Multiscale Analysis of Trauma

 描述(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，以开发一个多尺度的创伤模型。更好地阐明和定量测量血液动力学条件下的血液反应、血小板信号、中性粒细胞信号和内皮信号通路，是针对临床需要的：(I)对创伤引起的凝血(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)确定可以作为药物靶向或作为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和目标2侧重于开发与以下方面有关的生化和细胞功能的机械性和数据驱动的计算机模型：凝血、纤溶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。目标3然后开发了受损血管中的凝血和止血功能的多尺度模型。单细胞水平的单个子模型被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表现的实验室实验密切相关。AIM 3还涉及在不同病理条件下对人体血液进行微流控出血分析，以探索涉及与创伤相关的生化和生物学组合变化的出血情景。目标4将实施“粗略投影积分”(CPI)，以预测不断演变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。这些模拟旨在验证矽肺创伤患者，以便对TIC的风险分层。在目标5中，密集使用来自创伤患者的新鲜血液样本和来自创伤患者的注释记录将是多尺度CPI算法验证的一部分。关键的初步数据证实了创伤患者的血小板功能低下的检测和量化。AIM 6将利用一种新的体内小鼠损伤模型来研究创伤严重程度校准模型中的出血和止血。这些体内数据还将用于增强多尺度模型的预测能力，并潜在地识别用于分层人类TIC风险的生物标记物。此外，老鼠的工作强调使用专门为这项研究开发的新型荧光传感器。总体而言，这些目标代表了血小板、中性粒细胞和内皮信号模型与真实和分级的血流动力学/质量传输模拟的完全集成，这些模拟在与创伤相关的不同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.