Carbohydrate-Dependent Adhesion in Normal&Tumor Cells

这个项目研究了选择素配体的结构、生物合成和在细胞间通讯中的作用。它还旨在阐明碳水化合物结合蛋白-碳水化合物相互作用在肿瘤细胞扩散和炎症中的作用。该计划项目是研究人员之间的密切合作，这些研究人员的专长范围从碳水化合物合成化学、碳水化合物化学、碳水化合物生物合成到细胞和分子生物学。这项工作围绕唾液酸基Le/x和相关的寡糖结构展开，最初是由这项赠款的参与者作为E-选择素配体发现的。将研究E-、P-和L-选择素配体在人和小鼠体内的结构和生物合成。特别是，特定的岩藻糖基转移酶(S)和磺基转移酶(S)在选择素配体形成中的作用将通过基因敲除小鼠来确定。选择素或选择素相关分子与肿瘤细胞上唾液酸化Le/x的相互作用将被表征。特别是，肿瘤细胞碳水化合物在自然杀伤(NK)细胞介导的细胞溶解中的作用将被阐明。同时，NK细胞碳水化合物和黏附分子在肿瘤细胞靶向中的作用将被确定。这些研究将为正常和病理条件下选择素-碳水化合物以及选择素相关分子-碳水化合物相互作用提供新的信息。在这些研究中获得的知识可能有助于设计针对恶性肿瘤和其他疾病的改进的治疗干预措施。

This program project examines the structure, biosynthesis, and roles of selectin ligands in cell-cell communication. It also aims at elucidating the roles of carbohydrate binding protein-carbohydrate interactions in tumor cell dissemination and inflammation. This program project is a close collaboration among investigations whose expertise ranges from carbohydrate synthetic chemistry, carbohydrate chemistry, carbohydrate biosynthesis, to cellular and molecular biology. This work centers around the sialyl Le/x and related oligosaccharide structures originally discovered by the participants in this grant as E- selectin ligands. The structure and biosynthesis of E-, P-, and L-selectin ligands in humans and mice will be investigated. In particular, the roles of specific fucosyltransferase(s) and sulfotransferase(s) in the formation of selectin ligands will be determined by using knockout mice. Interactions of selectin or selectin-related molecules with sialyl Le/x on tumor cells will be characterized. In particular, the roles of tumor cell carbohydrates in nature killer (NK) cell-mediated cytolysis will be elucidated. Concurrently, the roles of NK cell carbohydrates and adhesion molecules will be determined in tumor cell targeting. These studies will provide new information on selectin-carbohydrate and selectin-related molecule-carbohydrate interactions under normal and pathological conditions. The knowledge obtained in these studies may help in the design of improved therapeutic interventions against malignancies and other diseases.