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Multiscale Analysis of Trauma

创伤的多尺度分析

基本信息

批准号：
9032214
负责人：
SCOTT L DIAMOND
金额：
$ 75.63万
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/9032214
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 Cell physiology Cells Cereals Clinical Clinical Data Coagulation Process Complement Complement component C6 Complex Computer Simulation Controlled Study DNA Data Databases Deep Vein Thrombosis Detection Development Diagnostic Diffusion Dose Elements Endothelial Cells Endothelium Event Exposure to Fibrinolysis Functional disorder Goals Hematologist Hemorrhage Hemostatic function Histones Hormonal Human In Vitro Individual Injury Kinetics Life Link Maps Measurement Measures Mediating Medical Methods Microfluidic Microchips Microfluidics Modeling Mus Muscle Mutation Operative Surgical Procedures Output Pathway interactions Patient Simulation Patient-Focused Outcomes Patients Pennsylvania Peptide Hydrolases Performance 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 clinical decision-making combinatorial cost cytokine database design design endothelial dysfunction hemodynamics improved in vivo in vivo Model innovation intercellular cell adhesion molecule laboratory experiment loss of function meter model building molecular scale mouse model multi-scale modeling neutrophil novel patient stratification pressure public health relevance receptor research study 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.