Mechanism of Traumatic Coagulopathy

创伤性凝血病的机制

• 批准号: 8133680
• 负责人: Mitchell Cohen
• 金额: $ 11.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-18 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133680
• 关键词: AIDS/HIV problem; Accident and Emergency department; Acidosis; Acute; Affect; Applications Grants; Basic Science; Blocking Antibodies; Blood Coagulation Disorders; Blood Coagulation Factor; Cause of Death; Cell membrane; Cell surface; Characteristics; Clinical Sciences; Coagulation Process; Complement; Complement Activation; Complex; Computer Simulation; Conceptions; Consumption; Data; Development; Elements; Endothelial Cells; Experimental Models; Fibrin; Fibrinolysis; Fluid Therapy; Generations; Grant; Graph; Hemorrhage; Human; IV Fluid; Imagery; In Vitro; Inflammation; Inflammation Mediators; Injury; Investigation; Ischemia; Laws; Link; Liquid substance; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial Ischemia; Organ; Outcome; Output; Pathway interactions; Patients; Protein C; Protein Inhibition; Reperfusion Therapy; Reporting; Research Personnel; Resuscitation; Role; Shock; Social Sciences; Stroke; Structure; System; Systems Biology; Techniques; Testing; Therapeutic; Thrombomodulin; Thrombosis; Time; Tissues; Trauma; Vascular Endothelium; activated Protein C; base; biological systems; citrate carrier; clinically significant; complement pathway; derepression; disability; in vitro Model; in vivo; interest; mortality; mouse model; programs; protein activation; research study; theories; tool

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?

描述（由申请人提供）：申请人将在本授权中检验以下假设：急性创伤性凝血功能障碍主要由组织灌注不足引起，导致补体介导的激活和随后的蛋白C途径耗竭（AIMS 1和2）。虽然AIMS 1和2中详述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，使用传统级联完全可视化。申请人将测试以下假设：网络拓扑和动态建模中的新技术将允许上级可视化并预测创伤后蛋白C系统的结构和功能的变化（AIM 3）。具体来说，他将首先使用创伤/休克的小鼠模型来确定创伤和灌注不足后蛋白C扰动的时间和机制。其次，他将使用体内小鼠模型以及内皮细胞缺血再灌注的体外模型来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通路。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构成了本基金申请的基本原理，表明凝血和补体异常在创伤后早期开始，并与显著的发病率和死亡率增加相关。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。这里的问题是，该模型确实复制了患者临床表现的元素。典型的创伤患者不仅遭受血管内容量的损失，而且还具有相关的组织损伤。受损的组织代表损伤负担的重要部分，并导致损伤后的动态平衡障碍。申请人需要直接考虑这将如何影响实验模型输出的解释。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。问题是如何验证它是否反映了创伤患者的情况？