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，以更好地阐明和解释创伤。血流动力学条件下血液反应、血小板信号传导、中性粒细胞信号传导和内皮信号传导通路的测量针对以下方面的定量临床需求：(i) 分层创伤诱发的凝血病(TIC) 风险，(ii) 提高输血治疗的安全性和有效性，以及 (iii) 确定可药理学靶向或作为改进的生物标志物的分子机制：目标 1 和 2 侧重于开发生物化学和细胞功能的机械和数据驱动计算机模型涉及：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。然后，目标 3 开发了受损血管中血液凝固和止血功能的多尺度模型，将单细胞水平的各个子模型组合成单位血管出血模型，该模型与测试血管功能性能的实验室实验密切相关。目标 3 还涉及在不同病理条件下对人类血液进行微流体分析，以探索与创伤场景相关的生物化学和生物学的出血组合变化。实施“粗投影积分”（CPI）来预测不断变化的体循环及其与受伤组织的相互作用，其中出血在单细胞、单血管和组织规模上进行量化。这些模拟旨在验证计算机模拟创伤患者。为了对 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，以证明检测和诊断的有效性。目标 6 将利用新型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情况，该体内数据也将用于增强多尺度模型的预测能力。潜在地识别用于对人类 TIC 风险进行分层的生物标志物。此外，小鼠工作还强调使用专门为本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传导的完全整合。具有真实且分层的血流动力学/质量传输模拟的模型，可在与创伤相关的各种尺度上调节出血和血液功能。