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Regulation of Helicobacter pylori by O-glycan

O-聚糖对幽门螺杆菌的调节

基本信息

批准号：
14082201
负责人：
NAKAYAMA Jun
金额：
$ 43.2万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

项目摘要

Aim of this study is to determine the role of O-glycans expressed in the gastric mucosa infected by Helicobacter pylori (H. pylori). The gland mucin secreted from lower portion of the gastric mucosa contains α1,4-GlcNAc-capped O-glycan (αGlcNAc). H.pylori exclusively colonizes the surface mucin, whereas this microbe is not found in the gland mucin. We demonstrated that H.pylori cultured in the presence of αGlcNAc exhibited its reduced cell growth and motility as well as abnormal morphology and that cholesteryl-α-D-glucopyranoside (CGL), a major cell wall of H.pylori, was critical for their survival. We identified CHLαGcT gene, which encodes the glycosyltransferase responsible for the biosynthesis of CGL, by expression cloning, and showed that its enzymatic activity was inhibited by αGlcNAc. These results combined together indicate that αGlcNAc functions as a natural antibiotic against H.pylori infection by suppressing the CGL biosynthesis. By manipulating the gene encoding α1,4-N-acety … More lglucosaminyltransferase responsible for αGlcNAc biosynthesis, we have generated both knockout mice deficient in αGlcNAc and transgenic mice ectopically expressing αGlcNAc in the surface mucin. The future study will be directed to elucidate the in vivo function of αGlcNAc in the gastric mucosa using these genetically-engineered mice.We then investigated the mechanism for lymphocyte infiltration in chronic active gastritis caused by H.pylori infection. It was demonstrated that the number of high endothelial venule (HEV)-like vessels expressing O-glycan having 6-sulfo sialyl Lewis X (ssLeX) increased as chronic inflammation progressed. We also found that these HEV-like vessels were bound by L-selectin-IgM chemeric protein. These results indicated that the L-selectin-mediated lymphocyte homing takes place in the chronic active gastritis.Thus, it is concluded that the two types of O-glycans, αGlcNAc and ssLeX, play pivotal roles in the gastric mucosa infected by H.pylori in a carbohydrate-dependent manner. Less

本研究旨在探讨幽门螺杆菌（H。pylori）。从胃粘膜下部分泌的腺粘蛋白含有α 1，4-GlcNAc-帽的O-聚糖（αGlcNAc）。幽门螺杆菌只在表面粘蛋白中定植，而这种微生物在腺体粘蛋白中没有发现。我们证明，在存在αGlcNAc的情况下培养的幽门螺杆菌表现出其细胞生长和运动性降低以及形态异常，并且幽门螺杆菌的主要细胞壁胆固醇-α-D-吡喃葡萄糖苷（CGL）对其存活至关重要。我们通过表达克隆的方法鉴定了CHLαGcT基因，该基因编码的糖基转移酶负责CGL的生物合成，并表明其酶活性受到αGlcNAc的抑制。这些结果结合在一起表明，αGlcNAc通过抑制CGL生物合成作为抗幽门螺杆菌感染的天然抗生素发挥作用。通过操纵编码α 1，4-N-乙酰基的基因 ...更多信息由于α-GlcNAc生物合成的关键酶是L-葡糖胺基转移酶，我们已经产生了α-GlcNAc缺陷的基因敲除小鼠和在表面粘蛋白中异位表达α-GlcNAc的转基因小鼠。本研究将进一步探讨αGlcNAc在胃粘膜中的功能，以及幽门螺杆菌感染引起的慢性活动性胃炎中淋巴细胞浸润的机制。研究表明，随着慢性炎症的进展，表达具有6-磺基唾液酸刘易斯X（ssLeX）的O-聚糖的高内皮微静脉（HEV）样血管的数量增加。我们还发现这些HEV样血管与L-选择素-IgM结合。结果表明，慢性活动性胃炎中存在L-选择素介导的淋巴细胞归巢，提示αGlcNAc和ssLeX两种O-聚糖在幽门螺杆菌感染的胃粘膜中以糖依赖的方式起关键作用。少