：
Royce Ellen Clifford
金额：
$ 79.72万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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

项目摘要

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.

老年人的跌倒相关伤害带有20％的死亡率，这是第六个主要原因该人群的死亡。前庭受体与年龄相关的功能障碍系统与这些老年跌倒高度相关，与年龄相关的重生是与几乎所有类型的前庭细胞有关。这项研究的总体目标是分析人和小鼠全基因组关联研究（GWAS），前庭特异性人和小鼠基因组表达和前庭系统特定位点的单细胞测序，然后测试在实验室中鉴定出的基因和相关途径。我们的目标是表征基因组学与年龄相关的失衡有关，以进行未来的预防和治疗。中心假设是通过此分析，我们可以确定与平衡系统相关的解剖和生理位点这对这两个物种都是常见的。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测试和最终治疗干预的相关基因和途径。建立在老年瀑布上的一个小gwas，与人类DCC和PTK2基因相关的同一途径相关正如DCC在混合小鼠多样性面板（HMDP）GWAS中确定的那样，我们的具体目标将是： 1）a。基于头晕/瀑布表型在大型荟萃分析中以头晕/跌倒表型进行gwas 数据集; b。基于行为和重力传感器功能表型的小鼠的GWA HMDP; 2）a。对小鼠和人类手术的前庭组织进行RNA测序标本； b。单个组织上的单细胞RNA-seq； c。比较确定的基因和通过计算方法评估从小鼠到人的途径的翻译的途径平衡系统； 3）使用AIM 2中定义的顶级候选者进行功能测试敲除/敲门小鼠。该项目的多次创新包括：1）重力的第一个GWA 老年小鼠和老年人的受体功能，2）综合基因目录以及与种间比较有关的前庭功能变化涉及的途径，作为一部分公平（可找到，可访问，可互操作，可重复使用）合规性，3）鼠标中的体内验证模型和对这些候选人的分析，以及4）未来的潜力用于靶向疗法。我们的结果是平衡系统的第一个比较GWA 在动物模型和人类之间。这项工作的影响将是为对平衡系统的有针对性治疗的发展，以减少老年人的跌倒。