Tuft cell effector functions in the small intestine
簇细胞效应器在小肠中发挥作用
基本信息
- 批准号:10343684
- 负责人:
- 金额:$ 55.96万
- 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:2020-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylcholineAllergensAllergic DiseaseAttentionBiological AssayCellsCellular MorphologyEffector CellElectron MicroscopyEosinophiliaEpidemicEpithelialEventFrequenciesFundingGene Expression ProfileGene Expression ProfilingGoalsGoblet CellsHealthHelminthsHumanHyperplasiaHypersensitivityImmuneImmune responseImmunityImmunologyIn VitroIncidenceIndividualInfectionInflammationInterleukin-13Interleukin-5IntestinesIonsLaboratoriesLeukotriene C4LeukotrienesLigandsLinkLipidsLiquid substanceLungLymphoid CellMeasuresMembraneModelingMouse StrainsMucous body substanceMusNeuromedin UNeuropeptidesPathway interactionsPeptidesPhysiologyPositioning AttributePrevalenceProductionPublishingReagentRegulationRoleSentinelSignal TransductionSmall IntestinesStimulusSuccinatesTestingTherapeutic InterventionTissuesTranscription Factor AP-1Transgenic MiceWorkbaseburden of illnesscell typecytokineexperimental studyhelminth infectionimmune functionin vitro Assayin vivoinnovationmicrobialmouse modelnew therapeutic targetnovelparacrinerelease of sequestered calcium ion into cytoplasmresponseskillstool
项目摘要
Project Summary/Abstract
Helminths, allergens, and certain protists all stimulate a type 2 immune response and contribute significantly to
the global disease burden. Currently, more than 1 billion individuals worldwide are infected with helminths, and
the rising incidence of allergic disease represents an emerging epidemic. The sensing and signaling events
that initiate type 2 immunity remain poorly understood, but in the small intestine they require epithelial tuft cells.
Tuft cells regulate a tuft-ILC2 circuit in which tuft cell-derived IL-25 activates group 2 innate lymphoid cells
(ILC2s) in the underlying tissue. ILC2s secrete the canonical type 2 cytokines IL-5, -9, and -13, which
collectively drive hallmarks of type 2 immunity, such as eosinophilia and tissue remodeling. IL-13 also
promotes a feed-forward response by inducing tuft and goblet cell hyperplasia. The immune function of tuft
cells requires a chemosensory pathway and recent studies identified the microbial metabolite succinate as an
intestinal tuft cell ligand that is sufficient to activate the tuft-ILC2 circuit. Tuft cells therefore act as IL-25-
secreting immune sentinels, but several lines of evidence support the central hypothesis of this proposal that
additional tuft cell effector functions must exist: (1) Tuft cells express IL-25 constitutively, but the feed-forward
tuft-ILC2 circuit is only activated in the presence of helminths or protists, suggesting additional activating
signals; (2) the initiation of tuft cell hyperplasia after immune sensing has occurred suggests tuft cells
contribute to the effector stages of type 2 immunity; and (3) helminth clearance is more delayed in tuft cell-
deficient mice than in mice that lack only IL-25. The goal of this proposal is therefore to discover and
characterize novel tuft cell effector functions in the small intestine. Using a combination of innovative in vitro
assays and in vivo helminth infection of genetically modified mouse strains, we propose to test the regulation
and function of tuft cell-derived IL-25, leukotriene C4, and acetylcholine. These studies should identify novel
targets for therapeutic intervention in both helminth infection and allergic disease.
项目概要/摘要
蠕虫、过敏原和某些原生生物都会刺激 2 型免疫反应,并显着促进
全球疾病负担。目前,全球有超过 10 亿人感染蠕虫,
过敏性疾病发病率的上升代表着一种新出现的流行病。传感和信号事件
启动 2 型免疫的机制仍知之甚少,但在小肠中它们需要上皮簇细胞。
簇细胞调节簇-ILC2 回路,其中簇细胞衍生的 IL-25 激活第 2 组先天淋巴细胞
(ILC2)位于下层组织中。 ILC2 分泌典型的 2 型细胞因子 IL-5、-9 和 -13,
共同驱动 2 型免疫的标志,例如嗜酸性粒细胞增多和组织重塑。 IL-13 也
通过诱导簇细胞和杯状细胞增生来促进前馈反应。毛簇的免疫功能
细胞需要化学感应途径,最近的研究发现微生物代谢物琥珀酸是一种化学感应途径。
足以激活 tuft-ILC2 回路的肠簇细胞配体。因此簇细胞充当 IL-25-
分泌免疫哨兵,但有几条证据支持该提议的中心假设:
必须存在额外的簇细胞效应功能:(1) 簇细胞组成型表达 IL-25,但前馈
tuft-ILC2 电路仅在存在蠕虫或原生生物的情况下才会被激活,这表明需要额外的激活
信号; (2) 免疫感应发生后簇细胞增生的开始表明簇细胞
有助于2型免疫的效应阶段; (3) 簇细胞中蠕虫的清除更加延迟-
缺陷小鼠与仅缺乏 IL-25 的小鼠相比。因此,本提案的目标是发现并
表征小肠中新型簇细胞效应功能。使用创新的体外组合
转基因小鼠品系的测定和体内蠕虫感染,我们建议测试调节
以及簇细胞衍生的 IL-25、白三烯 C4 和乙酰胆碱的功能。这些研究应该确定新颖的
蠕虫感染和过敏性疾病治疗干预的目标。
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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Jakob H. von Moltke其他文献
Jakob H. von Moltke的其他文献
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{{ truncateString('Jakob H. von Moltke', 18)}}的其他基金
A myeloid sentinel that secretes leukotrienes to activate type 2 immunity
分泌白三烯以激活 2 型免疫的骨髓前哨细胞
- 批准号:
10507701 - 财政年份:2022
- 资助金额:
$ 55.96万 - 项目类别:
Regulation of the tuft-ILC2 circuit in the small intestine
小肠 tuft-ILC2 回路的调节
- 批准号:
10580850 - 财政年份:2022
- 资助金额:
$ 55.96万 - 项目类别:
A myeloid sentinel that secretes leukotrienes to activate type 2 immunity
分泌白三烯以激活 2 型免疫的骨髓前哨细胞
- 批准号:
10659251 - 财政年份:2022
- 资助金额:
$ 55.96万 - 项目类别:
Regulation of the tuft-ILC2 circuit in the small intestine
小肠 tuft-ILC2 回路的调节
- 批准号:
10416908 - 财政年份:2022
- 资助金额:
$ 55.96万 - 项目类别:
Tuft cell effector functions in the small intestine
簇细胞效应器在小肠中发挥作用
- 批准号:
10555217 - 财政年份:2020
- 资助金额:
$ 55.96万 - 项目类别:
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