Novel multi-omics approach to the biology of healthy aging: Framingham Study

健康衰老生物学的新颖多组学方法：弗雷明汉研究

• 批准号: 9118529
• 负责人: Kathryn L Lunetta
• 金额: $ 47.38万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118529
• 关键词: Adult; Age; Aging; Alleles; Amino Acid Metabolism Pathway; Animal Model; Area; Biology; Citric Acid Cycle; Code; Cognition; Collaborations; Communities; DNA Methylation; DNA Repair Pathway; DNA Sequence Alteration; Data; Disease; Elderly; Framingham Heart Study; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic study; Genome; Genomics; Genotype; Goals; Hand; Health; Heritability; Human; Immune; Individual; Intervention; Knowledge; Lead; Longevity; Measures; Messenger RNA; Metabolic; Modeling; Molecular; Morbidity - disease rate; Muscle; Neurons; Oxidative Stress; Participant; Pathway interactions; Phenotype; Physical Function; Research Personnel; Resources; Sampling; Single Nucleotide Polymorphism; Site; Systems Biology; Transcript; Validation; Variant; Work; age related; base; cardiovascular disorder risk; cognitive function; differential expression; epigenome; fatty acid oxidation; gene function; genetic association; genome wide association study; genome-wide; grasp; healthy aging; improved; indexing; insight; interest; lipid metabolism; metabolomics; methylation pattern; novel; parent grant; repaired; therapeutic target; trait

 DESCRIPTION (provided by applicant): Aging is characterized by wide variation in healthspan; some adults become frail in early old age while others remain fit into their 90s and beyond. In animal models, genetic mutations that slow aging also delay a diverse set of age-related diseases. Our GWAS of longevity and age-related phenotypes have identified both genome- wide significant as well as interesting suggestive associations. Many genes function in neuronal, immune, and DNA repair pathways known to be of importance to aging. However, the causal mechanisms underlying the genetic associations have not been elucidated. We propose to use a systems biology approach to extend our genetic studies of aging to examine the relationships among healthy aging phenotypes, genetic polymorphisms, gene expression, DNA methylation, and metabolic factors. Framingham Heart Study (FHS) participants are deeply phenotyped including all domains of aging and have dense genotyping, gene expression (mRNA), DNA methylation, and state-of-the-art metabolomics data providing us with the unique opportunity to extend our GWAS findings to identify multi-omic profiles associated with healthy aging phenotypes. This renewal application seeks to leverage these existing resources in FHS participants using new teams of accomplished investigators in the areas of "omics". We hypothesize that using multiple-omics resources and novel integrative models will facilitate discovery of single genes and multi-gene biologic networks underpinning healthy aging phenotypes. Using cross-sectional and longitudinal healthy aging phenotypes from our parent grant (including longevity, morbidity-free survival, healthy aging index, grip strength, measures of physical and cognitive function) we propose the following specific aims: Aim 1. To identify mRNA transcripts associated with healthy aging phenotypes; Aim 2. To investigate genome-wide DNA methylation patterns in relation to healthy aging phenotypes; Aim 3. To investigate the association of metabolomic markers with healthy aging phenotypes; Aim 4. To integrate the results of the genomic and metabolomics associations in Aims 1- 3 and to identify molecular mechanisms underlying healthy aging phenotypes. Systematically integrating results across healthy aging phenotypes and Omics using network approaches will facilitate identification of key sets of genes and biologic pathways regulating aging. We will incorporate SNPs from existing GWAS and Exomechip data in the identified genes. Our established collaborations permit replication of findings in independent samples. We plan to take the most promising results on to future validation work in animal models. The knowledge gained from this proposal will elucidate important mechanistic insights into the molecular basis of aging. Ultimately the knowledge may lead to interventions to slow aging, and/or to identification of therapeutic targets to delay age-related disease so that older adults may enjoy good health.

 描述(申请人提供)：老龄化的特点是健康寿命变化很大；一些成年人在早年变得虚弱，而另一些成年人在90多岁或更高的时候仍然健康。在动物模型中，延缓衰老的基因突变也会延缓一系列与年龄相关的疾病。我们对长寿和与年龄相关的表型的GWA已经确定了全基因组的显着关联以及有趣的提示关联。许多基因在神经元、免疫和DNA修复途径中发挥作用，这些途径对衰老至关重要。然而，潜在的遗传关联的因果机制尚未阐明。我们建议使用系统生物学的方法来扩展我们对衰老的遗传学研究，以检查健康的衰老表型、遗传多态、基因表达、DNA甲基化和代谢因素之间的关系。弗雷明翰心脏研究(FHS)的参与者具有包括衰老所有领域的深度表型，并具有密集的基因分型、基因表达(MRNA)、DNA甲基化和最先进的代谢组学数据，这为我们提供了独特的机会，使我们能够扩展我们的GWAS发现，以确定与健康衰老表型相关的多组学特征。这一续签申请寻求利用FHS参与者的这些现有资源，使用在“组学”领域的新的经验丰富的调查团队。我们假设，使用多组学资源和新的整合模式将有助于发现支持健康衰老表型的单基因和多基因生物网络。利用我们父母GRANT的横截面和纵向健康衰老表型(包括长寿、无病存活、健康衰老指数、握力、身体和认知功能的测量)，我们提出了以下具体目标：目的1.鉴定与健康衰老表型相关的mRNA转录本；目的2.研究全基因组DNA甲基化模式与健康衰老表型的关系；目的3.研究代谢组标志物与健康衰老表型的关系；目的4.整合目标1-3中基因组和代谢组学的研究结果，并识别健康衰老表型的分子机制。使用网络方法系统地整合健康衰老表型和OMICS的结果将有助于识别调节衰老的关键基因和生物途径。我们将把现有的GWAs和Exomecip数据中的SNPs整合到已识别的基因中。我们已建立的合作关系允许在独立样本中复制研究结果。我们计划将最有希望的结果应用到未来的动物模型验证工作中。从这一提议中获得的知识将阐明对衰老的分子基础的重要机制见解。最终，这些知识可能会导致采取干预措施来延缓衰老，和/或确定治疗目标，以延缓与年龄相关的疾病，从而使老年人可以享受良好的健康。

项目成果

Cross-sectional relations of whole-blood miRNA expression levels and hand grip strength in a community sample.

在社区样本中，全血miRNA表达水平和手握力的横截面关系。

• DOI: 10.1111/acel.12622
• 发表时间: 2017-08
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Murabito JM;Rong J;Lunetta KL;Huan T;Lin H;Zhao Q;Freedman JE;Tanriverdi K;Levy D;Larson MG
• 通讯作者: Larson MG