Intestinal O-GlcNAc signaling and mucosal host defense

肠道 O-GlcNAc 信号传导和粘膜宿主防御

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要超过15亿人感染了全球蠕虫，主要分布在热带和亚热带地区。另一方面，在传染病明显降低的发达国家中是过敏，炎症和自身免疫性疾病的发生率的持续增加。卫生假设提出，由于缺乏暴露而导致的未刺激的免疫系统蠕虫，易于自身免疫性和过敏性炎症。迫切需要新的预防性以及用于粘膜感染和炎症的治疗药物。我的实验室的研究是专注于O连接的N-乙酰葡萄糖（O-GLCNAC）在细胞内的病理生理作用丝氨酸和苏氨酸残基的蛋白质。长期目标是阐明监管机制和 O-GLCNAC信号传导在肠内稳态和粘膜宿主防御中的生理功能。在拟议的研究，我们将通过激活STAT6信号传导来检验O-GLCNAC转移酶（OGT）的假设促进IL-25产生簇细胞的分化，并促进杯状细胞的IL-33分泌，从而诱发2型免疫反应，用于组织修复和炎症控制。在AIM 1中，我们试图定义功能影响，上游激活信号和簇状细胞中STAT6 O-Glcnacylation的下游目标分化，2型免疫激活和蠕虫驱逐。在AIM 2中，我们确定了一个新颖的，共同的目标在杯状细胞中与IL-33共定位的OGT和STAT6，并介导了IL-的非常规分泌 33启动2型免疫反应。在AIM 3中，使用药理学和遗传学方法来增加全球蛋白质O-Glcnacylation在肠上皮中，我们希望确定OGT-STAT6途径肠内稳态是必需的，并介导了结肠炎中蠕虫的治疗作用。提议研究将为开发新干预策略的发展提供宝贵的见解，以消除寄生虫发展中国家贫困地区的蠕虫，并治疗工业化的炎症性肠病国家。