Intestinal O-GlcNAc signaling and mucosal host defense

项目总结 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，在传染病显著减少的发达国家， 过敏性、炎症性和自身免疫性疾病的发病率持续增加。卫生问题 假说认为，免疫系统受刺激不足是由于没有接触到 蠕虫，易患自身免疫性和过敏性炎症。迫切需要新的预防措施 以及治疗粘膜感染和炎症的药物。我实验室的研究一直是 重点阐述了O-连接N-乙酰氨基葡萄糖(O-GlcNAc)修饰对细胞内的病理生理作用 丝氨酸和苏氨酸残基上的蛋白质。长期目标是阐明监管机制和 O-GlcNAc信号在肠道内稳态和粘膜宿主防御中的生理作用在 建议的研究中，我们将检验O-GlcNAc转移酶(OGT)，通过激活STAT6信号， 促进产生IL-25的丛状细胞分化，促进杯状细胞分泌IL-33，从而 唤起组织修复和炎症控制的2型免疫反应。在目标1中，我们试图定义 STAT6 O-GlcN酰化在TUFT细胞中的功能影响、上游激活信号和下游靶点 分化、2型免疫激活和蠕虫排出。在目标2中，我们确定了一个新的、共同的目标 OGT和STAT6在杯状细胞中与IL-33共定位并介导IL-33的非常规分泌 33以启动2型免疫反应。在目标3中，使用药理学和遗传方法来增加 全球蛋白O-GlcN在肠上皮中的酰化，我们期待建立OGT-STAT6途径 是肠道内环境稳定所必需的，并介导蠕虫对结肠炎的治疗效果。建议数 研究将为开发新的干预策略以根除寄生虫提供有价值的见解 在发展中国家的贫困地区治疗蠕虫，在工业化国家治疗炎症性肠病 国家。

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.