Define the role of REV-ERB in colonic RORgt+ regulatory T cells
定义 REV-ERB 在结肠 RORgt 调节性 T 细胞中的作用
基本信息
- 批准号:10753360
- 负责人:
- 金额:$ 28.5万
- 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:AgonistAntibodiesAutoimmune DiseasesAutoimmunityBindingBiological AssayCTLA4 geneCell LineageCell physiologyCellsColitisColonColonic inflammationDataDevelopmentEquilibriumFOXP3 geneFamilyGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGoalsHomeostasisHumanImmune systemImmunosuppressive AgentsInflammationInflammatoryInflammatory Bowel DiseasesInsulin-Dependent Diabetes MellitusInterleukin-10Knock-outKnockout MiceLamina PropriaLeadLinkLymphoproliferative DisordersMaintenanceMapsMediatingMolecularMultiple SclerosisMusNuclear Hormone ReceptorsNuclear ReceptorsOrphanOutcomeOutcome StudyPlayPopulationPredispositionReceptor InhibitionRegulatory T-LymphocyteRepressionResearchRoleRunningSideSpleenT-LymphocyteTestingTissuesTranscription CoactivatorTranscription Factor 3Transcription RepressorTretinoinWorkanti-tumor immune responseconditional knockoutexperimental studygenome-wideimmunopathologyin vivoin vivo Modelinsightloss of function mutationmembermouse modelmurine colitisnew therapeutic targetnext generation sequencingpreventprotective effectreceptorreceptor functiontherapeutic developmenttherapeutic targettranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY
Regulatory T cells (Treg) play a crucial role in keeping the immune system in balance and preventing
autoimmune disease. Defective Treg function leads to autoimmune diseases, while intra-tumor Tregs can block
effective anti-tumor immune responses. Tregs can undergo further specialization in adaptation to their tissue
microenvironment. Recent studies showed that a unique RORgt (retinoic acid–related orphan receptor gamma
t) expressing Treg cell population could be induced in the colon lamina propria. These RORgt+ Tregs play an
important role in the suppression of colon inflammation. In Treg cells, REV-ERBa is highly expressed in RORgt+
colonic Tregs, but not in RORgt- colonic Tregs or spleen Tregs. Mice with Treg-specific deletion of REV-ERB
were more susceptible to TNBS-induced colitis with decreased RORgt+ Treg cells and increased Th1/Th17 cell-
mediated inflammation in the colon. RNA-sequencing experiment showed that the expression of a set of genes
related to Treg function, including CTLA-4, IL-10, and c-Maf, were reduced in REV-ERB deficient colonic Tregs
compared to WT controls. To study the mechanism of gene regulation by REV-ERB in Tregs, Dr. Zheng’s lab
performed Cut & Run assays with WT RORgt+ iTregs using Foxp3, REV-ERBa, and RORgt antibodies to map
their binding peaks genome-wide. The results showed a significant overlap of the binding peaks of these 3
transcription factors, suggesting coordination in gene regulation among Foxp3, REV-ERB, and RORgt in Treg
cells. The overall objective of the proposed study is to define the role of REV-ERB in Treg function. This goal will
be accomplished by dissecting the molecular mechanism of REV-ERB function in RORgt+ Treg cells (Aim 1),
and characterizing the role of REV-ERB in Treg in mouse models of IBD (Aim 2). The outcomes of the proposed
study are expected to reveal the functional and mechanistic role of REV-ERB in RORgt+ Tregs. Such results are
expected to further advance our understanding of how the identity and function of RORgt+ Tregs are established
and maintained. Additionally, this study will provide key insights into how transcriptional repressor such as REV-
ERB serves as key regulator and tune the function of transcriptional activators in Treg cells. Finally, the outcomes
of this study could provide evidence supporting the development of therapeutics targeting REV-ERB for IBD
treatment.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ye Zheng其他文献
Ye Zheng的其他文献
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{{ truncateString('Ye Zheng', 18)}}的其他基金
A novel role of hypusination in controlling regulatory T cell function
hypusination 在控制调节性 T 细胞功能中的新作用
- 批准号:
10356173 - 财政年份:2021
- 资助金额:
$ 28.5万 - 项目类别:
Investigating the interplay of structural, molecular and spatial mechanisms that control SHP2 activity downstream of PD1
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- 批准号:
10002277 - 财政年份:2018
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Treg development and function controlled by cis-regulatory circuits
由顺式调节电路控制的 Treg 发育和功能
- 批准号:
10318638 - 财政年份:2014
- 资助金额:
$ 28.5万 - 项目类别:
Regulatory T cell lineage stability controlled by Foxp3 CNS2
Foxp3 CNS2 控制的调节性 T 细胞谱系稳定性
- 批准号:
9197261 - 财政年份:2014
- 资助金额:
$ 28.5万 - 项目类别:
Treg development and function controlled by cis-regulatory circuits
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