Endothelial Dysfunction and Restoration in Trauma Induced Coagulopathy

项目总结/摘要： 创伤性凝血病（TIC）是严重损伤后发病率和死亡率的主要驱动因素。 影响多达30%的危重创伤患者，TIC代表了一系列凝血表型 从早期的止血受损到后期的微血管和大血管血栓并发症。我们有 发现TIC患者有严重内皮损伤的证据，这些内皮标志物 损伤与创伤结局密切相关。此外，通过随机对照试验， 医院血浆作为复苏工具，我们已经确定血浆输注可以减少内皮细胞 即使在受伤严重程度最高的患者中也是如此。血浆输注可降低重度脑梗死后的死亡率 创伤，但确切的受益机制尚不清楚。在本建议中，我们针对中央 假设内皮是TIC的中心调节器。我们建议， 内皮作为适应不良反应的调节器和血栓形成-炎症的关键界面 串话。我们的策略将集中于确定创伤后诱导内皮细胞增殖的关键循环介质， 损伤我们将利用“线索，信号，反应”的框架，以强大的分子途径的特点 以及内皮反应如何与凝血变化相互作用 反应最后，我们将定义血浆输注产生的“修复性表型”， 内环境平衡。我们将用它来测试靶向治疗，以解决创伤中未满足的需求。 针对内皮健康的复苏。该方法将利用国家的科学和新颖的 蛋白质组学、转录组学、代谢组学、高级微血管成像和临床前研究技术 创伤和出血模型，以及先前收集的创伤患者的大量资料库 样品

Project summary/abstract: Trauma-induced coagulopathy (TIC) is a leading driver of morbidity and mortality following severe injury. Affecting as many as 30% of critically ill trauma patients, TIC represents a spectrum of coagulation phenotypes ranging from early impaired hemostasis to later micro and macrovascular thrombotic complications. We have identified that patients with TIC have evidence of severe endothelial damage, and these markers of endothelial injury correlate closely with outcomes in trauma. Further, through randomized controlled trials testing pre- hospital plasma as a resuscitation tool, we have identified that plasma transfusion can reduce endothelial injury, even in the patients with the highest injury severity. Plasma transfusion reduces mortality after severe trauma, but the exact mechanism of benefit is unknown. In the present proposal, we address the central hypothesis that the endothelium is a central regulator of TIC. We propose to characterize the role of the endothelium as the regulator of maladaptive response and a crucial interface for thrombosis-inflammation crosstalk. Our strategy will focus on identifying key circulating mediators after trauma that induce endothelial injury. We will utilize a “cue, signal, response” framework to robustly characterize the molecular pathways activated in the endothelial and how the endothelial response interfaces with changes in the coagulation response. Finally, we will define the “reparative phenotype” that plasma transfusion creates, restoring the endothelium to homeostasis. We will use this to test targeted therapies to address the unmet needs in trauma resuscitation targeting endothelial health. The approach will leverage state-of-the-science and novel techniques in proteomics, transcriptomics, metabolomics, advanced microvascular imaging, and pre-clinical models of trauma and hemorrhage in addition to a large repository of previously collected trauma patient samples.