项目名称: FVIIa-TF-FXa复合物介导的血管内皮细胞保护机制在进展性脑挫裂伤出血中的作用
项目编号: No.81471241
项目类型: 面上项目
立项/批准年度: 2015
项目学科: 医药、卫生
项目作者: 吴惺
作者单位: 复旦大学
项目金额: 70万元
中文摘要: 进展性脑挫裂伤出血是影响脑外伤患者预后的一个重要因素。在前期一系列的研究中,我们发现作为启动外源性凝血途径中的核心,血浆中FVIIa水平的降低直接参与了进展性脑挫裂伤出血的发生。FVIIa不仅通过直接外源性凝血途径减少血肿的进展,还可能通过维持微血管完整性减少进展性脑挫裂伤出血,其分子机制尚不明确。我们将以此为研究重点,联合运用EPCR low血管内皮细胞,TF/EPCR表达的CHO细胞,PARs酶切定量算法,FVII突变体等多种方法,探讨FVIIa-TF-FXa复合体对PAR2受体的直接激活作用,以及通过EPCR间接激活PAR1的作用,分析其对下游MAPK和NF-κB信号通路的影响。最后,研究FVIIa-TF-FXa复合体对内皮细胞通透性和骨架蛋白稳定性的维持作用,从而全面解释FVIIa-TF-FXa复合体在进展性脑挫裂伤出血中作用机制,为早期干预提供理论基础和实践指导。
中文关键词: 颅脑创伤;进展性脑出血;脑挫裂伤;第七因子;血管内皮细胞
英文摘要: Progressive brain contusion hemorrhage is an important factor affecting the prognosis of patients with TBI. In a series of preliminary studies, we found that as the core in extrinsic coagulation pathway, lower levels of FVIIa directly involved in the progression of brain contusion hemorrhage. FVIIa not only reduce progressive hemorrhage by activating the extrinsic coagulation pathway, but also by maintaining integrity of microvascular. However, its molecular mechanism is still unknown. We will focus on our point to the mechanism. Therefore, we explore the direct activation of PAR2 receptors by FVIIa-TF-FXa complex and the indirect activation of PAR1 through EPCR by FVIIa-TF-FXa complex, analyze its downstream MAPK and NF-κB signaling pathway, and investigate the protection of barrier function by FVIIa-TF-FXa complex by using EPCR lowe endothelial cells, TF/EPCR expressing CHO cells, quantification of PARs cleavage, and FVII mutant. Finally, we fully explain the mechanism of FVIIa-TF-FXa complex in reduction of progressive brain contusion hemorrhage, which provides the theoretical basis and practical guidance for early intervention.
英文关键词: traumatic brain injury;progressive hemorrhage;brain contusion;factor VII;endothelial cell