MOLECULAR INTERACTIONS IN INFLAMMATION AND COAGULATION

炎症和凝血中的分子相互作用

• 批准号: 2460142
• 负责人: Charles T Esmon
• 金额: $ 112.14万
• 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/2460142
• 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关过程 和血管损伤。为了解决这些途径的机制 我们的直接目标是分析结构-功能 特异性受体及其配体之间的关系 强调这些相互作用如何调节细胞的功能， 参与的蛋白质。项目1将分析 蛋白C和活化蛋白C（APC）与 内皮细胞蛋白C受体（EPCR），这种影响 APC功能和酶特异性的相互作用，以及EPCR的作用 项目2将研究炎症的分子机制， 负责有限的底物特异性表现出的 凝血酶，APC和Xa因子，以及这些因子的分子机制。 辅因子调节这些酶的功能。项目3将分析 P-和E-选择素关键结构-功能关系 与靶配体PSGL-1相互作用，并将这些发现与 在静态和流动条件下白细胞相互作用的研究。 项目4通过表征寡糖补充项目3 PSGL-1对P-selectin相互作用的关键作用以及PSGL-1的作用机制 1生物合成。我们的长期目标是了解这些 系统相互作用。我们设想这些问题之间存在以下潜在联系 项目P和E-介导的白细胞与内皮细胞的粘附 选择素可增加局部炎症介质浓度 （弹性蛋白酶或细胞因子），可以直接或间接抑制 蛋白C通路的功能。例如，EPCR下降 由肿瘤坏死因子（TNF）调节。APC表现出明显的抗- 体内炎症活性。结合APC的EPCR与 CD 1/MHC超家族参与炎症。这表明EPCR 可能与炎症有关，EPCR是一种候选药物， 有助于体内观察到的APC的抗炎活性。 白细胞与选择素的粘附可能调节EPCR 表达和功能。从这些数据中得到的结构信息 研究应该允许设计特定的抑制剂， 有助于分析细胞粘附和细胞粘附之间的生理联系， 炎症介导的血管损伤，以及蛋白C的作用 制度来规范这个过程。