Deconstructing how the microbiota influences the mucosal innate immune system

描述（由申请人提供）：本研究提案描述了一个为期5年的指导研究项目，其目标是了解肠道细菌如何影响肠道先天免疫系统。这个项目将建立在首席研究员在微生物学，粘膜免疫学和传染病的背景。成功完成研究项目将使主要研究者获得所需的技能 以确保独立的资金和过渡到一个独立的医生，科学家谁继续专注于主机之间的相互作用和免疫系统的关系。综合职业发展计划中详细说明的教学和实践培训相结合，将为主要研究者提供宿主-细菌关系方面的增强背景，大型数据集分析和解释方面的培训（例如，下一代测序和基因表达谱数据），并增加了与gnotobiotic小鼠合作的经验。拟议的研究将在哈佛医学院丹尼斯·卡斯珀博士的实验室进行，他是研究肠道细菌和宿主免疫之间界面的世界领导者;研究工作将受益于哈佛社区内丰富的科学资源和众多在与拟议工作相关的所有领域具有专业知识的同事。该研究旨在鉴定新型免疫调节细菌。尽管半个多世纪以来人们都知道，人体内的微生物比宿主细胞多10倍，对于宿主免疫系统的正常发育至关重要，但迄今为止只鉴定出4种具有免疫调节特性的微生物;所有这些例子都特异性地影响适应性免疫系统。该提案旨在使用一种新的策略，即共同饲养细菌和肠道免疫系统成熟状态不同的gnotobiotic小鼠，以生物信息学方式鉴定能够调节先天免疫反应的细菌。克隆排列的、分类学定义的培养物收集物将来自相关小鼠品系，并将允许验证这些寄生生物的免疫调节作用。最后，基因表达谱和免疫表型实验将表征这些细菌诱导的免疫学变化。最终，这些实验将揭示微生物群和先天免疫系统之间的相互作用，并深入了解卫生假说的真实性。此外，特异性免疫调节细菌的鉴定为各种炎症性疾病（如炎症性肠病、关节炎和多发性硬化症）提供了新疗法的潜力。

DESCRIPTION (provided by applicant): This research proposal describes a 5-year mentored research project that has the goal of understanding how commensal bacteria impact the intestinal innate immune system. This project will build upon the principal investigator's background in microbiology, mucosal immunology, and infectious diseases. Successful completion of the research project will enable the principal investigator to gain the skills needed to secure independent funding and transition into an independent physician-scientist who continues to focus on the nexus between host-commensal interactions and the immune system. A combination of didactic and practical training detailed in the comprehensive career development plan will provide the principal investigator with an enhanced background in host-bacterial relationships, training in the analysis and interpretation of large datasets (e.g., next-generation sequencing and gene expression-profiling data), and increased experience working with gnotobiotic mice. The proposed research will take place at Harvard Medical School in the laboratory of Dr. Dennis Kasper-a world leader in studying the interface between commensal bacteria and host immunity; the research work will benefit from the availability within the Harvard community of abundant scientific resources and numerous colleagues with expertise in all fields related to the proposed work. The proposed research aims to identify novel immunomodulatory commensal bacteria. Although it has been known for more than half a century that commensal organisms-which are 10 times more abundant than host cells in the human body-are critical for proper development of the host immune system, only 4 commensal bacteria with immunomodulatory properties have been identified thus far; all of these examples affect the adaptive immune system specifically. This proposal aims to use a novel strategy of co-housing gnotobiotic mice that differ in their bacteria and the maturation state of their intestinal immune system to bioinformatically identify bacteria that are able to modulate innate immune responses. Clonally arrayed, taxonomically defined culture collections will be derived from relevant mouse strains and will allow the immunomodulatory effects of these commensal organisms to be validated. Finally, gene expression-profiling and immunophenotyping experiments will characterize the immunological changes induced by these bacteria. Ultimately, these experiments will shed light on the interplay between the microbiota and the innate immune system and offer insight into the veracity of the hygiene hypothesis. Moreover, identification of specific immunomodulatory bacteria offers the potential of novel therapies for a variety of inflammatory conditions, such as inflammatory bowel disease, arthritis, and multiple sclerosis.