Population Genomics of Host-Microbiome Interactions

宿主-微生物组相互作用的群体基因组学

基本信息

批准号：
10622273
负责人：
Ran Blekhman
金额：
$ 39.95万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2028-07-31
项目状态：
未结题

项目摘要

Population Genomics of Host-Microbiome Interactions There is wide variation in the composition of the microbial communities that colonize the human body across individuals and populations, and this variation has been associated with numerous host traits and diseases. Understanding the factors that influence this variation, and the mechanism by which this variation affects host traits, is of central goal in human disease research. Although some of the variation in the microbiome is controlled by host genetics, we know very little about the genomic factors that control the interaction between humans and the microbiome and their effect on complex human disease. Disentangling genetic from environmental effects on the microbiome is challenging, and the microbiome is usually profiled in a single time point, which doesn’t account for microbiome longitudinal variation. Moreover, most of our knowledge on host-microbiome interactions consists of correlational associations, and we do not know how inter-individual and inter-population variation in microbiome composition affects host gene regulation. My laboratory’s research aims 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. My lab’s research program for the next five years is designed to answer fundamental questions about the genomic basis of host-microbiome interactions via three broad, complementary Project Areas, aiming to: (1) develop computational techniques to integrate microbiome and host genomic data, and apply these methods to achieve a systems-level understanding of host-microbiome interactions across populations and disease states; (2) characterize the heritability of functional components of the microbiome (microbial genes, strains, and pathways) and assess the effect of life-long longitudinal microbiome dynamics on host physiology in a primate model system; and (3) use novel in-vitro and ex-vivo systems to understand the causal effect of inter-individual and 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 factors in the gut across populations, environments, and diseases; a characterization of how microbiome longitudinal dynamics, as well as genes, pathways, and strains are controlled by host genetic; and a description of the mechanism with which 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 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寄生在人体的微生物群落的组成存在很大差异跨个体和群体，这种变异与许多宿主特征和了解影响这种变异的因素以及这种变异的机制。影响宿主特征，是人类疾病研究的中心目标，尽管存在一些变异。微生物组由宿主遗传学控制，我们对控制微生物组的基因组因素知之甚少。人类与微生物组之间的相互作用及其对复杂人类疾病的影响。环境对微生物组影响的遗传具有挑战性，微生物组通常被描述为单个时间点，这并不能解释微生物组的纵向变化。关于宿主-微生物组相互作用的知识由相关关联组成，我们不知道如何微生物组组成的个体间和群体间变异影响宿主基因调控。我实验室的研究旨在解决这些关键的知识差距。假设微生物组可以被视为数量性状，因此我们可以直接绘制宿主图谱控制微生物组变异的基因组因素，以及识别个体宿主基因和我的实验室未来五年的研究计划已设计完成。通过三个广泛的领域回答有关宿主-微生物组相互作用的基因组基础的基本问题，互补的项目领域，旨在：（1）开发计算技术来整合微生物组和宿主基因组数据，并应用这些方法来实现对宿主微生物组的系统级理解 (2) 表征功能成分的遗传力微生物组（微生物基因、菌株和途径）并评估终生纵向影响灵长类动物模型系统中微生物组动力学对宿主生理学的影响；以及（3）使用新颖的体外和离体模型；系统来了解个体间和人群间微生物组变异对宿主基因调控并描述潜在的调控机制。拟议的研究计划将提供分子之间相互作用的系统级视图肠道内不同人群、环境和疾病的宿主基因和微生物因素；研究微生物组纵向动态以及基因、途径和菌株如何受宿主控制遗传；以及微生物调节宿主基因的机制的描述。改变我们对人类基因组学和微生物组之间相互作用的理解，解释这是如何相互作用影响疾病，并促进基于微生物组的治疗和诊断的发展改善人类健康。