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TRYPANOSOME VARIANT SURFACE GLYCOPROTEIN CARBOHYDRATES

锥虫变体表面糖蛋白碳水化合物

基本信息

批准号：
2065209
负责人：
HERMAN VAN HALBEEK
金额：
$ 12.39万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-30 至 1995-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2065209
关键词：
Trypanosoma Trypanosoma brucei rhodesiense acetylcholinesterase carbohydrate structure erythrocytes glycoprotein structure glycosylation host organism interaction human tissue laboratory mouse laboratory rat mass spectrometry microorganism culture nuclear magnetic resonance spectroscopy oligosaccharides protozoal antigen surface antigens trypanosomiasis

项目摘要

African trypanosomiasis is a parasitic disease affecting large areas of the African continent. It presents a threat to man and drastically impedes effective cattle-rearing. The causative agents of this infectious disease are members of the genus Trypanosoma. The parasite evades the mammalian host's immunological response to its presence in body fluids by antigenic variation: the expression of a sequence of immunologically distinct glycoprotein coats over the entire surface of the cells of the invading organism. These variant surface glycoproteins (VSGs) have one or more N-linked glycans and are anchored in the trypanosome membrane by a glycosyl-phosphatidyl-inositol(GPI) moiety. Of the three classes of VSGs (distinguished on the basis of the C-terminal amino acid), the covalent structures of the GPI anchors and N-glycans of only two VSGs, both of class I, of only one trypanosome species (T. b. brucei) have been fully elucidated. The primary aim of the proposed research is to structurally characterize the GPI anchors and N-glycans of a variety of trypanosome VSGs to determine whether such oligosaccharides are significantly different to those of mammalian glycoproteins. Preliminary data indicate that the GPI anchors and the N-glycans of trypanosomes are different from those of the mammalian host. The GPI anchors in particular are considered prime potential targets for chemotherapeutic treatment of trypanosomiasis. We propose to characterize the carbohydrate structures of the VSGs of six trypanosome variant antigen types, and compare them with those of mammalian glycoproteins. In particular we propose to: 1. Isolate the VSGs and their carbohydrate moieties from T. b. rhodesiense LouTat 1 and 1A (both class I), and from T. b. rhodesiense LouTat 1.5 and T. congolense YNat 1.1 and 1.3 (all class II), grown in rodents and/or in vitro. Obtain a class III VSG and the GPI anchor from a mammalian glycoprotein (human erythrocyte acetylcholinesterase, AChE) from collaborators. 2. Characterize the structures of the VSG GPI anchors and compare them with each other. Look for host influence on VSG GPI glycosylation. Compare the structures to the structure of the GPI anchor of AChE. 3. Structurally characterize the N-glycans from the VSGs and investigate the presence of unusual structural elements. Look for host influence on VSG N-glycosylation. The long-term aim is to find a target for the development of chemotherapeutic agents. The proposed studies should provide the foundation necessary for further research leading to the development of new reagents for the treatment of African trypanosomiasis.

非洲锥虫病是一种寄生虫病，非洲大陆。它对人类构成威胁，有效的养牛。这种传染病的病原体属于锥虫属寄生虫避开哺乳动物宿主对体液中存在的抗原产生的免疫反应变异：一系列免疫学上不同的糖蛋白覆盖在入侵细胞的整个表面，有机体这些变体表面糖蛋白（VSG）具有一个或多个 N-连接的聚糖，并通过一个锚定在锥虫膜上。糖基-磷脂酰-肌醇（GPI）部分。在三类VSG中（基于C-末端氨基酸区分），共价键仅两个VSG的GPI锚和N-聚糖的结构，两者都是类 I，仅为一种锥虫（T. B.已充分阐明。拟议研究的主要目的是从结构上表征 GPI锚和各种锥虫VSG的N-聚糖，以确定这些低聚糖是否与哺乳动物糖蛋白初步数据显示GPI锚锥虫的N-聚糖与哺乳动物的不同，主持人特别是GPI锚被认为是主要的潜在目标用于锥虫病的化学治疗。我们建议表征了六种锥虫VSG的糖结构不同的抗原类型，并与哺乳动物的抗原类型进行比较，糖蛋白我们特别建议： 1. 从T. B. rhodesienseLouTat 1和1A（均为I类），以及T. B.罗德西亚 LouTat 1.5和T.刚果YNat 1.1和1.3（均为II类），生长于啮齿动物和/或体外。从以下机构获得III级VSG和GPI锚：哺乳动物糖蛋白（人红细胞乙酰胆碱酯酶，AChE），合作者 2. 描述VSG GPI锚钉的结构并进行比较彼此之间寻找宿主对VSG GPI糖基化的影响。将这些结构与乙酰胆碱酯酶GPI锚的结构进行比较。 3. 对VSG中的N-聚糖进行结构表征，调查是否存在不寻常的结构元素寻找主机影响VSG N-糖基化。长期目标是找到一个发展目标，化疗剂。拟议的研究应提供进一步研究所需的基础，导致新的发展治疗非洲锥虫病的试剂。