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）目前感染了10-2亿人类，是引起广泛发病率的原因。 蠕虫感染牲畜会导致巨大的经济损失。同时，过敏的发生率是 全球增加，但尤其是在缺乏蠕虫的地区。尽管看似无关，但 蠕虫和过敏原在免疫学上连接，因为它们都诱导2型免疫反应。这 2型免疫力的激活和调节仍然不完全理解，尤其是在小肠中 （SI）。我们最近发现，抗螺旋免疫需要罕见的化学感应上皮簇细胞 在SI中。簇细胞激活2组先天淋巴样细胞（ILC2），这又分泌2型规范 细胞因子以协调2型免疫力的标志，例如嗜酸性粒细胞和组织重塑。具体来说， 上皮祖细胞中的IL-13信号传导偏见其对簇细胞的谱系承诺，从而导致簇细胞 在蠕虫感染期间的增生和用tritrichomonas生物定殖的小鼠。这个塔夫特-ILC2电路是 当簇细胞感受到tritrichomonas分泌的琥珀酸酯时被激活，但是配体和受体介导 蠕虫的传感仍然未知。另外，簇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， 特别是在上皮内。在此提案中，我们检查了如何调节POU2F3以诱导簇状细胞 增生（AIM 1），测试塔夫特细胞中试剂盒信号传导的功能（AIM 2），并表征了新型的簇状细胞 配体及其激活的细胞内信号（AIM 3）。除了蠕虫感染外， 最近与细菌性营养不良诱导的肠道病毒感染和肠炎有关。因此， 该项目发现的监管机制有望确定治疗的治疗目标 许多SI病理。