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: 10679265
• 负责人: Ran Blekhman
• 金额: $ 39.96万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10679265
• 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 定植在人体内的微生物群落的组成在不同的环境中有很大的差异。 个体和种群，并已与许多主机性状和疾病。虽然 微生物组受环境因素的影响，一个强大的宿主遗传因素也有望控制微生物组。 人类和微生物之间的相互作用。了解遗传和环境的相对作用 宿主-微生物组相互作用中的因子是人类疾病研究的中心目标。然而，我们非常了解 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 对人类复杂疾病的影响。通常很难把遗传和环境对人类的影响区分开来。 微生物组，研究仅考虑单个时间点的微生物组，这可能是有问题的， 微生物组可以在日常生活中以及在个体的一生中发生显著变化。此外，由于大多数 微生物组研究确定了相关性，但我们不知道个体间和群体间的差异如何影响微生物组。 微生物组的组成影响宿主的生理。 在这份提案中，我概述了一个长期的研究战略，以解决这些关键的知识差距。 我实验室的研究是基于这样的假设，即微生物组可以被认为是一种数量性状， 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， 个体宿主基因和由微生物组调控的途径。在这里，我概述了我的实验室的研究 未来五年的计划，旨在回答有关宿主遗传基础的基本问题， 微生物组相互作用通过三个广泛的，互补的项目领域，旨在：（1）收集和整合宿主 和微生物组基因组数据，以实现对宿主微生物组分子的系统级理解 结肠中的相互作用;（2）描述结肠中终生纵向微生物组动态的遗传性 灵长类动物模型系统;和（3）使用新的体外和离体系统来理解间- 微生物组中的群体变异对宿主基因调控的影响，并描述潜在的调控机制。 机制 拟议的研究计划将提供一个系统级的分子间相互作用的看法， 肠道中的宿主基因和微生物分类群、基因和途径;微生物组如何 动态和类群是由宿主遗传变异控制的;和机制的描述， 微生物调节宿主基因。这些结果将改变我们对 人类基因组学和微生物组，解释了这种相互作用如何影响疾病， 开发基于微生物组的治疗和诊断方法，改善人类健康。