RII Track-4:NSF: Determining the Functional Consequences of Co-adaptation Between Host and Gut Microbiota Across Closely Related Host Species

该研究基础设施改进第4轨EPSCoR研究员（RII第4轨）项目将为内布拉斯加大学林肯分校的助理研究教授提供奖学金。这项工作将与华盛顿大学的研究人员合作进行。 存在于动物内脏中的细菌影响着宿主的广泛特性。这些包括他们的消化，代谢，免疫，疾病，甚至行为。然而，目前对一组健康的肠道细菌的了解相对较少。此外，这些集合如何随着它们的增长而在每个主机中构建也不为人所知。随着时间的推移，细菌已经适应了它们的宿主动物物种。适应实验室小鼠的细菌比来自其他小鼠物种的细菌更容易在实验室小鼠的肠道中生长。因此，这些细菌有一个主场优势。目前尚不清楚在其他小鼠物种中是否存在相反的情况。该项目将产生新的工具来研究宿主-细菌关系，包括与广泛使用的实验室小鼠密切相关的全新无菌小鼠。适应每种小鼠品系的细菌之间的竞争将显示这些动物如何适应它们的细菌。将特别注意宿主免疫系统如何对每组细菌做出反应，以及非适应性细菌是否会导致小鼠健康状况恶化。了解细菌和宿主如何相互适应，对于通过肠道治疗改善健康至关重要。 该项目将提高内布拉斯加大学的Gnotobiotic小鼠项目的能力，并增强内布拉斯加州和中西部地区的研究能力。众所周知，肠道微生物群对宿主的新陈代谢、免疫发育、行为和许多其他特征产生巨大影响。微生物和微生物群多年来相互适应，物种具有不同的细菌种群分布。然而，由于缺乏适当的模式生物，包括除实验室品系小家鼠外的无菌小家鼠物种，限制了研究宿主及其常驻微生物群之间适应和相互作用的分辨率。该项目的目标是确定宿主-微生物群的共适应性，这些共适应性影响肠道中微生物种群的组装并改变宿主发育。这个研究基础设施改善轨道-4 EPSCoR研究员（RII轨道-4）项目将提供奖学金，在内布拉斯加州林肯大学的助理研究教授。这项工作将与华盛顿大学的研究人员合作进行。该奖学金将在无菌小鼠再衍生技术方面对PI进行培训，并产生他们的第一种资源，即无菌Mus spicilegus（鼩 鼱小鼠）和Mus pahari（草原小鼠），这两种小鼠与实验室小鼠密切相关。它还将产生关于宿主和微生物之间适应性的关键数据，这些数据定义了微生物如何在肠道群落中组装以及宿主免疫反应如何受到这些细菌的影响。新的无菌小鼠品系将通过无菌剖腹产小鼠生产产生。新的小鼠模型将用同种（来自相同小鼠物种）和异种（来自替代小鼠物种）微生物群重建，以评估适应的细菌是否胜过非适应物种。分析由那些细菌训练的宿主免疫应答以确定由对那些细菌的应答驱动的宿主炎症的变化。了解这些基本的微生物-宿主相互作用及其机制为肠道微生物组的最终治疗改变提供了强有力的理由。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

This Research Infrastructure Improvement Track-4 EPSCoR Research Fellows (RII Track-4) project will provide a fellowship to an Assistant Research Professor at the University of Nebraska-Lincoln. This work will be conducted in collaboration with researchers at the University of Washington. The bacteria that reside in the guts of animals affect a wide range of host traits. These include their digestion, metabolism, immunity, disease, and even behavior. However, there is relatively little current understanding of what a healthy set of gut bacteria looks like. In addition, how these sets are built in each host as they grow is also not well known. Over time, bacteria have adapted to their host animal species. Lab mouse-adapted bacteria grow more easily in the gut of lab mice than bacteria that come from other mouse species. So, there is a home-site advantage for these bacteria. It is not known if the opposite is true in other mouse species. This project will generate new tools to look at host-bacteria relationships, including brand new germ-free mice that are closely related to widely-used lab mice. Competition between bacteria adapted to each mouse line will show how these animals adapt to their bacteria. Particular attention will be paid to how the host immune system responds to each set of bacteria and if non-adapted bacteria result in poorer health for the mice. Understanding how bacteria and hosts adapt to each other is vital to improving health via treatment of the gut. This project will advance the University of Nebraska’s Gnotobiotic Mouse program's capabilities and enhance research capacity in Nebraska and the Midwest region.The gut microbiota is known to exert a tremendous influence over host metabolism, immune development, behavior, and many other traits. Hosts and microbiota have adapted to each other over many years, and species have distinct bacterial population profiles. However, a lack of appropriate model organisms, including germ-free Mus species other than the laboratory strain Mus musculus domesticus, has limited the resolution at which research about adaptations and interactions between hosts and their resident microbiota can be addressed. The goal of this project is to determine host-microbiota co-adaptations that affect the assembly of microbial populations in the gut and alter host development. This Research Infrastructure Improvement Track-4 EPSCoR Research Fellows (RII Track-4) project will provide a fellowship to an Assistant Research Professor at the University of Nebraska-Lincoln. This work will be conducted in collaboration with researchers at the University of Washington. This fellowship will train the PI in germ-free mouse rederivation techniques and generate a first-of-their-kind resource, germ-free Mus spicilegus (shrew mouse) and Mus pahari (steppe mouse), two mouse species closely related to laboratory mice. It will also produce critical data on adaptations between hosts and microbes that define how microbes assemble within gut communities and how host immune responses are affected by those bacteria. The new germ-free mouse lines will be generated by sterile cesarean murine births. The new mouse models will be reconstituted with conspecific (from the same mouse species) and heterospecific (from alternate mouse species) microbiota to evaluate whether adapted bacteria outcompete non-adapted species. Host immune responses educated by those bacteria with be analyzed to determine changes in host inflammation driven by responses to those bacteria. Understanding these basic microbe-host interactions and the mechanisms underlying them provides a strong rationale for eventual therapeutic alterations of the gut microbiome.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.