Regulation of the tuft-ILC2 circuit in the small intestine

小肠 tuft-ILC2 回路的调节

• 批准号: 10580850
• 负责人: Jakob H. von Moltke
• 金额: $ 56.03万
• 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/10580850
• 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 Cells; Epithelium; 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; LoxP-flanked allele; Lymphoid Cell; Mediating; Morbidity - disease rate; Mus; Organoids; Osmolar Concentration; Output; Pathologic; Pathology; Pathway interactions; Physiological; Positioning Attribute; Predisposition; Proliferating; Proto-Oncogene Protein c-kit; Regulation; Role; STAT6 gene; Sampling; Sensory; 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; 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.

项目概要 目前，寄生虫感染了 1-20 亿人，是造成广泛发病的原因。 牲畜的蠕虫感染导致巨大的经济损失。与此同时，过敏的发生率 全球范围内增加，特别是在没有蠕虫的地区。虽然看似毫无关联， 蠕虫和过敏原在免疫学上是相关的，因为它们都会诱导 2 型免疫反应。这 2 型免疫的激活和调节仍不完全清楚，尤其是在小肠中 （SI）。我们最近发现，抗蠕虫免疫需要罕见的化学感应上皮簇细胞 在国际单位制中。簇细胞激活 2 类先天淋巴细胞 (ILC2)，进而分泌典型 2 型淋巴细胞 细胞因子协调 2 型免疫的标志，例如嗜酸性粒细胞增多和组织重塑。具体来说， 上皮祖细胞中的 IL-13 信号传导使它们的谱系偏向于簇细胞，从而导致簇细胞 蠕虫感染期间和被三滴虫原生生物定植的小鼠中的增生。该簇-ILC2电路是 当簇细胞感知到三滴虫分泌的琥珀酸时被激活，但配体和受体介导 蠕虫感应仍然未知。此外，虽然 tuft-ILC2 电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。在这个提案中，我们研究了如何调节 POU2F3 来诱导簇细胞 增生（目标 1），测试簇细胞中 KIT 信号传导的功能（目标 2），并表征新型簇细胞 配体及其激活的细胞内信号（目标 3）。除了蠕虫感染之外，tuft-ILC2 回路 最近被认为与肠道病毒感染和细菌失​​调引起的回肠炎有关。因此， 该项目揭示的监管机制有望确定治疗的治疗靶点 许多 SI 病理。