Population Genomics of Host-Microbiome Interactions

宿主-微生物组相互作用的群体基因组学

• 批准号: 10289962
• 负责人: Ran Blekhman
• 金额: $ 4.32万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289962
• 关键词: Address; Affect; Area; Binding; Biological Models; Colon; Complex; Development; Diagnostic; Disease; Environmental Risk Factor; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Variation; Genomics; Goals; Health; Heritability; Human; Human Genetics; Human Microbiome; Human body; In Vitro; Individual; Knowledge; Life; Maps; Microbe; Pathway interactions; Physiology; Population; Predisposition; Primates; Research; Role; System; Techniques; Therapeutic; Time; Variant; base; design; gene function; genomic data; gut microbiome; host microbiome; human disease; human genomics; improved; insight; microbial; microbial community; microbial composition; microbiome; microbiome composition; microbiome research; microbiota; novel; programs; trait

Population Genomics of Host-Microbiome Interactions The composition of the microbial communities that colonize the human body varies widely across individuals and populations, and has been associated with numerous host traits and diseases. Although the microbiome is influenced by environmental factors, a strong host genetic factor is also expected to control the interaction between humans and the microbiome. Understanding the relative role of genetic and environmental factors in host-microbiome interactions is a central goal in human disease research. However, we know very little about the genomic factors that control the interaction between humans and the microbiome and their effect on complex human disease. It is often difficult to disentangle genetic from environmental effects on the microbiome, and studies only consider the microbiome in a single time point, which could be problematic given the microbiome can vary dramatically day-to-day and throughout an individual’s life. Moreover, as most microbiome studies identify correlations, we do not know how inter-individual and inter-population variation in microbiome composition affects host physiology. In this proposal, I outline a long-term research strategy to address these critical gaps in knowledge. Research in my lab is based on the hypothesis that the microbiome can be considered a quantitative trait, and thus we can directly map host genomic factors controlling the variation in the microbiome, as well as identify individual host genes and pathways that are regulated by the microbiome. Here, I outline my lab’s research program for the next five years, designed to answer fundamental questions about the genetic basis of host-microbiome interactions via three broad, complementary Project Areas, aiming to: (1) collect and integrate host and microbiome genomic data to achieve a systems-level understanding of host-microbiome molecular interactions in the colon; (2) characterize the heritability of life-long longitudinal microbiome dynamics in a primate model system; and (3) use novel in vitro and ex vivo systems to understand the effect of inter-population variation in the microbiome on host gene regulation and describe the underlying regulatory mechanism. The proposed research program will provide a systems-level view of the molecular interactions between host genes and microbial taxa, genes, and pathways in the gut; a characterization of how microbiome dynamics and taxa are controlled by host genetic variation; and a description of the mechanism with which the microbes regulate host genes. These results would transform our understanding of the interplay between human genomics and the microbiome, explain how this interaction affects disease, and would enable development of microbiome- based therapeutics and diagnostics that improve human health.

宿主 - 微生物组相互作用的种群基因组学 微生物群落的组成，使人体遍布各种各样的人体 个人和人群，并与许多宿主特征和疾病有关。虽然 微生物组受环境因素的影响，强大的宿主遗传因素也有望控制 人与微生物组之间的相互作用。了解遗传和环境的相对作用 宿主 - 微生物组相互作用的因素是人类疾病研究中的核心目标。但是，我们非常知道 关于控制人与微生物组之间相互作用的基因组因素及其影响 关于复杂的人类疾病。通常很难将遗传脱离对环境的影响 微生物组，研究仅考虑一个时间点中的微生物组，这可能是有问题的 微生物组可以每天以及整个人的生活变化。而且，大多数 微生物组研究确定了相关性，我们不知道个人间和人群间的变化 微生物组组成会影响宿主生理。 在此提案中，我概述了一项长期研究策略，以解决知识中的这些关键差距。研究 在我的实验室中，基于以下假设：微生物组可以被视为定量特征，因此我们可以 直接绘制控制微生物组变化的宿主基因组因子，并识别单个宿主 由微生物组调节的基因和途径。在这里，我概述了我的实验室研究计划 接下来的五年，旨在回答有关宿主 - 微生物组遗传基础的基本问题 通过三个宽整个项目领域进行互动，目的是：（1）收集和集成的主机和 微生物组基因组数据，以实现对宿主 - 微生物组分子相互作用的系统级别的理解 在结肠； （2）表征私人模型中终身纵向微生物组动态的遗传力 系统; （3）使用新颖的体外和离体系统来了解人群间变化在 宿主基因调节的微生物组并描述了潜在的调节机制。 拟议的研究计划将为宿主之间的分子相互作用提供系统级别的视图 肠道中的基因和微生物类群，基因和途径；微生物组动力学和 分类单元受宿主遗传变异的控制；并描述了微生物的机制 调节宿主基因。这些结果将改变我们对人类基因组之间相互作用的理解 和微生物组，解释这种相互作用如何影响疾病，并将能够发展微生物组 - 基于改善人类健康的治疗和诊断。