Characterizing human-microbiome interactions via molecular and functional genomic approaches

项目摘要 人体内有多种复杂的微生物生态系统，包括细菌、古细菌、病毒和 真菌-统称为微生物群。微生物群影响人类健康， 各种各样的复杂疾病。因此，了解微生物群是如何在整个 身体非常重要。我的研究项目集中在调查导致 微生物组是人类宿主中微生物组的组成，并确定微生物组如何影响人类健康。 具体来说，我从人类遗传学家的角度来解决这些问题。我把微生物组当作 复杂的性状，并使用人类遗传学方法来了解其遗传基础。最近的工作从 我和其他人揭示了宿主遗传学对粪便微生物组组成的影响。我们的主要差距 然而，对微生物组遗传性的理解仍然存在，我的目标是在我的实验室解决这个问题。比如我们 缺乏对宿主遗传学是否影响直接邻近粘膜表面的微生物群的了解， 潜在的宿主生理机制，以及宿主遗传学是否影响真核生物 病毒、真菌或微生物群中的其他单细胞真核生物，如细菌和古细菌 迄今为止，微生物群的组成一直是焦点。我实验室的研究试图解决这些差距 通过开发和应用微生物组和功能基因组研究方法的组合， 更好地理解宿主与体内微生物群相互作用的生理基础。超过 在接下来的五年里，我将领导三大主题下的项目：（1）确定宿主基因之间的关系 和粘膜细菌和古细菌丰度，（2）鉴定微生物群的非原核成分 与人类基因表达相关，以及（3）确定微生物组与 两个不同的身体部位的宿主特征：肠道和肺。具体来说，我的努力将集中在生理上， 相关采样，包括对来自肺和肠粘膜表面的微生物群进行配对测序， 邻近宿主组织的单细胞RNA-seq。利用这些数据，我将确定单个微生物类群，宿主细胞 类型和宿主途径，对维持健康个体的跨王国相互作用很重要。通过 通过检查两个不同的器官系统，我将识别出宿主共有的和独特的组成部分 组织类型。遗传流行病学方法的应用和体外验证将为遗传学的发展确立方向。 因果关系：微生物群的哪些方面驱动宿主基因表达的变化，反之亦然？ 从我的研究项目的结果将提供深入了解的生理机制， 微生物群的遗传性。最终，这将提高我们对微生物组的宿主控制的理解 并提供对微生物组的哪些元素可以被靶向以获得治疗益处的洞察。

Project Summary The human body hosts multiple complex microbial ecosystems consisting of bacteria, archaea, viruses, and fungi — collectively referred to as the microbiota. The microbiota impact human health and are associated with a wide variety of complex diseases. Therefore, understanding how the microbiota is maintained across the body is of major importance. My research program focuses on investigating the factors responsible for microbiota composition in the human host and determining how the microbiome influences human health. Specifically, I tackle these questions from the perspective of a human geneticist. I treat the microbiome as a complex trait and use human genetic approaches to understand its genetic underpinnings. Recent work from myself and others revealed the effect of host genetics in fecal microbiome composition. Major gaps in our understanding of microbiome heritability remain, however, which I aim to tackle in my lab. For example, we lack an understanding of whether host genetics impacts microbiota directly adjacent to mucosal surfaces, what the underlying host physiological mechanisms are, and whether host genetics influences the eukaryotic viruses, fungi, or other single-cell eukaryotic organisms in the microbiota, as the bacterial and archaeal components of the microbiota have been the focus to date. Research in my lab seeks to address these gaps by developing and applying a combination of microbiome and functional genomic research methods to gain a better understanding of the physiological underpinnings of host-microbiota interactions across the body. Over the next five years I will lead projects under three broad themes: (1) identify relationships between host genes and mucosal bacterial and archaeal abundance, (2) identify non-prokaryotic elements of the microbiota associated with human gene expression, and (3) determine causal relationships between the microbiome and host traits across two distinct body sites: gut and lung. Specifically, my efforts will focus on physiologically relevant sampling, including pairing sequencing of the microbiota from lung and gut mucosal surfaces with single-cell RNA-seq of adjacent host tissues. Using these data, I will identify individual microbial taxa, host cell types, and host pathways important for maintaining cross-kingdom interactions in healthy individuals. By examining two distinct organ systems, I will identify components both shared across and unique to the host tissue type. Application of genetic epidemiological methods and confirmation in vitro will establish direction of causality: Which aspects of the microbiota drive changes in gene expression in the host, and vice versa? Results from my research program will provide insights into the physiological mechanisms that underlie heritability of the microbiota. Ultimately, this will improve our understanding of host control of the microbiome and provide insight into which elements of the microbiome could be targeted for therapeutic benefit.