β4GalT1调节TNFR1的糖基化修饰在小胶质细胞炎性激活中的作用

项目名称： β4GalT1调节TNFR1的糖基化修饰在小胶质细胞炎性激活中的作用

项目编号： No.31500647

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 张冬梅

作者单位： 南通大学

项目金额： 20万元

中文摘要： β-1,4-半乳糖基转移酶-1（β4GalT1）调控的蛋白质糖基化修饰及肿瘤坏死因子-α（TNF-α）自分泌循环在小胶质细胞激活和中枢神经系统（CNS）炎症反应中发挥重要作用。课题组前期发现β4GalT1可调节肿瘤坏死因子受体1（TNFR1）的糖基化修饰，据此提出β4GalT1通过调控TNFR1糖基化修饰，影响其与TNF-α的结合，参与TNF-α自分泌循环，调节小胶质细胞炎性激活和CNS炎症反应。课题拟首先明确TNFR1的糖基化修饰、分析其对TNFR1配受体结合能力、胞内转运及蛋白稳定性的影响；接着分析β4GalT1对TNFR1糖基化修饰的调控机制；在此基础上明确β4GalT1调节TNFR1糖基化修饰对小胶质细胞TNF-α自分泌循环的影响；最后分析上述修饰调节在小胶质细胞炎性激活及继发性神经元炎性损伤中的作用。本研究为阐明蛋白质糖基化修饰在CNS疾病中的作用提供实验依据。

中文关键词： β1；4-半乳糖基转移酶-1；肿瘤坏死因子受体1；糖基化修饰；小胶质细胞；神经炎症

英文摘要： Accumulating evidence demonstrated that beta 1,4-galactosyltransferaseⅠ(β4GalT1)-regulated protein glycosylation and the autocrine loop of tumor necrosis factor receptor-α (TNF-α) greatly contribute to microglia activation and the inflammation of central nervous system (CNS). The results of our preliminary experiments suggested that β4GalT1 could bind with TNF-α receptor 1 (TNFR1) and regulate TNFR1 glycosylation in microglia. Based on these findings, we hypothesized that, in microglia, β4GalT1 modulates TNFR1 glycosylation and facilitates its capability of binding with TNF-a, through which β4GalT1 promotes the formation of TNF-α autocrine loop, advances microglia activation and thus participates in the CNS inflammation. To verify this hypothesis, in this project, first, we will study the glycosylation of TNFR1 in mice microglia, and analyze its influence on the protein stability, intracellular transport and ligand binding capability of TNFR1; next, we plan to analyze the interaction between β4GalT1 and TNFR1, and evaluate β4GalT1-mediated TNFR1 glycosylation in microglia; then, we are going to explore the influences of β4GalT1-mediated TNFR1 glycosylation on the TNF-α autocrine loop in microglia; finally, we aim to demonstrate its significance in microglia inflammatory activation and the subsequent neural injury. Based on the above observations, we are going to systematically analyze the biological significance of β4GalT1-regulated TNFR1 glycosylation during microglia activation and CNS inflammation. By this study, we aim to provide some valuable experimental evidence for a better understanding of the significance of protein glycosylation in microglia inflammatory activation and CNS disease.

英文关键词： beta 1;4-galactosyltransferaseⅠ(β4GalT1);tumor necrosis factor receptor 1 (TNFR1);glycosylation;microglia;neuroinflammation