Contact-dependent interbacterial responses modulate intestinal colonization by Bacteroides species

项目概要/摘要 不同的类杆菌目是人类肠道微生物群的主要组成部分，与许多肠道菌群相关。 疾病过程。在属和种水平上操纵拟杆菌目具有治疗潜力，但 需要更详细地了解肠道生态系统。拟杆菌属基因组编码 多糖利用位点（PUL），允许酶分解，膜运输和利用 复合碳水化合物拟杆菌属在肠道环境中相互拮抗， 通过接触依赖的VI型分泌系统（T6 SS）的毒性效应，导致改变的能力， 殖民化和持久性。这一建议的中心假设是，拟杆菌属之间的接触。 导致动态适应性反应，改变细胞行为，并有助于在肠道中持续存在 环境拟议的实验将发现接触依赖性蛋白质组反应， 利用尖端的蛋白质组学技术（Aim 1）在拟杆菌群落内进行竞争。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T6 SS- 介导的递送hcp-效应融合物（目的3），将被阐明并转化为竞争性生长， 肠道定植在gnotobiotic小鼠模型。一个长期的研究目标是了解 肠道共生体之间潜在的细菌间相互作用，用于靶向治疗的开发。 这个职业发展奖的候选人是一个医学博士/博士医生科学家与董事会认证， 解剖和临床病理学。这项拨款申请所建议的研究将在 导师Joseph Mougous博士，微生物学教授，和Matthew Yeh博士，病理学教授。 候选人将加入一个拥有充足临床资源的部门，以发展专业 胃肠道病理学的专业知识，建立NIH资助的研究人员和研究基础设施，以及 对医生科学家的大力支持的记录。这位候选人致力于成为一名医生 科学家，并寻求进一步的科学培训。职业发展计划包括参加当地相关的 和国家会议，先进的教学法和讲习班，以获得细菌学方面的专门知识， 研究沟通和赠款写作技巧，并发展领导和管理技能。这一指导 临床科学家发展奖将促进候选人的过渡，成为一个有竞争力的NIH资助 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.