Decode and design T cell induction by a complex gut microbial community
复杂肠道微生物群落解码和设计 T 细胞诱导
基本信息
- 批准号:10572613
- 负责人:
- 金额:$ 13.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-11 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Advisory CommitteesAnti-Inflammatory AgentsAntigensAutoimmune DiseasesAwardB-LymphocytesBacteriaBacterial AntigensBiologicalCD4 Positive T LymphocytesCell CommunicationCell LineCell physiologyCellsCellular biologyCoculture TechniquesColitisCommunicable DiseasesCommunitiesComplementComplexDiseaseDropoutDropsEcosystemEpitopesEscherichia coliFecesGene ClusterGerm-FreeGoalsHumanHuman MicrobiomeHybridomasImmuneImmune responseImmune systemImmunologicsImmunologyIndividualInflammatoryInflammatory Bowel DiseasesInterleukin-10KnowledgeLibrariesLogicMHC antigenMalignant NeoplasmsMentorsMentorshipMetabolic DiseasesMetagenomicsMethodsMicrobeMicrobiologyModelingMolecularMolecular BiologyMusPaperPatternPeptide LibraryPhenotypePhysiologicalRegulatory T-LymphocyteReportingResearchResolutionRoleShotgunsSignal TransductionSiteStimulusT cell responseT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTCR ActivationTaxonomyTechnologyTestingTherapeuticTherapeutic EffectTimeTrainingVariantWorkadaptive immune responseantigen-specific T cellsbacterial communitybacterial geneticscancer therapydesignfecal transplantationgenetic signaturegut microbiomegut microbiotahost-microbe interactionsimmune functionimmunoreactionimmunoregulationimprovedin vivoinsightmedical specialtiesmembermicrobialmicrobial communitymicrobiomemicrobiome componentsmicrobiotamouse modelneglectnew technologynovel therapeutic interventionnovel therapeuticspredictive toolsprogramsrational designresponsescreeningsingle cell technologythree dimensional structuretool
项目摘要
Project Summary/Abstract
Immune modulation holds tremendous promise for the treatment of cancer, autoimmune disease, metabolic
disease, and infectious disease. New ways to generate antigen-specific T and B cells inexpensively and with
minimal reactogenicity are badly needed. Certain bacterial strains from the gut microbiome elicit a potent,
specific adaptive immune response. The underlying mechanisms could guide new therapeutic strategies in
which bacteria-specific immune responses are rationally altered or re-directed. The gut is the site of a wide
variety of microbe-microbe and microbe-host interactions. However previous papers have characterized
microbial strains of the microbiome under artificial conditions of mono-colonization. This approach can identify
strains that are capable of modulating immune cells, but it is unknown how a strain functions in the presence of
other members of the complex microbiota. This knowledge gap hinders a logical design of a microbial
therapeutic.
My long-term research objective is to develop new technologies to understand the “physiological” gut
ecosystem at the level of molecular mechanisms so that I can identify immune modulatory bacteria from the
microbiome and build new therapeutics. In this proposal, I will establish a “physiological” gut by colonizing
germ-free mice with a complex defined gut community (104 strains) and profile T cell responses to each strain
individually. In Aim1, I will identify a set of bacteria-reactive TCRs and their stimulatory strain by single cell
technologies, so that I can provide a big picture of the strain-T-cell interactions at the single TCR level. In
Aim2, I will identify and characterize a bacterial antigen common to multiple strains. In Aim3, the result of T cell
profiling will be used to “design” therapeutic bacterial communities in which inflammatory strains will be
dropped out for building a tolerogenic community to treat colitis in an IBD mouse model. The successful
completion of this project will “decode” a strain-by-strain view of immune modulation by the gut microbiome
and provide a molecular basis for “designing” the new therapy that logically modulates immune response to
treat IBD and other devastating systemic disorders.
Support from the K99 and mentors will complement my expertise in immunology with state-of-art
technologies in microbiology and single cell biology. I will accomplish this with training from Dr. Michael
Fischbach (primary mentor, bacterial genetics), Dr. Daniel Mucida (co-mentor, single-cell biology and T cell
biology), Dr. Justin Sonnenburg (advisory committee, metagenomic analysis), and Dr KC Huang, (advisory
committee, a synthetic microbial community). The training and mentorship I receive during my K99/R00 award
will provide a critical stepping stone for me to achieve my academic goal of establishing a vibrant independent
research program that can answer an important question in the gut ecosystem for establishing a new
therapeutic.
项目总结/文摘
项目成果
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