Intestinal O-GlcNAc signaling and mucosal host defense

肠道 O-GlcNAc 信号传导和粘膜宿主防御

• 批准号: 10444727
• 负责人: Hai-Bin Ruan
• 金额: $ 48.84万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-23 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444727
• 关键词: Ablation; Allergic; Allergic inflammation; Anthelmintics; Area; Autoimmune Diseases; CCL4 gene; Cell Differentiation process; Cells; Chronic; Colitis; Communicable Diseases; Developed Countries; Development; Disease; Epithelial; Epithelial Cells; Exposure to; Future; Gene Family; Genetic; Goals; Goblet Cells; Granuloma; Helminths; Host Defense; Host Defense Mechanism; Human; Hygiene; Hyperplasia; Immune; Immune response; Immune system; Immunity; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interferon Type II; Interleukins; Intervention; Intestinal Mucosa; Intestinal parasite; Intestines; Knockout Mice; Knowledge; Laboratories; Link; Lymphoid Cell; Mediating; Medicine; Modernization; Modification; Mucous Membrane; Mus; O-GlcNAc transferase; Organoids; Parasitic infection; Pathway interactions; Persons; Pharmacology; Physiological; Physiology; Play; Population; Post-Translational Protein Processing; Poverty Areas; Preventive; Production; Proteins; Research; Role; STAT6 gene; Serine; Signal Transduction; Societies; Source; TSLP gene; Testing; Therapeutic; Therapeutic Effect; Threonine; autoimmune inflammation; cell type; citrate carrier; cytokine; enteric infection; extracellular; genetic approach; gut inflammation; helminth infection; insight; interest; intestinal epithelium; intestinal homeostasis; novel; pathogen; response; tissue-repair responses; tool; transcription factor

PROJECT SUMMARY More than 1.5 billion people are infected with helminths worldwide, predominantly distributed in tropical and subtropical areas. On the other hand, in developed countries with markedly reduced infectious diseases, there is a continuing increase in the incidences of allergic, inflammatory, and autoimmune diseases. The hygiene hypothesis proposes that an under-stimulated immune system resulting from the absence of exposure to helminths, predisposes to autoimmune and allergic inflammation. There is an urgent need for new preventive and therapeutic medicines for mucosal infection and inflammation. The research in my laboratory has been focused on the pathophysiological role of O-linked N-Acetylglucosamine (O-GlcNAc) modification on intracellular proteins at serine and threonine residues. The long-term goal is to elucidate the regulatory mechanisms and physiological functions of O-GlcNAc signaling in intestinal homeostasis and mucosal host defense. In the proposed study, we will test the hypothesis that O-GlcNAc transferase (OGT), by activating STAT6 signaling, promotes the differentiation of IL-25-producing tuft cells and facilitates IL-33 secretion from goblet cells, thus evoking type 2 immune responses for tissue repair and inflammation control. In Aim 1, we seek to define the functional impact, upstream activating signals, and downstream targets of STAT6 O-GlcNAcylation in tuft cell differentiation, type 2 immune activation, and helminth expulsion. In Aim 2, we identify a novel, common target of OGT and STAT6 that colocalizes with IL-33 in goblet cells and mediates the unconventional secretion of IL- 33 to initiate type 2 immune responses. In Aim 3, using pharmacological and genetic approaches to increase global protein O-GlcNAcylation in the intestinal epithelium, we expect to establish that the OGT-STAT6 pathway is required for intestinal homeostasis and mediates the therapeutic effect of helminths in colitis. The proposed study will provide valuable insights into the development of new intervention strategies to eradicate parasitic worms in areas of poverty in the developing world and to treat inflammatory bowel disease in industrialized countries.

项目摘要 全世界有超过15亿人感染蠕虫，主要分布在热带和 亚热带地区。另一方面，在传染病明显减少的发达国家， 过敏性、炎症性和自身免疫性疾病的发病率持续增加。卫生 一种假说提出，由于缺乏接触， 寄生虫，易患自身免疫性和过敏性炎症。迫切需要新的预防措施 以及粘膜感染和炎症的治疗药物。我实验室的研究 集中于O-连接的N-乙酰氨基葡萄糖（O-GlcNAc）修饰对细胞内 丝氨酸和苏氨酸残基处的蛋白质。长期目标是阐明监管机制， O-GlcNAc信号传导在肠内稳态和粘膜宿主防御中的生理功能。在 提出的研究，我们将测试的假设，O-GlcNAc转移酶（OGT），通过激活STAT 6信号， 促进产生IL-25的簇状细胞的分化，并促进杯状细胞分泌IL-33， 引起用于组织修复和炎症控制的2型免疫应答。在目标1中，我们试图定义 簇状细胞中STAT 6 O-GlcNAc化的功能影响、上游激活信号和下游靶点 分化、2型免疫激活和蠕虫驱逐。在目标2中，我们确定了一个新的共同目标， OGT和STAT 6与杯状细胞中的IL-33共定位，并介导IL-33的非常规分泌。 33启动2型免疫反应。在目标3中，使用药理学和遗传学方法， 通过观察肠上皮细胞中蛋白质O-GlcNAc化，我们预期OGT-STAT 6通路 是肠内稳态所必需的，并介导结肠炎中蠕虫的治疗效果。拟议 这项研究将为制定新的干预战略以根除寄生虫病提供有价值的见解。 蠕虫在发展中国家的贫困地区，并在工业化国家治疗炎症性肠病， 国家