Mechanisms of human immune modulation by oral N-acetylglucosamine

口服N-乙酰氨基葡萄糖调节人体免疫的机制

• 批准号: 8851521
• 负责人: MICHAEL DEMETRIOU
• 金额: $ 39.65万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851521
• 关键词: Acetylglucosamine; Anabolism; Animals; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Carbohydrates; Cell Differentiation process; Cell physiology; Cell surface; Cells; Child; Cholecalciferol; Complex; Data; Defect; Disease; Endocytosis; Environment; Environmental Risk Factor; Enzymes; Galactose Binding Lectin; Genetic; Genetic Polymorphism; Genetic Risk; Genome; Glycoproteins; Golgi Apparatus; Growth Inhibitors; Health; Human; Hyperactive behavior; Immune; In Vitro; Individual; Inflammatory; Inflammatory Bowel Diseases; Interleukin 2 Receptor; Interleukin 7 Receptor; Macromolecular Complexes; Membrane Glycoproteins; Metabolic; Modeling; Molecular; Multiple Sclerosis; Mus; Mutation; Oral; Pathway interactions; Patients; Polysaccharides; Production; Protein Glycosylation; Proteins; Publishing; Regulation; Regulatory T-Lymphocyte; Resistance; Signal Transduction; Supplementation; Surface; T-Cell Receptor; T-Lymphocyte; Therapeutic; cell growth; dietary supplements; genetic risk factor; genetic variant; glycosylation; human female; immunoregulation; improved; in vivo; male; mouse model; personalized medicine; response; sugar; vitamin metabolism

DESCRIPTION (provided by applicant): Our published data in mice has revealed that the simple sugar and dietary supplement N- acetylglucosamine (GlcNAc) inhibits T cell function and autoimmunity by enhancing N-glycosylation in T cells. Virtually all cell surface and secreted proteins in metazoans are modified by the addition of complex carbohydrates in the ER/Golgi secretory pathway, imparting substantial molecular information not encoded by the genome. We find that genetic, metabolic and environmental regulation of Golgi N-glycosylation controls macromolecular complexes on the cell surface to influence cell growth, differentiation and disease states. The branching and number of N-glycans per protein molecule cooperate to regulate binding to galectins, forming a galectin-glycoprotein lattice that controls the distributin, clustering and endocytosis of surface glycoproteins in a predictable manner. N-glyan branching deficiency induces T cell hyper-activity and spontaneous autoimmune disease in mice by enhancing T cell receptor clustering/signaling, reducing surface retention of the growth inhibitors CTLA-4 and TGF-ßRI/II and promoting differentiation into pro-inflammatory TH1/TH17 cells. In humans, multiple genetic and environmental risk factors for Multiple Sclerosis (MS) converge to dysregulate N- glycosylation and CTLA-4 surface retention. These include genetic variants in interleukin-7 receptor-α, interleukin-2 receptor-α, MGAT1, MGAT5 and CTLA-4 as well as Vitamin D3 and metabolic production of UDP-GlcNAc, the substrate for MGAT1 and MGAT5. Rescuing N-glycan branching deficiency in T cells in vitro and in vivo by metabolically increasing UDP-GlcNAc with the dietary supplement N-acetylglucosamine (GlcNAc), suppresses T cell growth, enhances CTLA-4 and TGF-ßRI/II surface expression, blocks TH1/TH17 differentiation, inhibits MS and autoimmune diabetes models and rescues N-glycan branching deficiency induced by MS genetic risk factors. Therapeutic supplementation to N-glycan biosynthesis with GlcNAc may provide a personalized medicine approach to suppress an underlying molecular defect promoting human autoimmunity. Here we propose to examine whether oral GlcNAc in humans enhances N-glycan branching to suppress T cell function and induce immune deviation, focusing on individuals with genetic polymorphisms that promote MS and down-regulate N-glycan branching in T cells. Specific Aim 1 examines whether in vitro GlcNAc regulates hypomorphic N-glycan branching in male vs female human T cells to suppress pro- autoimmune TH1/TH17 cells while enhancing anti-autoimmune T regulatory cells. Specific Aim 2 examines whether oral GlcNAc enhances N-glycan branching to suppress pro-autoimmune TH1/TH17 responses while enhancing anti-autoimmune T regulatory cells in MS patients with genetic defects in N-glycosylation.

描述（由申请人提供）：我们在小鼠中发表的数据显示，单糖和膳食补充剂N-乙酰氨基葡萄糖（GlcNAc）通过增强T细胞中的N-糖基化来抑制T细胞功能和自身免疫。在后生动物中，几乎所有的细胞表面和分泌蛋白都被内质网/高尔基体分泌途径中添加的复合碳水化合物修饰，从而传递了大量非基因组编码的分子信息。我们发现高尔基n -糖基化的遗传、代谢和环境调控控制细胞表面的大分子复合物，影响细胞生长、分化和疾病状态。每个蛋白质分子的分支和n-聚糖的数量协同调节与半乳糖凝集素的结合，形成半乳糖凝集素-糖蛋白晶格，以可预测的方式控制表面糖蛋白的分布、聚集和内吞作用。N-glyan分支缺陷通过增强T细胞受体聚集/信号传导，减少生长抑制剂的表面保留，在小鼠中诱导T细胞过度活跃和自发自身免疫性疾病