Contact-dependent interbacterial responses modulate intestinal colonization by Bacteroides species

项目摘要/摘要 不同的类杆菌是人类肠道微生物区系的主要组成部分，与许多 疾病过程。在属和种水平上操纵类杆菌具有治疗潜力，但 需要对肠道生态系统有更详细的了解。拟杆菌属基因组编码 多糖利用位点(PUL)，允许酶的分解、膜的运输和利用 复杂的碳水化合物。拟杆菌属在肠道环境中通过传递 通过接触依赖型VI型分泌系统(T6SS)产生的毒性效应器，导致对 殖民主义和坚持不懈。这一建议的中心假设是类杆菌属之间的接触。 导致动态适应性反应，从而改变细胞行为并有助于肠道内的持久性 环境。拟议中的实验将发现接触依赖的蛋白质组反应对 使用尖端蛋白质组学技术的类杆菌群落内的竞争(目标1)。分子 两种已知的接触依赖性反应的机制，改变多糖利用(AIM 2)和T6SS- HCP-效应器融合的介导性传递(目标3)将被阐明并转化为竞争性增长和 诺生菌小鼠模型中的肠道定植。一个长期的研究目标是了解机制 肠道共生菌之间潜在的细菌间相互作用，用于靶向治疗的开发。 这一职业发展奖的候选人是医学博士/博士内科科学家，拥有 解剖和临床病理学。这项拨款申请建议的研究将在 微生物学教授Joseph Mougous和病理学教授Matthew Yeh博士的指导。 应聘者将进入一个拥有充足临床资源的院系，以发展专科 胃肠道病理学方面的专业知识，NIH资助的现有调查人员和研究基础设施，以及 对内科科学家给予大力支持的记录。这位候选人致力于内科医生的事业 并寻求进一步的科学培训。职业发展计划包括参与相关的本地 以及国家会议、高级教学和讲习班，以获得共生细菌学方面的专业知识，建立 研究沟通和授予写作技能，并培养领导和管理技能。这位导师 临床科学家发展奖将促进候选人转变为具有竞争力的NIH资助的 独立调查员。

Project Summary/Abstract The diverse group Bacteroidales is a predominant component of human intestinal microbiota, linked to numerous disease processes. Manipulation of Bacteroidales at the genus and species level holds therapeutic potential, but requires a more detailed understanding of the intestinal ecosystem. Bacteroides spp. genomes encode polysaccharide utilization loci (PUL), allowing enzymatic breakdown, membrane transport, and utilization of complex carbohydrates. Bacteroides spp. antagonize one another within the intestinal environment by delivering toxic effectors via contact-dependent type VI secretion systems (T6SS), resulting in altered capacities for colonization and persistence. The central hypothesis of this proposal is that contact among Bacteroides spp. results in dynamic adaptive responses that alter cellular behavior and contribute to persistence in the intestinal environment. The proposed experiments will discover contact-dependent proteomic responses important for competition within Bacteroides communities using cutting-edge proteomics technology (Aim 1). Molecular mechanisms of two known contact-dependent responses, altered polysaccharide utilization (Aim 2) and T6SS- mediated delivery of hcp-effector fusions (Aim 3), will be elucidated and translated to competitive growth and intestinal colonization in a gnotobiotic mouse model. A long-term research goal is to understand mechanisms underlying interbacterial interactions among intestinal symbionts for the development of targeted therapeutics. The candidate for this career development award is an M.D./Ph.D. physician scientist with board certification in anatomic and clinical pathology. The research proposed in this grant application will be conducted under the mentorship of Dr. Joseph Mougous, Professor of Microbiology, and Dr. Matthew Yeh, Professor of Pathology. The candidate will join faculty in a department with ample clinical resources for development of specialized expertise in gastrointestinal pathology, established NIH-funded investigators and research infrastructure, and a track record of strong support for physician scientists. The candidate is committed to a career as a physician scientist and seeks further scientific training. Career development plans include participation in relevant local and national meetings, advanced didactics and workshops to gain expertise in commensal bacteriology, build research communication and grant writing skills, and develop leadership and management skills. This mentored clinical scientist development award will facilitate the candidate’s transition to become a competitive NIH-funded independent investigator.