Engineered Probiotics for Closed-Loop Control of Disease-Associated Gut Metabolites in Gut-On-Chip Models
用于闭环控制芯片肠道模型中疾病相关肠道代谢物的工程益生菌
基本信息
- 批准号:10572700
- 负责人:
- 金额:$ 15.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Anti-Inflammatory AgentsArchitectureBiological AssayButyratesChemicalsClinicalComplexConsensusConsumptionCrohn&aposs diseaseDataDirected Molecular EvolutionDiseaseElectron TransportEngineered ProbioticsEngineeringEnsureEnvironmentEnzymesEpithelialEquilibriumEscherichia coliGelGeneticHealthHumanHydrogen SulfideIn SituIn VitroIndividualInflammationIntegration Host FactorsIntestinesKineticsLinkLogicMeasurementMetabolic PathwayMetabolismMicrobeMitochondriaModalityModelingMucous MembraneMucous body substanceOrganOutputOxygenPathway interactionsPatientsPerformancePhysiologicalPhysiologyPlayProbioticsProductionPropertyPublishingReactive Oxygen SpeciesResearchResolutionRheologyRoleStructureSulfidesSystemTechnologyTestingTherapeuticThickTranscriptional RegulationTubeUlcerative ColitisValidationWorkbasecommensal microbesdesigndesign-build-testdisorder controlgenotoxicitygut microbiotahigh rewardhigh riskhuman tissueinflammatory markerinterestmathematical modelmicrobialmucosal microbiotanovelnovel therapeuticsoperationoxidationpromoterresponsesensorsmall moleculespatiotemporalsynthetic biologytherapy outcometranscription factor
项目摘要
PROJECT SUMMARY
Engineered commensal microbes represent a promising platform for controlling microbial metabolism in
the gut microbiota for therapeutic outcomes. While strains have been successfully engineered to either reduce
the concentration of a toxic metabolite or produce a therapeutic one, strains capable of controlling the level of a
metabolite within a narrow window have not been developed. Such ‘smart probiotics’, able to dynamically
respond to the environment and either produce or consume a compound based on the local concentration, would
be particularly useful for stabilizing metabolites which play a concentration-dependent role in host health and
disease. For example, ulcerative colitis and Crohn’s disease have been linked to microbially produced hydrogen
sulfide (H2S), with a growing consensus that low levels of this molecule have anti-inflammatory properties and
support a healthy epithelium, whereas high concentrations of H2S are genotoxic, inhibit mitochondrial function
and butyrate oxidation, and potentially weaken the mucosal barrier. Given that H2S concentration varies spatially
and temporally throughout the mucosa, controlling H2S within a tight range is not possible with current small-
molecule sulfide donors, which release sulfide regardless of local concentration. We propose a new synthetic
biology-based approach to controlling microbial metabolites in situ, in which the engineered microbe uses a
transcription factor responsive to the metabolite of interest to dynamically balance the expression of metabolic
pathways for production and consumption of the metabolite. This will produce a stable, titratable concentration
in a manner analogous to a thermostat. In this proposal, we will demonstrate this technology by developing
engineered strains of E. coli Nissle to dynamically control the level of H2S in situ, incorporating mathematical
modeling and a human organ-chip platform into the design-built-test cycle to achieve robust and stable operation
in the complex gut environment. If successful, the proposed research will establish the design rules for a novel
synthetic biology control strategy applicable to many gut metabolites with concentration-dependent roles in
disease, identify and mitigate host factors that impact engineered strain performance, and facilitate greater
translatability of synthetic probiotics.
项目总结
项目成果
期刊论文数量(0)
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Benjamin Michael Woolston其他文献
Benjamin Michael Woolston的其他文献
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{{ truncateString('Benjamin Michael Woolston', 18)}}的其他基金
Engineered Probiotics for Closed-Loop Control of Disease-Associated Gut Metabolites in Gut-On-Chip Models
用于闭环控制芯片肠道模型中疾病相关肠道代谢物的工程益生菌
- 批准号:
10703502 - 财政年份:2022
- 资助金额:
$ 15.7万 - 项目类别:
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