MECHANISM OF HUMAN TRANSENDOTHELIAL LEUKOCYTE MIGRATION

人类跨内皮白细胞迁移机制

• 批准号: 2771366
• 负责人: SAMUEL CHARLES SILVERSTEIN
• 金额: $ 27.51万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2771366
• 关键词: calcium flux; cell migration; chemoattractants; human tissue; intercellular connection; monocyte; myosin light chain kinase; myosins; phosphoproteins; phosphorylation; tissue /cell culture; vascular endothelium; vascular endothelium permeability

Inflammation plays a major role in the pathogenesis of many diseases including atherosclerosis, immune complex-mediated responses and the long term sequelae of many infections. Leukocyte migration across the vascular endothelium is a critical step in an inflammatory response. While much is known about leukocyte adhesion to EC, the mechanism by which leukocytes open the junctions between EC is unknown. Stimulated PMN signal an increase in EC cytosolic free calcium concentrations. Such increases in EC (Ca++ (i) regulate transendothelial migration indicated that simulated PMN produce an extracellular substance. Monocytes and a human monocytic cell line, THP-1, also initiate increases in EC *(Ca+++(i) which regulates transendothelial monocyte migration. These findings form the basis for the hypothesis that leukocytes signal the opening of junctions between EC in order to migrate across EC barrier. The following aspects of the hypothesis will be studied: 1). identify/characterize the substance (s) by stimulated PMN s that increase in EC ((Ca++(i), phosphorylation of EC MLC, and the permeability of EC MLC, and the permeability of EC megalocytes establish the biological properties of this product 3). determine the role of EC protein kinases, such as MLC kinase, in medicating leukocyte migration across EC monolayers. An in vitro system of culturing EC on human amniotic membranes and methods for measuring EC ((Ca++(i), EC monocyte permeability to ions, EC MLC phosphorylation and leukocyte migration across EC monolayers will be used to perform these studies. The studies proposed in this application should contribute to an understanding of the mechanisms by which leukocytes migrate across EC barriers and by which EC regulate vascular permeability. An understanding of these processes well provide a basis for developing rational strategies for athe prevention/treatment of diseases characterized by inflammation.

炎症在许多疾病的发病机制中起主要作用 包括动脉粥样硬化，免疫复合物介导的反应和长期的 许多感染的长期后遗症。 白细胞穿过血管迁移 内皮是炎症反应中的关键步骤。 虽然很多 关于白细胞粘附EC的已知，白细胞粘附EC的机制， 打开EC之间的连接是未知的。 中性粒细胞刺激信号 EC胞浆游离钙浓度增加。 EC的这种增加 (Ca++（i）调节跨内皮迁移表明模拟PMN 产生细胞外物质。 单核细胞和人单核细胞 细胞系THP-1也启动EC *（Ca+（i））的增加， 跨内皮单核细胞迁移。 这些发现构成了 假设白细胞信号EC之间的连接打开 以便跨越EC屏障迁移。 的以下方面 假设将被研究：1）。 鉴别/表征物质 通过刺激的PMN增加EC（（Ca++（i），EC的磷酸化 MLC和EC的渗透性MLC和EC的渗透性 巨细胞确立了该产品的生物学特性3）。 确定EC蛋白激酶如MLC激酶在药物治疗中的作用， 白细胞跨EC单层迁移。 一种体外培养系统， 人羊膜上的EC和用于测量EC（（Ca++（i），EC 单核细胞离子渗透性、EC MLC磷酸化和白细胞 跨EC单层的迁移将用于进行这些研究。 的 本申请中提出的研究应有助于理解 白细胞通过EC屏障迁移的机制， EC调节血管通透性。 了解这些 过程很好地为制定合理的可持续发展战略提供了基础 预防/治疗以炎症为特征的疾病。