Multiscale Analysis of Trauma

 描述（由申请人提供）：为了响应PAR-15-085，宾夕法尼亚大学和普林斯顿大学组建了一个由生物工程师、计算科学家、创伤外科医生和血液学家组成的跨学科团队，以开发创伤的多尺度模型。在血液动力学条件下更好地阐明和定量测量血液反应、血小板信号传导、中性粒细胞信号传导和内皮信号传导途径针对以下方面的临床需求：（i）对创伤诱导的凝血病（TIC）风险进行分层，（ii）提高输血治疗的安全性和有效性，以及（iii）鉴定可以靶向阻断或用作改进的生物标志物的分子机制。提出了六个具体目标：目标1和2侧重于开发与凝血、纤维蛋白溶解和补体组装的蛋白酶级联以及血小板、中性粒细胞和内皮功能有关的生化和细胞功能的机械和数据驱动的计算机模型。目的3，然后开发一个多尺度模型的血液凝固和止血功能在受损的血管。将单细胞水平的各个子模型组合成单位血管出血模型，该模型与测试小鼠和人类患者血液在极端创伤条件下的功能性能的实验室实验密切相关。目的3还涉及在不同病理条件下人类血液的微流体出血测定，其探索涉及与创伤相关的生物化学和生物学的组合改变的出血情况。目标4将实施“粗投影积分”（CPI），以预测不断变化的体循环及其与创伤组织的相互作用，其中出血在单细胞到单血管到组织的尺度上进行量化。这些模拟旨在验证计算机模拟创伤患者，以便对TIC风险进行分层。在目标5中，大量使用创伤患者的新鲜血液样本和创伤患者的注释记录将成为多尺度CPI算法验证的一部分。关键的初步数据表明，检测和定量血小板功能低下的创伤患者。目的6将利用一种新的体内小鼠损伤模型，在创伤严重程度的校准模型中研究出血和止血。该体内数据还将用于增强多尺度模型的预测能力，并可能识别用于对人类TIC风险进行分层的生物标志物。此外，小鼠工作强调使用专门为此研究开发的新型荧光传感器。总的来说，这些目标代表了血小板、中性粒细胞和内皮信号传导模型与现实和分层的血流动力学/物质转运模拟的完全整合，这些模拟在与创伤相关的各种尺度上调节出血和血液功能。

 DESCRIPTION (provided by applicant): In response to PAR-15-085, the University of Pennsylvania and Princeton University have assembled an interdisciplinary team of bioengineers, computational scientists, trauma surgeons, and hematologists to develop a multiscale model of trauma. Better elucidation and quantitative measurement of blood reactions, platelet signaling, neutrophil signaling, and endothelial signaling pathways under hemodynamic conditions are directed at clinical needs in: (i) stratifying trauma induced coagulopathy (TIC) risks, (ii) improving the safety and efficacy of transfusion therapy, and (iii) identifying moleculr mechanisms that can be targeted pharmacologically or serve as improved biomarkers. Six specific aims are proposed: Aims 1 and 2 focus on the development of mechanistic and data-driven computer models of biochemical and cellular function relating to: protease cascades of coagulation, fibrinolysis, and complement assembly, as well as platelet, neutrophil and endothelial function. Aim 3 then develops a multiscale model of blood clotting and hemostatic function in a damaged blood vessel. The individual sub-models at the single cell level are combined into the unit vessel bleeding model which is related closely to laboratory experiments that test the functional performance of mouse and human patient blood under the extreme conditions of trauma. Aim 3 also involves microfluidic bleeding assays of human blood under diverse pathological conditions that explore bleeding scenarios involving combinatorial alterations of biochemistry and biology relevant to trauma. Aim 4 will implement "coarse projective integration" (CPI) to make prediction of the evolving systemic circulation and its interaction with a traumatized tissue where bleeding is quantified at the single cell to single vessel to tissue scale. These simulations are designed to validate an in silico trauma patient in order to stratify the risk of TIC. In Aim 5, the intensive use of fresh blood samples from trauma patients and annotated records from trauma patients will be part of the validation of the multiscale CPI algorithm. Key preliminary data demonstrates detection and quantification of platelet hypofunction in trauma patients. Aim 6 will utilize a novel in vivo mouse injury model to study bleeding and hemostasis in a calibrated model of trauma severity. This in vivo data will also be used to enhance the predictive capability of the multiscale model and to potentially identify biomarkers for stratifying TIC risks in humans. Also the mouse work emphasizes the use of novel fluorescent sensors developed specifically for this research. Overall, these aims represent the full integration of platelet, neutrophil, and endothelial signaling models with realistic and hierarchical hemodynamic/mass transport simulations that regulate bleeding and blood function at the various scales relevant to trauma.