权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10555217
负责人：
Jakob H. von Moltke
金额：
$ 55.43万
依托单位：
UNIVERSITY OF WASHINGTON
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：
https://reporter.nih.gov/project-details/10555217
关键词：
Acetylcholine Allergens Allergic Disease Attention Biological Assay Cell secretion Cells Effector Cell Electron Microscopy Eosinophilia Epithelium Event Frequencies Funding Gene Expression Profile Gene Expression Profiling Goals Goblet Cells Health Helminths Human Hyperplasia Hypersensitivity Immune Immune response Immunity Immunology In Vitro Incidence Individual Infection Inflammation Interleukin-13 Interleukin-5 Intestines Ions Laboratories Leukotriene C4 Leukotrienes Ligands Link Lipids Liquid substance Lung Lymphoid Cell Measures Membrane Modeling Morphology Mouse Strains Mucous body substance Mucus-Secreting Cell Mus NF-kappa B Neuromedin U Neuropeptides Pathway interactions Peptides Physiology Positioning Attribute Prevalence Production Publishing Reagent Regulation Role Sensory Sentinel Signal Induction Signal Transduction Small Intestines Stimulus Succinates Testing Therapeutic Intervention Tissues Transcription Factor AP-1 Transgenic Mice Work burden of illness cytokine experimental study helminth infection immune function in vitro Assay in vivo innovation microbial mouse model new epidemic new therapeutic target novel nuclear factors of activated T-cells paracrine release of sequestered calcium ion into cytoplasm response skills tool

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.

项目总结/文摘