REGULATION OF LEUKOCYTE RECIRCULATION

白细胞再循环的调节

• 批准号: 2095966
• 负责人: THOMAS F TEDDER
• 金额: $ 18.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2095966
• 关键词: biological signal transduction; cell adhesion; cell migration; chimeric proteins; enzyme linked immunosorbent assay; epitope mapping; genetic library; human tissue; immunoglobulin G; laboratory mouse; leukocyte adhesion molecules; lymphocyte; molecular cloning; monoclonal antibody; neutrophil; phosphorylation; protein sequence; protein structure function; vascular endothelium

The regulation of leukocyte adhesion to endothelial cells is an essential and complex aspect of leukocyte migration and metastasis. The ability of leukocytes to home to, or localize in, areas of inflammation is also critical for the generation of a rapid immune response. This study will examine the molecules which mediate the interactions between leukocytes and endothelial cells, focusing on the Leukocyte Adhesion Molecule-1. LAM-1 (also called TQ1, Leu-8) is a member of a new family of cellular adhesion molecules, termed selectins, which contain a lectin-like domain at their amino terminus, followed by an epidermal growth factor-like domain and short consensus repeat units similar to those found in complement regulatory proteins. LAM-1 plays a critical role in lymphocyte trafficking by mediating binding to the high endothelial venules (HEV) of peripheral lymph nodes. In addition, LAM-1 is also likely to play a role in the regulation of leukocyte migration to sites of inflammation. LAM-1 is shed from the cell-surface following cellular activation and may therefore also regulate leukocyte migration as a circulating agent. The purpose of this study is to determine the role of LAM-1 in lymphocyte and neutrophil adhesion, how the expression of this cell-surface molecule regulates the migration of leukocytes to regions of importance, and how the structure of LAM-1 dictates its function. The functional capacity of the shed LAM-1 will also be examined to determine its potential role for modifying leukocyte migration. The ligand(s) of this adhesion receptor will also be identified and characterized. In addition to providing a clearer understanding of the molecular events that regulate leukocyte migration and adhesion, these studies may provide biological reagents with clinical utility. For example, we have engineered a soluble form of LAM-1 which blocks binding of leukocytes to endothelial cells. This reagent may prove useful for blocking the dissemination of certain lymphoid tumors or inhibiting the entry of cytotoxic T cells into transplanted organs. Also, since LAM-1 is shed by leukocytes during activation, quantification of the levels of LAM-1 in serum of patients with malignancies or inflammatory disorders may be useful for diagnosis and monitoring of disease status. Finally these studies will also provide a solid basis for understanding the mechanisms by which currently used biologic response modifying agents, such as GM-CSF and IL-2, are able to dramatically alter leukocyte migration in cancer patients undergoing cytokine therapy.

白细胞与内皮细胞粘附的调节是 白细胞迁移和转移的重要且复杂的方面。 白细胞归巢或定位于以下区域的能力 炎症对于快速免疫的产生也至关重要 回复。 这项研究将检查介导 白细胞和内皮细胞之间的相互作用，重点关注 白细胞粘附分子-1。 LAM-1（也称为 TQ1、Leu-8）是 细胞粘附分子新家族的成员，称为 选择素，其氨基处含有凝集素样结构域 末端，随后是表皮生长因子样结构域和 类似于补体中发现的短共有重复单元 调节蛋白。 LAM-1在淋巴细胞中起关键作用 通过介导与高内皮微静脉的结合进行贩运 (HEV) 周围淋巴结。 此外，LAM-1也有可能 在白细胞迁移至以下部位的调节中发挥作用 炎。 LAM-1 随细胞从细胞表面脱落 激活，因此也可能作为调节白细胞迁移的 循环剂。 本研究的目的是确定 LAM-1在淋巴细胞和中性粒细胞粘附中的作用，如何 该细胞表面分子的表达调节 白细胞与重要区域的关系，以及 LAM-1 的结构如何 决定了它的功能。 棚 LAM-1 的功能容量 还将进行检查以确定其修改的潜在作用 白细胞迁移。 该粘附受体的配体将 也被识别和表征。 除了提供 更清楚地了解调节白细胞的分子事件 迁移和粘附，这些研究可能提供生物试剂 具有临床实用性。 例如，我们设计了一种可溶性 LAM-1 形式，可阻断白细胞与内皮细胞的结合 细胞。 该试剂可能有助于阻止传播 某些淋巴肿瘤或抑制细胞毒性 T 的进入 细胞进入移植器官。 另外，由于 LAM-1 是由 激活期间的白细胞，LAM-1 水平的定量 患有恶性肿瘤或炎症性疾病的患者的血清中可能存在 可用于诊断和监测疾病状态。 最后 这些研究也将为理解 目前使用的生物反应调节机制 GM-CSF 和 IL-2 等药物能够显着改变 接受细胞因子治疗的癌症患者的白细胞迁移。