The role of host-derived reactive oxygen species in the outgrowth of Escherichia coli during non-infectious colitis
非感染性结肠炎期间宿主衍生的活性氧在大肠杆菌生长中的作用
基本信息
- 批准号:9909963
- 负责人:
- 金额:$ 3.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Anaerobic BacteriaAnimal ModelAntibioticsAutomobile DrivingBacteriaBiological ModelsBiological ProcessBystander EffectCell RespirationChemical ModelsChemicalsColitisCommunicationCommunitiesCytochromesDNA DamageDataDevelopmentDiseaseDoctor of PhilosophyEnterobacteriaceaeEnzymesEpithelial CellsEscherichia coliExhibitsFamilyFoundationsGastrointestinal tract structureGene Expression RegulationGenetic ModelsGoalsGrowthHospitalsIn VitroInflammationInflammatoryInflammatory Bowel DiseasesLaboratoriesLipidsMeasuresMentorsMetabolic PathwayMetabolismMetagenomicsMicroelectrodesModelingMolecularMucositisMusNADPNADPH Oxidase 1OutcomeOxidantsOxidasesOxygenPathogenesisPathway interactionsPatientsPeroxidesPhagocytesPiroxicamPlayPopulationProcessProductionProteinsRNAReactionReactive Oxygen SpeciesRegulationRelapseReporterResearchResearch PersonnelRespiratory BurstRoleSchoolsSodium Dextran SulfateSourceStainsSuperoxide DismutaseSystemTechnical ExpertiseTechnologyTestingTherapeuticTrainingUniversitiesWorkantimicrobialbacterial geneticsbactericidebasecareer developmentcatalasedysbiosisexperienceexperimental studyfitnessgastrointestinal epitheliumgut microbesgut microbiotahost-microbe interactionsin vitro Modelinflammatory disease of the intestineinnovationmembermicrobialmicrobial communitymicrobiotamouse modelmutantnovelresponseskillssuccesstreatment strategytributyrin
项目摘要
Project Summary
Patients with Inflammatory Bowel Disease (IBD) experience relapsing and remitting periods of inflammation in
their gastrointestinal tract. During periods of inflammation, many patients exhibit an alteration in colonic microbial
communities resulting in an increase in facultative anaerobes (primarily members of the Enterobacteriaceae
family, such as E. coli). Similar changes in the gut microbiota composition are observed in murine models of
colitis. Previous work from our laboratory indicates that the expansion of the Enterobacteriaceae population can
be abrogated in part, by inhibiting two of the metabolic pathways utilized by these bacteria to outgrow during
inflammation. Inhibition of this Enterobacteriaceae bloom reduced gut inflammation. This finding suggests that
microbial dysbiosis aggravates inflammation leading to poorer host outcomes and supports the approach of
specifically targeting the microbiota as a means of ameliorating disease. The objective of this study is to further
elucidate the metabolic pathways utilized by facultative anaerobes to outgrow during inflammatory conditions.
My preliminary data suggest a counterintuitively positive relationship between host-derived reactive oxygen
species and the outgrowth of Enterobacteriaceae. I hypothesize that reactive oxygen species allow facultative
anaerobic Enterobacteriaceae to respire in the inflamed gut lumen. The specific aims of this proposal are to
(1) determine the contribution of host-derived reactive oxygen species in the outgrowth of E. coli in murine
models of colitis and (2) determine the mechanistic relationship between cytochrome bd-II oxidase (AppBC) and
reactive oxygen species in vitro. To test my hypotheses, I will use a strategic combination of host and bacterial
genetics in both chemically-induced and genetic models of colitis. Changes in oxygen metabolism will be
characterized using immunohistochemical staining, bacterial reporter strains, microelectrode-based technology,
and metagenomics. The potential impact of my research will be to understand how oxygen availability influences
Enterobacteriaceae outgrowth during inflammation and explore the role reactive oxygen species play in this
process. A positive outcome may lay the foundation for novel treatment strategies for IBD patients.
Additionally, the training plan I have laid out will help me achieve my goal of becoming an academic researcher
at a major university or hospital system. I will be mentored by my Spnosor Sebastian Winter, Ph.D., an expert in
host-microbe interactions during inflammation, and by my Co-Sponsor Vanessa Sperandio, Ph.D., an expert in
bacterial pathogenesis and gene regulation. Along with support from the Graduate School and Career
Development Office, Dr. Winter and Dr. Sperandio will help me attain and strengthen skills necessary for success
in academic research, including responsible conduct, technical expertise, and scientific communication skills.
项目摘要
炎症性肠病(IBD)患者经历炎症复发和缓解期
他们的胃肠道。在炎症期,许多患者的结肠微生物会发生改变。
导致兼性厌氧菌(主要是肠杆菌科成员)增加的群落
家庭,如大肠杆菌)。在小鼠模型中也观察到肠道微生物区系组成的类似变化
结肠炎。我们实验室以前的工作表明,肠杆菌科种群的扩张可以
通过抑制这些细菌利用的两条新陈代谢途径在
发炎。抑制这种肠杆菌科水华可以减少肠道炎症。这一发现表明
微生物失调会加剧炎症,导致较差的宿主结局,并支持
专门针对微生物区系作为一种改善疾病的手段。这项研究的目的是进一步
阐明兼性厌氧菌在炎症条件下生长的代谢途径。
我的初步数据表明,宿主衍生的活性氧与人的直觉相反
肠杆菌科的种类和副产物。我假设,活性氧物种允许兼性
厌氧肠杆菌在发炎的肠腔内呼吸。这项建议的具体目的是
(1)确定宿主来源的活性氧在小鼠大肠杆菌生长过程中的作用
结肠炎模型的建立和(2)细胞色素BD-II氧化酶(AppBC)与结肠炎发病机制的关系
体外产生的活性氧物种。为了验证我的假设,我将使用寄主和细菌的策略性组合
化学性结肠炎和遗传性结肠炎的遗传学研究。氧代谢的变化将是
采用免疫组织化学染色、细菌报告菌株、微电极技术、
和元基因组学。我的研究的潜在影响将是了解氧气供应如何影响
肠杆菌科细菌在炎症过程中的生长并探讨活性氧在其中所起的作用
进程。积极的结果可能为IBD患者的新治疗策略奠定基础。
此外,我制定的培训计划将帮助我实现成为一名学术研究人员的目标
在主要的大学或医院系统。我将由我的Spnosor Sebastian温特博士指导,他是
炎症过程中宿主-微生物的相互作用,以及我的共同赞助人Vanessa Sperandio博士,她是
细菌的致病机制和基因调控。以及研究生院和职业生涯的支持
发展办公室、温特博士和斯佩兰迪奥博士将帮助我获得和加强成功所必需的技能
在学术研究方面,包括负责任的行为、技术专长和科学沟通技能。
项目成果
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