Elucidation of Host and Bacterial Factors that Influence Resilience and Robustnes

描述（由申请人提供）：人类肠道的微生物-称为“微生物组”-代表了由500多个物种和100万亿个细胞组成的动态和多样的群落。在过去的十年中，基因组学的进步极大地促进了这种复杂的多物种共生体的表征。已经发现，微生物群中的门级组成变化（其可以由环境、宿主和细菌因素诱导）与人类疾病相关并促进人类疾病。该研究领域的下一个前沿是了解微生物群中潜在的有害变化是如何发生的，以及如何纠正这种变化以治疗疾病。在本文中，我描述了一种系统生物学方法，以确定微生物群鲁棒性（抗扰动）和弹性（从扰动中恢复）的分子和细胞决定因素。指导我的研究计划的首要假设是，细菌和宿主衍生的特性都有助于微生物群的组成完整性。为了解决这个假设，我将采用一个gnotobiotic斑马鱼主机模型系统，是经得起高通量和真实的时间调查主机相关的微生物群落动态。我的目标1将确定一个自然的斑马鱼细菌分离所需的细菌基因抵抗入侵物种的殖民。AIM 2将解决暂时性宿主免疫抑制对微生物群多样性和功能的影响。在AIM 3中，我将研究物种灭绝事件的作用，这可能是抗生素使用的结果，对微生物群的组成和功能。在这项工作中进行的观察将为设计更有效的益生菌和治疗方案提供信息，用于治疗与微生物群致病性改变相关的疾病。

DESCRIPTION (provided by applicant): The microorganisms of the human intestinal tract-known as the 'microbiota'-represent a dynamic and diverse community made up of over 500 species and 100 trillion cells. Advancements in genomics over the last decade have greatly facilitated the characterization of this complex multi-species symbiont. It has been found that phylum-level compositional shifts in the microbiota, which can be induced by environmental, host and bacterial factors, correlate with and promote human disease. The next frontier in this research field is to understand how potentially deleterious shifts in the microbiota occur and how such shifts might be corrected to treat disease. Herein I describe a systems biology approach to identify molecular and cellular determinants of microbiota robustness (resistance to perturbation) and resilience (recovery from perturbation). The overarching hypothesis guiding my research plan is that both bacteria and host-derived properties contribute to the compositional integrity of the microbiota. To address this hypothesis, I will employ a gnotobiotic zebrafish host model system that is amenable to high-throughput and real time investigation of host-associated microbial community dynamics. AIM 1 of my proposal will identify bacterial genes within a natural zebrafish bacterial isolate required to resist the colonization of an invasive species. AIM 2 will address the consequences of temporary host immunosuppression on the diversity and function of the microbiota. And in AIM 3 I will investigate the role of specie extinction events, which can be a consequence of antibiotic use, on the composition and function of the microbiota. Observations made during this work will inform the design of more effective probiotic and therapeutic regimes for treating diseases associated with pathogenic alterations of the microbiota.