THE A(1,3)FUCOSYLTRANSFERASE GENES AND SELECTIN LIGAND EXPRESSION

A(1,3)岩藻糖基转移酶基因和选择素配体表达

• 批准号: 6103249
• 负责人: JOHN B LOWE
• 金额: $ 26.5万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6103249
• 关键词: animal breeding; carbohydrate structure; carcinogenesis; cell adhesion; disease /disorder model; enzyme substrate; fucose; gene expression; hexosyltransferase; laboratory mouse; leukocytes; ligands; lymphoma; myelogenous leukemia; oligosaccharides; selectins; tissue /cell culture; transfection; vascular endothelium

Several fucosylated oligosaccharides function as essential components of ligands for human E-, P-, and L-selection. Selectin-dependent leukocyte- endothelial cell adhesion is dependent upon these specific fucosylated, sialylated and/or sulfated moieties, represented by the sialyl-LeX molecule (sLeX) and its structural isomers. These fucosylated charged oligosaccharides, and the alpha(1,3)fucosyltransferases (alpha(1,3)FTs) that can regulate their synthesis, represent pivotal targets for therapeutic intervention in circumstances involving selectin-dependent cell adhesion, in malignancy and in inflammation. Studies in this Project will focus on defining the oligosaccharide products of two Fuc-Ts (Fuc-TIV and Fuc-TVII) that direct expression of leukocytic and endothelial cell selectin ligands, on three other Fuc-Ts (Fuc-TIII, V, and VI) that can direct expression of selectin ligands on cancer cells, and on the role of these enzymes and their products in the pathogenesis of leukocytic malignancy. Specific Aims are as follows: (1) To define the sulfated and/or sialylated oligosaccharide acceptor substrate specificities of Fuc-TIV and Fuc-pTVII relevant to selectin ligands. (2) To determine the structures and functions of oligosaccharides directed by Fuc=TIV and Fuc-TVII utilizing mouse null mutant cells generated by gene knock-out and transfected cell lines. (3) To determine the roles of selectin ligands in the pathogenesis of leukocyte malignancy utilizing Fuc-TVII with null mutant mice and alpha- mannosidase IIx deficient mice. These studies will allow us to understand the roles of two fucosyltransferases in selectin ligand presentation, development of an organism, and hematopoietic cell malignancy.

几种岩藻糖基化低聚糖作为 用于人E-、P-和L-选择的配体。 选择素依赖性白细胞- 内皮细胞粘附依赖于这些特定的岩藻糖基化， 唾液酸化和/或硫酸化部分，由唾液酸化-LeX分子表示 （sLeX）及其结构异构体。 这些岩藻糖基化的电荷 寡糖和α（1，3）岩藻糖基转移酶（α（1，3）FT） 可以调节它们的合成，代表了 在涉及选择素依赖性细胞的情况下的治疗性干预 粘附，在恶性肿瘤和炎症中。 本项目的研究将 重点定义两种Fuc-T的寡糖产物（Fuc-TIV和 Fuc-TVII）直接表达白细胞和内皮细胞 选择素配体，在其他三个Fuc-T（Fuc-TIII，V和VI），可以 选择素配体在癌细胞上的直接表达，以及 这些酶及其产物在白细胞性白血病发病机制中的作用 恶性肿瘤 具体目标如下： (1)定义硫酸化和/或唾液酸化低聚糖受体 与选择素相关Fuc-TIV和Fuc-pTVII的底物特异性 配体。 (2)为了确定寡糖的结构和功能， 通过Fuc=TIV和Fuc-TVII利用由基因产生的小鼠无效突变细胞 敲除和转染的细胞系。 (3)目的探讨选择素配体在原发性肝癌发病机制中的作用。 白细胞恶性肿瘤利用Fuc-TVII与无效突变小鼠和α- 甘露糖苷酶IIx缺陷小鼠。 这些研究将使我们了解两个 岩藻糖基转移酶在选择素配体呈递中的作用， 生物体和造血细胞恶性肿瘤。