Mechanism of Traumatic Coagulopathy

描述（由申请人提供）：申请人将在本拨款中验证急性创伤性凝血功能障碍主要是由组织灌注不足引起的，导致补体介导的激活和随后的蛋白C通路耗竭（AIMS 1和2）。虽然AIMS 1和2中详细介绍的体外和体内方法将提供关于急性创伤性凝血病的重要机制信息，但凝血系统非常复杂，无法使用传统的级联完全可视化。申请人将测试网络拓扑和动态建模的新技术将允许优越的可视化和预测创伤后蛋白C系统结构和功能的变化的假设（AIM 3）。具体来说，他将首先使用创伤/休克小鼠模型来确定创伤和低灌注后蛋白C扰动的时间和机制。其次，他将采用小鼠体内模型和体外内皮细胞缺血再灌注模型，测试补体在创伤和休克后蛋白C活化中的作用。第三，他将利用蛋白C通路的网络表示和新构建的蛋白C动态模型，对创伤和休克后的蛋白C通路进行计算机模拟。在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表现的要素。典型的创伤患者不仅有血管内体积的损失，而且有相关的组织损伤。受损组织是损伤负担的重要组成部分，并有助于损伤后的动态平衡失调。这将如何影响实验模型输出的解释需要由申请人直接考虑。Aim 3需要基于Aim 1和Aim 2数据的结果进行动态建模，因此这是一种有趣的方法。问题是如何验证它是否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?