Deconstructing how the microbiota influences the mucosal innate immune system

描述(由申请人提供)：这项研究提案描述了一项为期5年的指导性研究项目，其目标是了解共生细菌如何影响肠道固有免疫系统。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方面的背景之上。研究项目的成功完成将使首席调查员能够获得所需的技能 确保独立的资金，并转变为一名独立的内科科学家，继续专注于宿主-共生相互作用与免疫系统之间的联系。综合职业发展计划中详述的讲授和实践培训相结合，将使首席调查员在宿主-细菌关系方面有更好的背景，在分析和解释大数据集(例如，下一代测序和基因表达谱数据)方面的培训，并增加与灵知生物素小鼠的工作经验。这项拟议的研究将在哈佛医学院的丹尼斯·卡斯珀博士的实验室进行，他是研究共生细菌和宿主免疫之间相互作用的世界领先者；这项研究工作将受益于哈佛社区内丰富的科学资源和与拟议工作相关的所有领域的众多专业知识同事。这项拟议的研究旨在鉴定新的免疫调节共生菌。尽管半个多世纪以来人们就知道共生生物--它们的数量是人体内宿主细胞的10倍--对宿主免疫系统的正常发育至关重要，但到目前为止，只发现了4种具有免疫调节特性的共生细菌；所有这些例子都专门影响适应性免疫系统。这项提议旨在使用一种新的策略，即共同居住在不同细菌和肠道免疫系统成熟状态的诺生菌小鼠身上，以生物信息识别能够调节先天免疫反应的细菌。克隆排列的、分类定义的培养集合将来自相关的小鼠品系，并将使这些共生生物的免疫调节作用得到验证。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，这些实验将阐明微生物区系和先天免疫系统之间的相互作用，并为卫生假说的真实性提供洞察。此外，特异性免疫调节细菌的鉴定为各种炎症性疾病提供了新的治疗方法的可能性，如炎症性肠病、关节炎和多发性硬化症。

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.