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-乙酰葡糖胺（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质都通过在ER/高尔基体分泌途径中添加复合碳水化合物来修饰，从而赋予基因组不编码的大量分子信息。我们发现，高尔基体N-糖基化的遗传、代谢和环境调节控制细胞表面的大分子复合物，从而影响细胞的生长、分化和疾病状态。每个蛋白质分子的N-聚糖的分支和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，其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-聚糖分支缺陷通过增强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性自身免疫病 CTLA-4和TGF-β RI/II，并促进分化为促炎性TH 1/TH 17细胞。在人类中，多发性硬化症（MS）的多种遗传和环境风险因素汇聚成N-糖基化和CTLA-4表面保留失调。这些包括白细胞介素-7受体-α、白细胞介素-2受体-α、MGAT 1、MGAT 5和CTLA-4以及维生素D3和UDP-GlcNAc（MGAT 1和MGAT 5的底物）的代谢产物的遗传变异。通过用膳食补充剂N-乙酰葡糖胺（GlcNAc）代谢增加UDP-GlcNAc，在体外和体内挽救T细胞中的N-聚糖分支缺陷，抑制T细胞生长，增强CTLA-4和TGF-β RI/II表面表达，阻断TH 1/TH 17分化，抑制MS和自身免疫性糖尿病模型，并挽救由MS遗传风险因子诱导的N-聚糖分支缺陷。用GlcNAc对N-聚糖生物合成进行治疗性补充可以提供个体化的药物方法来抑制促进人类自身免疫的潜在分子缺陷。 在这里，我们建议检查是否口服GlcNAc在人类中增强N-聚糖分支抑制T细胞功能和诱导免疫偏离，集中在个人的遗传多态性，促进MS和下调T细胞中的N-聚糖分支。具体目的1检查体外GlcNAc是否调节男性与女性人类T细胞中的亚型N-聚糖分支以抑制促自身免疫性TH 1/TH 17细胞，同时增强抗自身免疫性T调节细胞。具体目标2检查口服GlcNAc是否增强N-聚糖分支以抑制促自身免疫性TH 1/TH 17应答，同时增强具有N-糖基化遗传缺陷的MS患者中的抗自身免疫性T调节细胞。