Mechanism of Traumatic Coagulopathy

申请者描述(由申请人提供)：申请人将在本授权书中检验以下假设，即急性创伤性凝血障碍主要是由组织低灌流引起的，导致补体介导的激活和随后的蛋白C途径耗尽(目标1和2)。虽然AIMS 1和AIMS 2中详细介绍的体外和体内方法将提供有关急性创伤性凝血障碍的重要机制信息，但凝血系统如此复杂，无法使用传统的级联方法完全可视化。申请人将检验这样的假设，即网络拓扑和动态建模中的新技术将允许卓越的可视化，并预测创伤后蛋白C系统的结构和功能的变化(目标3)。具体地说，他将首先使用创伤/休克的小鼠模型来确定创伤和低灌流后蛋白C的扰动时间和机制。其次，他将使用体内小鼠模型和体外内皮细胞缺血再灌注模型来测试补体在创伤和休克后蛋白C激活中的作用。第三，他将利用蛋白C途径的网络表示以及新构建的蛋白C动态模型来模拟创伤和休克后的蛋白C途径。这些实验中获得的信息将对人类具有重要的治疗意义。来自创伤患者的初步数据构成了这项赠款申请的基础，这些数据表明，凝血和补体异常在创伤后早期就开始了，并与显著的发病率和死亡率增加有关。因此，了解与创伤后凝血和补体异常相关的分子和系统水平的机制可能为创伤患者的治疗提供新的途径。这里的担忧是，该模型确实复制了患者临床上出现的元素。典型的创伤患者不仅遭受血管内容量的损失，而且还伴有组织损伤。损伤组织是损伤负担的重要组成部分，也是造成损伤后动态平衡失调的重要原因。这将如何影响对实验模型输出的解释需要由申请人直接考虑。目标3需要基于目标1和目标2数据的结果进行动态建模，因此是一种有趣的方法。问题是，它将如何被验证为反映了创伤患者的情况？

DESCRIPTION (provided by applicant): The applicant will test in this grant the hypothesis that acute traumatic coagulopahty is primarily caused by tissue hypoperfusion resulting in a complement mediated activation and subsequent depletion of the protein C pathway (AIMS 1 and 2). While the in vitro and in vivo approaches detailed in AIMS 1 and 2 will provide important mechanistic information regarding acute traumatic coagulopathy, the coagulation system is of such complexity to be completely visualized using the traditional cascade. The applicant will test the hypothesis that new techniques in network topology and dynamic modeling will allow for superior visualization and predict changes in the structure and function of the protein C system after trauma (AIM 3). Specifically he will first use a mouse model of trauma/shock to determine the timing and mechanism of perturbations in protein C after trauma and hypoperfusion. Secondly, he will use both the in vivo mouse model as well as an in vitro model of endothelial cell ischemia reperfusion to test the role of complement in activation of protein C after trauma and shock. Third, he will utilize a network representation of the protein C pathway as well as a newly constructed dynamic model of protein C to model in silico the protein C pathway after trauma and shock. The information obtained in these experiments will have important therapeutic significance in humans. The preliminary data from trauma patients that form the rationale for this grant application indicates that coagulation and complement abnormalities begin early after trauma, and are associated with significant morbidity and increased mortality. Thus understanding the molecular and systems level mechanisms associated with post traumatic coagulation and complement abnormalities may provide new avenues for therapy in trauma patients. The concerns here are that the model does replicate elements of what patients present with clinically. The typical trauma patient has not suffered only a loss on intravascular volume but has associated tissue injury. Damaged tissue represents an important part of the injury burden and contributes to the post injury dyshomeostasis. How this will impact the interpretation of the experimental model output needs to be directly considered by the applicant. Aim 3 entails dynamic modeling based on the results of Aim 1 and 2 data and as such is an interesting approach. The question is how will it be validated as reflective of what occurs in trauma patients?