NOVEL L-SELECTIN LIGAND

新型L-选择素配体

• 批准号: 2656769
• 负责人: RORY M MARKS
• 金额: $ 10万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2656769
• 关键词: laboratory rabbit; leukocyte adhesion molecules; ligands; selectins; vascular endothelium

Selectin adhesion molecules are principally responsible for the initial rolling-adhesion interaction between circulating leukocytes and vascular endothelium. Rolling-adhesion is a necessary prelude to the leukocyte immobilization, transendothelia migration, and tissue accumulation that occurs as part of normal inflammation, as well as in pathological inflammation that causes tissue injury in autoimmune diseases. Endothelial E-, and P- Selectin, and leukocyte L-Selectin are a gene family of 3 closely related molecules, whose amino-terminal lectin domain is principally responsible for binding to fucosylaated, sialylated, and sulfated oligosacchardide counter-receptors expressed on leukocytes and endothelial cells respectively. Leukocyte L-Selectin was originally described as a lymphocyte homing receptor for lymph nodes. However L-Selectin is expressed on all leukocytes, including neutrophils, and it is clear that L-Selectin is required for expression of a normal inflammatory response in non-lymphoid tissues. This implies that endothelial cell ligands for L-Selectin are expressed in acute inflammation, however, none have been identified. In the first specific aims we propose to complete the characterization and identification of a novel L-Selectin ligand expressed by rabbit (non-lymphoid) aortic endothelial cells. Preliminary experiments have indicated a single molecular species of molecular weight 240,000 that is not functionally dependent on sialylation, but is however, dependent on sulfation. The molecule does not have the characteristics of a glycosaminoglycan, indicating that it is likely to be an O-linked mucin related to other L-Selectin ligands. The molecule is expressed on the apical surface of the endothelial cells, indicating its relevance to leukocyte adhesion. In the second specific aim we propose to utilize the mono-specific binding assay we have developed to assess L-Selectin binding to native ligands, to discover compounds, whose structure is based on the structure of known selectin ligands, that have potential to block L-Selectin-dependent leukocyte-endothelial adhesion.

选择素粘附分子主要负责 循环白细胞间的初始滚动-粘附相互作用 和血管内皮。 轧制-粘附是必要的前奏 白细胞固定，跨内皮细胞迁移， 作为正常炎症的一部分发生的组织积聚，如 以及导致组织损伤的病理性炎症， 自身免疫性疾病内皮E-和P-选择素，以及 白细胞L-选择素是3个密切相关基因家族 分子，其氨基末端凝集素结构域主要是 负责结合岩藻糖基化、唾液酸化和硫酸化 白细胞上表达的寡糖反受体， 内皮细胞。 白细胞L-选择素最初是 被描述为淋巴结的淋巴细胞归巢受体。 然而，L-选择素在所有白细胞上表达，包括 中性粒细胞，很明显，L-选择素是必需的， 非淋巴组织中正常炎症反应的表达 组织中 这意味着L-选择素的内皮细胞配体 在急性炎症中表达，然而， 鉴定 在第一个具体目标中，我们建议完成 一种新的L-选择素配体的结构鉴定 由兔（非淋巴）主动脉内皮细胞表达。 初步实验表明， 分子量为240，000，在功能上不依赖于 唾液酸化，但是依赖于硫酸化。 分子 不具有糖胺聚糖的特征， 这表明它可能是一种O-连接的粘蛋白，与其他 L-选择素配体。该分子表达在细胞的顶端 表面的内皮细胞，表明其相关性 白细胞粘附 在第二个具体目标中，我们建议 利用我们开发的单特异性结合测定， 评估L-选择素与天然配体的结合，以发现 化合物，其结构是基于已知的结构， 选择素配体，具有阻断L-选择素依赖性 白细胞-内皮细胞粘附。