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种群基因组学微生物群落的组成有很大差异，使人体定居在个人和人群之间，这种差异与许多宿主特征有关疾病。了解影响这种变化的因素以及这种变异的机制影响宿主特征，是人类疾病研究中的核心目标。虽然微生物组受宿主遗传学的控制，我们对控制的基因组因子知之甚少人与微生物组之间的相互作用及其对复杂人类疾病的影响。解开来自环境影响微生物组的遗传性具有挑战性，微生物组通常在一个时间点，该时间点无法解释微生物组纵向变化。而且，我们的大多数关于宿主 - 微生物组相互作用的知识包括相关关联，我们不知道如何微生物组组成的个体间和人口间变化会影响宿主基因调节。我实验室的研究旨在解决知识中的这些关键差距。我实验室的研究是基于微生物组可以视为定量性状的假设，因此我们可以直接映射主机控制微生物组变异的基因组因子，并鉴定单个宿主基因和由微生物组调节的途径。我的实验室的未来五年研究计划是设计的回答有关宿主 - 微生物组相互作用的基因组基础的基本问题，互补项目领域，旨在：（1）开发计算技术以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 - 微生物组的系统级别的理解人群和疾病状态之间的相互作用；（2）表征功能组件的遗传力微生物组（微生物基因，菌株和途径），并评估终身纵向的影响私人模型系统中宿主生理学的微生物组动力学；（3）使用新颖的体外和前体内了解微生物组中个体间和人口间变化的因果关系的系统宿主基因调节并描述潜在的调节机制。拟议的研究计划将提供有关分子相互作用的系统级别的视图人群，环境和疾病之间的肠道基因和微生物因子；一个特征微生物组纵向动力学以及基因，途径和菌株如何由宿主控制通用的;以及微生物调节宿主基因的机制的描述。这些结果将是改变我们对人类基因组学与微生物组之间相互作用的理解，解释如何互动会影响疾病，并能够开发基于微生物组的治疗和诊断改善人类健康。