Regulation of the tuft-ILC2 circuit in the small intestine

小肠 tuft-ILC2 回路的调节

• 批准号: 10416908
• 负责人: Jakob H. von Moltke
• 金额: $ 55.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10416908
• 关键词: Address; Agonist; Allergens; Attenuated; Binding Sites; Biochemical; Biological Assay; Cations; Cell Differentiation process; Cell physiology; Cells; Cellular Assay; Chemicals; Chromosome 9; Chromosome Mapping; Cre driver; Cues; Developmental Process; Economics; Enteral; Eosinophilia; Epithelial; Epithelial Cells; Equilibrium; Food Hypersensitivity; Fractionation; Frequencies; Genes; Genetic Transcription; Helminths; Hematopoiesis; Human; Hyperplasia; Hypersensitivity; Ileitis; Immune; Immune response; Immunity; Immunologics; Inbred BALB C Mice; Incidence; Individual; Inflammation; Interleukin-13; Intestinal Diseases; Lamina Propria; Leukotrienes; Ligands; Link; Livestock; Lymphoid Cell; Mediating; Morbidity - disease rate; Mus; Organoids; Osmolar Concentration; Output; Pathologic; Pathology; Pathway interactions; Physiological; Positioning Attribute; Predisposition; Proto-Oncogene Protein c-kit; Regulation; Role; STAT6 gene; Sampling; Signal Pathway; Signal Transduction; Small Intestines; Succinates; TRPM5 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tritrichomonas; Virus; cytokine; dysbiosis; enteric virus infection; epigenomics; extracellular; genomic locus; helminth infection; in vitro Assay; inhibitor; insight; interleukin-13 receptor; intestinal epithelium; intestinal homeostasis; intestinal injury; microbial host; new therapeutic target; novel; nutrient absorption; progenitor; promoter; receptor; stem; stem cells; therapeutic target; tool; transcription factor; transcriptome sequencing

Project Summary Parasitic worms (helminths) currently infect 1-2 billion humans and are the cause of widespread morbidity. Helminth infections of livestock result in large economic losses. Meanwhile, the incidence of allergies is increasing globally, but particularly in regions where helminths are absent. Although seemingly unrelated, helminths and allergens are immunologically linked as they both induce a type 2 immune response. The activation and regulation of type 2 immunity remain incompletely understood, especially in the small intestine (SI). We recently discovered that rare chemosensory epithelial tuft cells are required for anti-helminth immunity in the SI. Tuft cells activate group 2 innate lymphoid cells (ILC2s), which in turn secrete canonical type 2 cytokines to coordinate hallmarks of type 2 immunity, such as eosinophilia and tissue remodeling. Specifically, IL-13 signaling in epithelial progenitors biases their lineage commitment towards tuft cells, leading to tuft cell hyperplasia during helminth infection and in mice colonized with Tritrichomonas protists. This tuft-ILC2 circuit is activated when tuft cells sense succinate secreted by Tritrichomonas, but the ligand and receptor mediating helminth sensing remain unknown. Additionally, while the cells and intercellular signals of the tuft-ILC2 circuit are emerging, the intracellular signaling pathways that regulate the circuit remain completely unknown, especially within the epithelium. In this proposal, we examine how POU2F3 is regulated to induce tuft cell hyperplasia (Aim 1), test the function of KIT signaling in tuft cells (Aim 2), and characterize novel tuft cell ligands and the intracellular signals they activate (Aim 3). In addition to helminth infection, the tuft-ILC2 circuit has recently been implicated in enteric virus infection and ileitis induced by bacterial dysbiosis. Therefore, the regulatory mechanisms uncovered by this project promise to identify therapeutic targets for the treatment of numerous SI pathologies.

项目摘要 寄生虫（蠕虫）目前感染10 - 20亿人，是广泛发病的原因。 家畜的蠕虫感染导致巨大的经济损失。同时，过敏症的发病率是 在全球范围内增加，但特别是在没有蠕虫的地区。虽然看起来不相关， 蠕虫和过敏原在免疫学上是相关的，因为它们都诱导2型免疫应答。的 2型免疫的激活和调节仍然不完全清楚，特别是在小肠中 （SI）。我们最近发现抗蠕虫免疫需要罕见的化学感受上皮簇细胞 在SI中。簇细胞激活第2组先天性淋巴样细胞（ILC 2），其反过来分泌典型的2型 细胞因子以协调2型免疫的标志，如嗜酸性粒细胞增多和组织重塑。具体地说， 上皮祖细胞中的IL-13信号传导使其谱系定型偏向于簇细胞，导致簇细胞分化。 寄生虫感染期间的增生和三毛滴虫原生生物定殖的小鼠。该簇-ILC 2电路是 当簇状细胞感受到三毛滴虫分泌的琥珀酸时激活，但配体和受体介导的琥珀酸受体被激活。 蠕虫的感应仍然未知。此外，虽然簇-ILC 2回路的细胞和细胞间信号 正在出现，调节电路的细胞内信号通路仍然完全未知， 尤其是在上皮内。在这个提议中，我们研究了POU 2F 3是如何被调节以诱导簇状细胞 目的1，测试簇细胞中KIT信号传导的功能（目的2），并表征新的簇细胞 配体和它们激活的细胞内信号（Aim 3）。除了蠕虫感染，簇状ILC 2回路 最近与肠道病毒感染和细菌生态失调引起的回肠炎有关。因此 该项目揭示的调控机制有望确定治疗靶点， 许多SI病理。