Contact-dependent interbacterial responses modulate intestinal colonization by Bacteroides species

接触依赖性细菌间反应调节拟杆菌属的肠道定植

基本信息

批准号：
10636949
负责人：
Dustin E Bosch
金额：
$ 16.15万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-18 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636949
关键词：
Affect Anatomy Applications Grants Bacteria Bacteriology Bacteroides Bacteroides fragilis Bacteroides thetaiotaomicron Bacteroidetes Board Certification Carbohydrates Cells Clinical Clinical Pathology Coculture Techniques Communication Communities Complex DNA Development Development Plans Diet Disease Doctor of Medicine Doctor of Philosophy Ecosystem Educational workshop Elements Environment Faculty Funding Genome Germ-Free Gnotobiotic Goals Grant Growth Human Immunity Individual Intestines K-Series Research Career Programs Lateral Leadership Link Mannans Mediating Mentored Clinical Scientist Development Award (K08)Mentorship Microbiology Molecular Mus Pathology Physicians Polysaccharides Process Proteins Proteomics Research Research Infrastructure Research Personnel Resource Development Role Scientist Shapes Starch Structural Protein System Technology Testing Therapeutic Toxin Training Translating Transmembrane Transport United States National Institutes of Health Writing Yeasts antagonist bacterial genetics career career development cell behavior experimental study gastrointestinal gut colonization gut microbiota human disease meetings microbiota mouse model novel nuclease professor response skills symbiont targeted treatment

项目摘要

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.

项目摘要/摘要潜水员群菌甲虫是人类肠道菌群的主要成分，与许多人有关疾病过程。在属和物种水平上对拟菌素的操纵具有热势，但需要对肠生态系统有更详细的了解。细菌属。基因组编码多糖利用率（PUL），允许酶促分解，膜传输和利用复杂的碳水合物。细菌属。通过交付在肠道环境中彼此对抗通过接触依赖性型VI分泌系统（T6S）的有毒作用，导致能力改变殖民和持久性。该提议的中心假设是菌孢子菌属之间的接触。导致动态自适应反应改变细胞行为并导致肠道持久性环境。提出的实验将发现接触依赖性蛋白质组学反应对使用最先进的蛋白质组学技术（AIM 1）在细菌社区内部的竞争。分子两种已知接触依赖性响应的机制，多糖的利用率改变（AIM 2）和T6SS- 介导的HCP效应融合融合（AIM 3）的传递将被阐明并转化为竞争性增长和在gnotobiotic小鼠模型中肠道定殖。一个长期的研究目标是了解机制肠道符号之间的潜在无菌互动，以开发靶向治疗。该职业发展奖的候选人是M.D./ph.d。具有董事会认证的物理科学家解剖和临床病理。本赠款申请中提出的研究将根据微生物学教授Joseph Mougus博士和病理学教授Matthew Yeh博士的指导。候选人将加入拥有充足临床资源的部门的教职员工，以开发专业胃肠道病理学的专业知识，已建立的NIH资助的研究人员和研究基础设施以及对物理科学家的强烈支持的记录。候选人致力于从事物理科学家的职业科学家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，高级教学和研讨会，以获得共生细菌学的专业知识，建立研究沟通和授予写作技巧，并发展领导力和管理技能。这很重要临床科学家发展奖将促进候选人的过渡，成为NIH资助的竞争性独立研究者。