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（由适用提供）：我们在小鼠中发布的数据表明，简单的糖和饮食补充剂N-乙酰葡萄糖胺（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性。实际上，通过在ER/Golgi秘密途径中添加复杂的碳水合物来改变后生动物中的所有细胞表面和分泌的蛋白质，传授的大量分子信息未由基因组编码。我们发现高尔基N-糖基化的遗传，代谢和环境调节控制细胞表面上的大分子复合物，以影响细胞生长，分化和疾病状态。每个蛋白质分子的N-聚糖的分支和数量配合以调节甘叶蛋白的结合，形成甲状腺蛋白 - 糖蛋白晶格，以可预测的方式控制表面糖蛋白的分布素，聚类和内吞作用。 N-Glyan分支缺乏通过增强T细胞受体聚类/信号传导来诱导小鼠的T细胞过度运动和发挥自身免疫性疾病，从而减少生长抑制剂的表面保留率 CTLA-4和TGF-ßRI/II并促进促炎性TH1/TH17细胞的分化。在人类中，多发性硬化症（MS）的多种遗传和环境危险因素会融合到非调节N-糖基化和CTLA-4表面保留率。这些包括白介素-7受体-α，白介素-2受体-α，MGAT1，MGAT1和CTLA-4以及维生素D3的遗传变异以及UDP-GLCNAC的代谢产生，MGAT1和MGAT5的底物的代谢产生。通过与饮食补充N-乙酰葡萄糖胺（GLCNAC）代谢增加UDP-GLCNAC（GLCNAC），从而在体外和体内挽救N-聚糖分支缺乏，从而抑制T细胞的生长，增强CTLA-4和TGF-ßRI/II表面表达，并使TH1/TH1/TH17差异化，从而抑制CTLA-4和tgf-ßri/ii II的差异化。 MS遗传危险因素引起的N-聚糖分支缺乏。用GLCNAC补充N-聚糖生物合成的治疗性可以提供个性化的药物方法来抑制促进人自身免疫性的潜在分子缺陷。在这里，我们建议检查人类中的口服GlcNAC是否增强了N-聚糖分支以抑制T细胞功能并诱导免疫降解，重点是促进MS和下调T细胞中N-聚糖分支的遗传多态性的个体。特定的目标1检查是否在体外GLCNAC是否调节男性与女性T细胞中的低形态N-聚糖分支，以抑制pro-automune TH1/TH17细胞，同时增强抗自动免疫性调节细胞。具体目标2检查是否会增强N-聚糖分支以抑制促肌免疫性TH1/TH17反应，同时增强N-糖基化遗传缺陷的MS患者的抗自动免疫性T调节细胞。