MOLECULAR INTERACTIONS IN INFLAMMATION AND COAGULATION

炎症和凝血中的分子相互作用

• 批准号: 2233263
• 负责人: Charles T Esmon
• 金额: $ 106.74万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2233263
• 关键词: blood coagulation; coagulation factor X; inflammation; protein C; selectins

Inflammation and coagulation are linked processes leading to thrombosis and vascular injury. To address the mechanisms by which these pathways interact, our immediate goal is to analyze structure-function relationships between specific receptors and their ligands with an emphasis on how these interactions may modulate the function of the proteins involved. Project 1 will analyze the molecular basis for the interaction of protein C and activated protein C (APC) with the endothelial cell protein C receptor (EPCR), the influence of this interaction on APC function and enzyme specificity, and the role EPCR plays in inflammation Project 2 will examine the molecular mechanisms responsible for the restricted substrate specificity exhibited by thrombin, APC, and factor Xa, and the molecular mechanisms by which the cofactors modulate the function of these enzymes. Project 3 will analyze structure-.function relationships critical to P- and E-selectin interaction with a target ligand, PSGL-1, and correlate these findings with studies of leukocyte interaction under static and flow conditions. Project 4 complements Project 3 by characterizing the oligosaccharides on PSGL-1 critical for P-selectin interaction and the mechanisms of PSGL- 1 biosynthesis. Our long term objective is to understand how these systems interact. We envision the following potential links among these projects. Adhesion of leukocytes to endothelium mediated by P and E- selectin can increase the local concentration of inflammatory mediators (elastase or cytokines) that can either directly or indirectly inhibit the function of the protein C pathway. For instance, EPCR is down regulated by tumor necrosis factor (TNF). APC exhibits apparent anti- inflammatory activity in vivo. EPCR, which binds APC, is homologous to the CD1/MHC superfamily involved in inflammation. This suggests that EPCR may be involved in inflammation and that EPCR is a candidate to contribute to the anti-inflammatory activity of APC observed in vivo. Leukocyte adhesion to selectins is likely to modulate both EPCR expression and function. The structural information derived from these studies should allow the design of specific inhibitors that would facilitate analysis of the physiological links between cell adhesion and inflammation-mediated vascular damage, and the role of the protein C system in regulating this process.

炎症和凝血是导致血栓形成的相互关联的过程 以及血管损伤。为了解决这些途径的机制 互动，我们的直接目标是分析结构-功能 特异性受体及其配体与血管紧张素转换酶的关系 强调这些相互作用可能如何调节 所涉及的蛋白质。项目1将对分子基础进行分析 蛋白C与活化蛋白C(APC)的相互作用 血管内皮细胞蛋白C受体(EPCR)的表达及其影响 APC功能与酶特异性的相互作用及EPCR的作用 在炎症项目2中发挥作用将研究分子机制 对受限制的底物专一性负责 凝血酶、APC和凝血因子Xa，以及 辅因子调节这些酶的功能。项目3将分析 结构-功能关系对P-和E-选择素至关重要 与靶配体PSGL-1的相互作用，并将这些发现关联起来 研究静态和流动条件下的白细胞相互作用。 项目4通过表征低聚糖来补充项目3 P-选择素相互作用的关键因子PSGL-1及其作用机制 1生物合成。我们的长期目标是了解这些 系统相互作用。我们设想了以下这些之间的潜在联系 项目。P和E-受体介导的白细胞与内皮细胞的黏附 选择素可以增加局部炎症介质的浓度 (弹性酶或细胞因子)可直接或间接抑制 蛋白C途径的功能。例如，EPCR出现了故障 受肿瘤坏死因子(TNF)的调节。APC表现出明显的反 体内炎症活性。与APC结合的EPCR同源于 CD1/MHC超家族参与炎症反应。这表明，EPCR 可能与炎症有关，而外源聚合酶链式反应是 有助于在体内观察到APC的抗炎活性。 白细胞与选择素的黏附可能调节两种EPCR 表情和功能。从这些数据中得出的结构信息 研究应该允许设计特定的抑制剂，以 促进分析细胞黏附和细胞间的生理联系 炎症介导的血管损伤和蛋白C的作用 监管这一过程的制度。