Project 3: Systems Biology Multi-Omic Studies Of Healthy Aging In Companion Dogs

项目 3：伴侣犬健康衰老的系统生物学多组学研究

• 批准号: 10440340
• 负责人: Daniel Edward Promislow
• 金额: $ 87.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440340
• 关键词: Accounting; Address; Affect; Age; Age Factors; Aging; Animal Model; Biochemical; Biological; Biological Assay; Biological Clocks; Biological Markers; Biological Models; Biology of Aging; Canis familiaris; Collaborations; Companions; Complex; Data; Dependence; Development; Diagnosis; Diagnostic; Disease; Drosophila genus; Elements; Environment; Environmental Risk Factor; Epigenetic Process; FarGo; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Health Status; Human; Human Microbiome; Individual; Internet; Intervention; Invertebrates; Lead; Link; Longevity; Maps; Measures; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Network-based; Pathway interactions; Pharmacology; Phenotype; Population; Prevention; Process; Research; Research Personnel; Resolution; Risk Factors; Role; Shapes; System; Systems Biology; Technology; Testing; Translating; Variant; Work; age effect; age related; base; biological systems; burden of illness; chromatin modification; clinically relevant; computerized tools; diagnostic tool; economic cost; epigenetic variation; epigenome; epigenomics; genome wide association study; healthy aging; human disease; improved; metabolome; metabolomics; microbiome; microbiome research; mortality; multiple omics; novel; programs; small molecule; social; tool; trait; transcriptome; translational potential

PROJECT 3: SYSTEMS BIOLOGY MULTI-OMIC STUDIES OF HEALTHY AGING IN COMPANION DOGS ABSTRACT Aging is an extremely complex phenotype, involving many genes and a large array of environmental factors. Moreover, these determinants of aging do not operate independently but rather interact through a complex and highly intertwined web of molecular processes and functional pathways. To fully understand how genetic and environmental variation lead to variation in aging and age-related disease, one must therefore incorporate these processes and pathways to create a more comprehensive, biologically realistic genotype-environment- phenotype map. Until now, genome-wide association studies in human populations have explained little of the substantial natural variation in lifespan and other age-related phenotypes. This Project aims to address this challenge, using the companion dog as a powerful new model of aging, and focusing on several key mechanisms linking genetic and environmental factors to aging phenotypes. Specifically, three key biological domains — the metabolome, the microbiome, and the epigenome — will be explored in a set of three complementary Specific Aims. Preliminary work by the investigators, whose combined expertise spans all three domains, and by other researchers, suggests that these domains represent important functional layers through which genetic and environmental variation shapes downstream phenotypic variation in aging and in age-related disease. To systematically characterize the role of these intermediate functional layers, each of the three domains will be rigorously assayed on an unprecedented scale, using state-of-the-art high-throughput `omic' technologies. By combining data from each -omic domain with ancillary information on genetic, environmental, and age-related phenotypic variation, and working closely with the other Cores and Projects of this P01, this Project will identify molecular elements that are affected by genetic and environmental factors, and which, in turn, are associated with age-related phenotypes. Such analyses will pinpoint specific functional pathways connecting genetic and environmental variation to phenotypic variation in aging. Finally, in a fourth Specific Aim, all three -omic domains will be integrated using novel systems biology and network-based approaches to construct a comprehensive, predictive, multi-omic model of aging in natural populations. Notably, this Project's focus on functional domains and the proposed multi-omic, systems level analysis, go far beyond classical genotype-phenotype associations, mapping functional pathways through which genetics and environment impact aging. Combined, the four Specific Aims of this project will therefore not only facilitate the discovery of new aging biomarkers, but will also provide an improved mechanistic understanding of the aging process, ultimately leading to an analytical, clinically relevant model that can improve prediction, diagnosis, treatment, and prevention of age-related disease in dogs. Importantly, findings that arise from this research also have high translational potential, given that dogs and humans share a common environment, disease burden and attendant risk factor of age.

项目3：伴犬健康衰老的系统生物学多组学研究 摘要 衰老是一种极其复杂的表型，涉及许多基因和大量的环境因素。 此外，衰老的这些决定因素不是独立运行的，而是通过复杂的 分子过程和功能途径的高度交织的网络。为了充分了解基因和基因 环境的变化会导致衰老和与年龄相关的疾病的变化，因此必须将 这些过程和途径创造了一个更全面的、生物上真实的基因环境-- 表型图谱。到目前为止，对人类群体的全基因组关联研究还很少解释 寿命和其他与年龄相关的表型有很大的自然差异。本项目旨在解决这一问题 挑战，将伴犬作为一种强大的衰老新模式，并重点关注几个关键 将遗传和环境因素与衰老表型联系起来的机制。具体地说，三个关键的生物学 新陈代谢组、微生物组和表观基因组这三个领域将被分成三组进行研究。 互补的具体目标。调查人员的初步工作，他们的综合专业知识涵盖了所有 由其他研究人员提出的三个领域表明，这些领域代表着重要的功能层 通过遗传和环境变异形成下游的表型变异，在衰老和 与年龄相关的疾病。为了系统地描述这些中间功能层的作用，每个 将使用最先进的高吞吐量在前所未有的规模上对三个域进行严格分析 “体裁”技术。通过将来自每个基因组领域的数据与关于遗传的辅助信息相结合， 与环境和年龄相关的表型变异，并与其他核心和项目密切合作 这个P01，这个项目将识别受遗传和环境因素影响的分子元件， 而这反过来又与年龄相关的表型有关。这样的分析将精确地定位特定的功能 将遗传和环境变异与衰老中的表型变异联系起来的途径。最后，在第四个 具体目标是，所有三个组学领域将使用新的系统生物学和基于网络的 构建自然人口老龄化的综合性、预测性、多组学模型的方法。值得注意的是， 这个项目的重点是功能领域和拟议的多组学、系统层次分析，远远超出了 经典的基因型-表型关联，绘制遗传学和表型的功能途径 环境影响老化。因此，该项目的四个具体目标加在一起，不仅将有助于 新的衰老生物标志物的发现，但也将提供对衰老的更好的机制理解 过程，最终导致一个分析性的，临床相关的模型，可以改善预测，诊断， 治疗和预防狗的年龄相关疾病。重要的是，这项研究的发现 也有很高的翻译潜力，因为狗和人类共享一个共同的环境，疾病 年龄负担和随之而来的危险因素。