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

几种岩藻糖化低聚糖的功能是 人类E-、P-和L-选择的配体。选择素依赖的白细胞- 内皮细胞的黏附依赖于这些特定的岩藻糖基化， 唾液酸化和/或硫酸盐化部分，由唾液酸基-Lex分子表示 (SLeX)及其结构异构体。这些岩藻糖化的电荷 低聚糖和α(1，3)岩藻糖基转移酶(α(1，3)FTs) 可以调节它们的合成，代表着 涉及选择素依赖细胞的情况下的治疗干预 粘连，在恶性肿瘤和炎症中。这个项目中的研究将 重点确定两种Fuc-ts的寡糖产品(Fuc-TIV和Fuc-TIV FUC-TVii)直接表达白细胞和内皮细胞 其他三种Fuc-T(Fuc-TiII、V和VI)上的选择素配体 选择素配体在肿瘤细胞上的直接表达及其作用 这些酶及其产物在白细胞发病机制中的作用 恶毒。 具体目标如下： (1)确定硫化和/或唾液酸化的寡糖受体 与选择相关的Fuc-TIV和Fuc-pTVII的底物特异性 配基。 (2)确定低聚糖的结构和功能 利用基因产生的小鼠零突变细胞获得Fuc=TIV和Fuc-TVii 基因敲除细胞系和转基因细胞系。 (3)探讨选择素配体在糖尿病发病机制中的作用。 利用Fuc-TVii对突变小鼠和α-T细胞的杀伤作用 甘露糖苷酶IIx缺陷小鼠。 这些研究将使我们了解两个人的角色 岩藻糖基转移酶在选择素配体呈递中的研究进展 生物体和造血细胞恶性肿瘤。

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.