Multiscale Analysis of Trauma

创伤的多尺度分析

基本信息

批准号：
9264028
负责人：
SCOTT L DIAMOND
金额：
$ 75.71万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264028
关键词：
Accounting Acute Acute Lung Injury Agonist Algorithms Animal Model Antigens Behavior Biochemical Biochemistry Biological Biological Assay Biological Markers Biological Neural Networks Biology Biomedical Engineering Blood Blood Circulation Blood Coagulation Disorders Blood Platelets Blood Vessels Blood Volume Blood coagulation Blood specimen Cardiac Case Study Cell Death Cell model Cells Cereals Clinical Clinical Data Coagulation Process Complement Complex Computer Simulation Controlled Study DNA Data Databases Deep Vein Thrombosis Detection Development Diagnostic Diffusion Dose Elements Endothelial Cells Endothelium Event Exposure to Extravasation Fibrinolysis Functional disorder Goals Hematologist Hemorrhage Hemostatic function Histones Hormonal Human In Vitro Individual Injury Kinetics Life Link Liquid substance Maps Measurement Measures Mediating Medical Methods Microfluidic Microchips Microfluidics Modeling Mus Muscle Mutation Operative Surgical Procedures Output Pathologic Pathway interactions Patient Simulation Patient-Focused Outcomes Patients Pennsylvania Peptide Hydrolases Performance Pharmacology Plasma Population Process Production Reaction Records Research Risk Rupture Safety Scanning Scientist Sepsis Severities Side Signal Pathway Signal Transduction Stimulus Surgeon Techniques Testing Thrombin Thrombosis Time Tissue Model Tissues Tracer Training Transfusion Trauma Trauma patient United States National Institutes of Health Universities Validation Vascular Permeabilities Whole Blood Whole Organism Work base biochemical model clinical decision-making combinatorial cost cytokine database design design endothelial dysfunction experimental study hemodynamics high dimensionality improved in vivo in vivo Model innovation intercellular cell adhesion molecule laboratory experiment loss of function meter molecular scale mouse model multi-scale modeling neutrophil novel patient stratification pressure public health relevance receptor response sensor simulation syndecan

项目摘要

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.

描述（由适用提供）：响应于15-085 PAR，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，以开发一种多叶的创伤模型。在血液动力学条件下的血液反应，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的更好阐明和定量测量指向血液动力学条件下的内皮信号传导途径。作为改进的生物标志物。提出了六个具体目的：目标1和2的侧重于开发生化和细胞功能的机械和数据驱动的计算机模型，该模型与：凝结，纤维蛋白溶解和补体组装的蛋白酶级联有关，以及血小板，中性粒细胞和内皮功能。 AIM 3然后在受损的血管中开发出血液凝结和止血功能的多尺度模型。单细胞水平的单个子模型合并为单位血管出血模型，该模型与实验室实验密切相关，这些实验在极端的创伤条件下测试了小鼠和人类患者血液的功能性能。 AIM 3还涉及在潜水病理条件下人类血液的微流体出血，探索出血情景涉及与创伤有关的生物化学和生物学的组合改变。 AIM 4将实施“粗糙的投射整合”（CPI），以预测不断发展的全身循环及其与受伤的组织的相互作用，在该组织中，单细胞将出血定量到单个容器至单血管至组织尺度。这些仿真旨在验证一名硅酸创伤患者的患者，以分层TIC的风险。在AIM 5中，大量使用创伤患者的新鲜血液样本以及创伤患者的注释记录将是对多尺度CPI算法验证的一部分。关键的初步数据表明，创伤患者的血小板功能功能低下的检测和定量。 AIM 6将利用一种新型的体内小鼠损伤模型来研究校准的创伤严重程度模型中的出血和止血。该体内数据还将用于增强多尺度模型的预测能力，并有可能识别生物标志物来分层人类的TIC风险。同样，小鼠的工作强调了专门为这项研究开发的新型荧光传感器的使用。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的完整整合，该模型具有逼真的和分层的血液动力学/质量传输模拟，这些模拟在与创伤有关的各种尺度上调节出血和血液功能。