The interaction effects of genetic variants, age, diet, sex and mitochondrial copy number on Alzheimer's disease, aging-phenotypes and longevity

遗传变异、年龄、饮食、性别和线粒体拷贝数对阿尔茨海默病、衰老表型和寿命的相互作用

• 批准号: 10367582
• 负责人: David George Ashbrook
• 金额: $ 49.14万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367582
• 关键词: Address; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Behavioral; Bioinformatics; Biological Assay; Biological Markers; Biological Models; Biology; Blood; Candidate Disease Gene; Cell physiology; Cognition; Cognitive; Collection; Complex; DNA; DNA copy number; Data; Data Set; Databases; Diet; Disease; Environment; Etiology; Family; Fatty acid glycerol esters; Future; Generations; Genes; Genetic; Genetic Engineering; Genetic Variation; Genome; Health; High Fat Diet; Hippocampus (Brain); Human; Human Genome; Impaired cognition; Inbreeding; Individual; Internet; Intervention; Kidney; Learning; Link; Liver; Liver Mitochondria; Longevity; Measures; Mediating; Memory; Metabolic; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Motor; Mouse Strains; Mus; Muscle; Outcome; Outcome Measure; Outcome Study; Pathogenicity; Performance; Peripheral; Phenotype; Population; Process; Proteome; Proxy; QTL Genes; Quantitative Trait Loci; Reactive Oxygen Species; Recombinants; Reproducibility; Research Proposals; Sampling; Services; Severity of illness; Sex Differences; Skin; System; Testing; Tissues; Transgenes; Transgenic Organisms; Translating; Variant; Whole Organism; Work; age effect; age related; biobank; cell type; clinical application; cognitive performance; cohort; data integration; endophenotype; familial Alzheimer disease; functional decline; gene environment interaction; genetic analysis; genetic resource; genetic variant; genome wide association study; genome-wide; genomic locus; healthy aging; improved; metabolome; mouse model; novel; novel therapeutic intervention; phenome; precision medicine; sex; success; trait; transcriptome sequencing; web site

As the average age of the population increases, understanding the biology of longevity and diseases of aging is increasingly important. The key role of mitochondria in Alzheimer’s disease (AD) and pathogenic aging has been established in studies across species and mechanistically validated using genetically engineered models. Mitochondrial DNA copy number (mtDNAcn) changes with age and diet, in various tissues, and across species. Higher mtDNAcn is associated with better health outcomes in aging and with increased longevity, while decreased mtDNAcn is linked to disorders of aging including AD. However, we do not understand the mechanistic interaction between genetic variants, mtDNAcn, diet, sex, aging and AD. Here we propose to identify gene-by-environment interactions (GxE) that link mtDNAcn to AD- and aging- relevant phenotypes already collected in the recombinant inbred BXD and transgenic AD-BXD mouse lines, including longevity, memory, learning, motor, and neuroanatomical phenotypes. In Aims 1 and 2, we will test GxE, and identify loci underlying these interactions in three “peripheral” (skin, blood, muscle) and three “central” (liver, kidney, hippocampus) tissues. We will use previously gathered tissue from 45 BXD strains between 6- and 24-months old that had been fed either standard chow or high-fat diet, and quantify mtDNAcn. In Aim 3, we will identify relationships between mtDNAcn, age, sex and the familial AD transgenes (5XFAD), using tissue already collected from the AD-BXD. As part of Aims 2 and 3, we will re-produce a subset of the above strains and carry out analysis of mitochondrial function and reactive oxygen species generation to determine the link between mtDNAcn and mitochondrial function across tissues. In Aim 4, we will integrate our generated data with extensive behavioral data on age-related cognitive and other behavioral and CNS changes generated from BXD and AD-BXD. This will allow us to define loci, candidate genes, and mechanisms of AD and longevity and to systematically test for associations with age, sex, diet, and linked changes in mitochondrial DNAcn or function. Finally, we will integrate previously generated -omics data that we have for BXD and other genomes (e.g., RNA-seq, meth-seq, metabolomes and proteomes) with data from large human AD and mtDNAcn GWASs, and other existing -omics data. All results will be shared openly using robust internet services—Mouse Phenome Database, GeneNetwork, etc. Data and workflows will be FAIR-compliant. Key deliverables are far more quantitative, unbiased, global, and replicable data on genetic, molecular, and environmental processes that act with mitochondria to mediate cognitive loss, AD and longevity. We will also deliver causal molecular and mechanistic models that incorporate realistically high levels of genetic diversity— 6 million DNA variants. This work empowers in-depth, unbiased analyses of age-related functional decline that translates to human populations. Success will provide a platform in which to test novel interventions in this genomically- and environmentally- replicable population — so called “experimental precision medicine”.

随着人口的平均年龄增加，了解寿命的生物学和衰老的疾病 越来越重要。线粒体在阿尔茨海默氏病（AD）和致病性衰老中的关键作用具有 在跨物种的研究中建立，并使用基因工程进行机械验证 型号。线粒体DNA拷贝数（mTDNACN）随着年龄和饮食的不同而变化， 跨物种。较高的mtdnaCn与衰老的健康状况更好，并且随着增加而增加 长寿的同时下降了mtdnaCn，与包括AD在内的衰老障碍有关。但是，我们没有 了解遗传变异，MTDNACN，饮食，性别，衰老和AD之间的机械相互作用。这里 我们建议确定将mtdnaCn与AD和衰老相关的基因相互作用（GXE） 已经收集的表型已经收集在重组的近交BXD和转基因AD-BXD小鼠系中，包括 寿命，记忆，学习，运动和神经解剖表型。在目标1和2中，我们将测试GXE，并 在三个“外围”（皮肤，血液，肌肉）和三个“中央”（肝脏， 肾脏，海马组织。我们将在6-和6和6之间的45个BXD菌株中使用以前收集的组织 24个月大的年龄，已被喂食标准食物或高脂饮食，并量化mtdnaCn。在AIM 3中，我们 将使用组织确定MTDNACN，年龄，性别和家庭广告翻译（5xFAD）之间的关系 已经从AD-BXD收集。作为目标2和3的一部分，我们将重新生产上述菌株的子集 并进行线粒体功能和活性氧的产生分析以确定联系 在组织之间的mtdnaCn和线粒体功能之间。在AIM 4中，我们将整合生成的数据 借助与年龄相关的认知和其他行为和中枢神经系统变化产生的广泛行为数据 来自BXD和AD-BXD。这将使我们能够定义局部，候选基因以及AD的机制和 寿命并系统地测试与年龄，性别，饮食和线粒体的连接变化的关联 DNACN或功能。最后，我们将集成以前生成的 - 摩学数据，我们为BXD和其他 基因组（例如RNA-seq，Meth-Seq，代谢组和蛋白质组），并带有来自大型人类AD的数据 mtdnacn gwass和其他现有的 - 摩学数据。所有结果将使用强大的互联网公开共享 服务 - Mouse现象数据库，GenEnetwork等。数据和工作流程将是合理的。钥匙 可交付成果更具定量性，无偏见，全球和可复制的数据，有关遗传，分子和分子 用线粒体起作用的环境过程可以介导认知损失，AD和寿命。我们也会 提供因果分子和机械模型，这些模型结合了现实水平的遗传多样性 - 600万个DNA变体。这项工作使对年龄相关功能下降的深入，无偏分析 这转化为人口。成功将提供一个测试新颖干预措施的平台 这种在基因组和环境上可复制的人群 - 所谓的“实验精确医学”。