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（由适用提供）：衰老的特征是HealthSpan的差异很大；一些成年人在老年时就变得脆弱，而另一些成年人仍然适合90年代及以后。在动物模型中，缓慢衰老的基因突变也延迟了一组与年龄相关的疾病。我们的长寿和与年龄相关的表型的GWA都确定了基因组广泛且有趣的暗示性关联。许多基因在神经元，免疫学和DNA修复途径中起作用，已知对衰老很重要。但是，尚未阐明遗传关联的因果机制。我们建议使用一种系统生物学方法扩展我们对衰老的遗传研究，以检查健康衰老表型，遗传多态性，基因表达，DNA甲基化和代谢因素之间的关系。 Framingham心脏研究（FHS）参与者的参与者被深深表现出来，包括所有衰老的领域，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，为我们提供了独特的机会，可以扩展我们的GWAS发现，以扩展我们的GWAS发现，以识别与健康的衰老型均质相关的多种概况。该续签应用程序旨在利用“ OMIC”领域的新研究人员团队利用FHS参与者中的这些现有资源。我们假设使用多摩学资源和新颖的综合模型将有助于发现单个基因和基于健康衰老表型的多基因生物网络。我们提出以下特定目的：使用横截面和纵向健康的衰老表型（包括寿命，无发病率生存期，健康衰老指数，抓地力，身体和认知功能的度量），我们提出了以下特定目的：目标1。确定与健康衰老表型相关的mRNA转录；目的2。研究与健康衰老表型有关的全基因组DNA甲基化模式；目的3。研究代谢组标记与健康衰老表型的关联；目标4。在目标1-3中整合基因组和代谢组相关的结果，并确定健康衰老表型的分子机制。使用网络方法在健康衰老表型和OMICS中进行系统整合的结果将有助于鉴定基因的关键集和调节衰老的生物学途径。我们将将来自现有GWA的SNP和Exomephip数据中的SNP纳入确定的基因中。我们既定的合作允许在独立样本中复制调查结果。我们计划将最有望的结果带入动物模型中的未来验证工作。从该提案中获得的知识将阐明重要的机理洞察力对衰老的分子基础。最终，知识可能会导致衰老缓慢的干预措施，并/或确定延迟与年龄相关的疾病的治疗靶标，以使老年人身体健康。

项目成果

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

• 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