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
基本信息
- 批准号:10551316
- 负责人:
- 金额:$ 46.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAgeAge MonthsAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease riskBehavioralBioinformaticsBiological AssayBiological MarkersBiological ModelsBiologyBloodCandidate Disease GeneCell physiologyCognitionCognitiveCognitive agingCollectionComplexDNADNA copy numberDataData SetDatabasesDietDiseaseEnvironmentEtiologyFamilyFatty acid glycerol estersFutureGenerationsGenesGeneticGenetic EngineeringGenetic VariationGenomeGenomicsHealthHigh Fat DietHippocampusHumanHuman GenomeImpaired cognitionInbreedingIndividualInternetInterventionKidneyLearningLinkLiverLiver MitochondriaLongevityMeasuresMediatingMemoryMetabolicMethamphetamineMitochondriaMitochondrial DNAModelingMolecularMotorMouse StrainsMusMuscleNeuroanatomyOutcomeOutcome MeasureOutcome StudyPathogenicityPerformancePeripheralPhenotypePopulationProcessProteomeProxyQTL GenesQuantitative Trait LociReactive Oxygen SpeciesRecombinantsReproducibilityResearch ProposalsSamplingServicesSeverity of illnessSex DifferencesSkinSystemTestingTissuesTransgenesTransgenic OrganismsTranslatingVariantWhole OrganismWorkage effectage relatedbiobankcell typeclinical applicationcognitive performancecohortdata integrationempowermentendophenotypefamilial Alzheimer diseasefunctional declinegene environment interactiongene networkgenetic analysisgenetic resourcegenetic variantgenome wide association studygenome-widegenomic locushealthy agingimprovedmetabolomemouse modelnovelnovel therapeutic interventionphenomeprecision medicinesegregationsexsuccesstraittranscriptome sequencingweb site
项目摘要
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”.
随着人口平均年龄的增加,了解长寿的生物学和衰老疾病
线粒体在阿尔茨海默病(AD)和致病性衰老中的关键作用越来越重要。
已在跨物种研究中建立,并使用基因工程进行机械验证
不同组织中线粒体 DNA 拷贝数 (mtDNAcn) 随年龄和饮食的变化而变化。
在不同物种中,较高的 mtDNAcn 与更好的衰老健康结果相关,并且与衰老相关。
长寿,而 mtDNAcn 减少与包括 AD 在内的衰老疾病有关。
了解遗传变异、mtDNAcn、饮食、性别、衰老和 AD 之间的机制相互作用。
我们建议确定将 mtDNAcn 与 AD 和衰老相关的基因与环境相互作用 (GxE)
已在重组近交 BXD 和转基因 AD-BXD 小鼠系中收集的表型,包括
长寿、记忆力、学习力、运动力和神经解剖学表型 在目标 1 和 2 中,我们将测试 GxE,以及
确定三个“外周”(皮肤、血液、肌肉)和三个“中枢”(肝脏、
我们将使用之前从 6 至 6 岁之间收集的 45 个 BXD 菌株的组织。
已喂食标准食物或高脂肪饮食的 24 个月大的动物,并在目标 3 中量化 mtDNAcn。
将利用组织识别 mtDNAcn、年龄、性别和家族性 AD 转基因 (5XFAD) 之间的关系
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生成的分析以确定其中的联系
在目标 4 中,我们将整合生成的数据。
产生与年龄相关的认知和其他行为和中枢神经系统变化的广泛行为数据
来自 BXD 和 AD-BXD,这将使我们能够定义 AD 和 AD 的基因座、候选基因和机制。
长寿并系统地测试与年龄、性别、饮食和线粒体相关变化的关系
最后,我们将整合之前生成的 BXD 和其他组学数据。
基因组(例如 RNA-seq、meth-seq、代谢组和蛋白质组)以及来自大型人类 AD 和
mtDNAcn GWAS 和其他现有组学数据所有结果将使用强大的互联网公开共享。
服务——小鼠表型组数据库、基因网络等。数据和工作流程将符合 FAIR 关键。
可交付成果是关于遗传、分子和生物多样性的更加定量、公正、全球性和可复制的数据。
与线粒体作用介导认知丧失、AD 和长寿的环境过程。
提供包含实际高水平遗传多样性的因果分子和机制模型 -
这项工作能够对与年龄相关的功能衰退进行深入、公正的分析。
这将转化为人类群体的成功将为测试新的干预措施提供一个平台。
这种基因组和环境可复制的群体——所谓的“实验精准医学”。
项目成果
期刊论文数量(0)
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{{ truncateString('David George Ashbrook', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 46.2万 - 项目类别:
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