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群体基因组学 定植于人体的微生物群落的组成在不同地区差异很大 个体和人群，并与许多宿主特征和疾病有关。虽然 微生物群受到环境因素的影响，强大的宿主遗传因素也有望控制 人类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的中心目标。然而，我们非常清楚 关于控制人类与微生物组之间相互作用的基因组因素及其影响知之甚少 关于复杂的人类疾病。通常很难将遗传与环境对基因的影响区分开来。 微生物组，并且研究仅考虑单个时间点的微生物组，这可能是有问题的 微生物组每天以及在人的一生中可能会发生巨大变化。此外，正如大多数 微生物组研究确定了相关性，但我们不知道个体间和人群间的差异如何 微生物组的组成影响宿主的生理机能。 在本提案中，我概述了一项长期研究策略，以解决这些关键的知识差距。研究 在我的实验室中，基于微生物组可以被视为数量性状的假设，因此我们可以 直接绘制控制微生物组变异的宿主基因组因子，并识别个体宿主 受微生物组调节的基因和途径。在这里，我概述了我的实验室的研究计划 未来五年，旨在回答有关宿主微生物组遗传基础的基本问题 通过三个广泛的、互补的项目领域进行互动，旨在：(1) 收集和整合主办方和 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理解 在结肠中； (2) 表征灵长类动物模型中终生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群体间变异的影响 微生物组对宿主基因的调控并描述潜在的调控机制。 拟议的研究计划将提供宿主之间分子相互作用的系统级视图 肠道中的基因和微生物分类群、基因和通路；微生物组动力学和 类群受宿主遗传变异控制；以及微生物作用机制的描述 调节宿主基因。这些结果将改变我们对人类基因组学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，并将促进微生物组的发展 基于改善人类健康的治疗和诊断。