PREDICTIVE MATHEMATICAL MODEL OF INFLAMMATION FOR SHOCK/TRAUMA

休克/创伤炎症的预测数学模型

• 批准号: 6861601
• 负责人: YORAM VODOVOTZ
• 金额: $ 24.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861601
• 关键词: T lymphocyte; biological signal transduction; cell differentiation; computer program /software; computer system design /evaluation; dendritic cells; enzyme inhibitors; hemorrhagic shock; human subject; inflammation; injury; laboratory mouse; laboratory rat; macrophage; mathematical model; mitogen activated protein kinase; model design /development; natural killer cells; nitric oxide; organ; patient oriented research; regulatory gene; resuscitation; stress; trauma

Trauma and hemorrhage elicit an acute inflammatory response. This process involves migration and activation of leukocytes, secretion of cytokines, and the production of free radicals. Together, these changes may result in severe organ dysfunction and death. We have developed a mathematical model that describes the mediators of acute inflammation, and is calibrated in mice subjected to endotoxemia, surgical trauma, and hemorrhagic shock. This model was further calibrated in human endotoxemia. Though informed by circulating mediators, this model expresses the physiological derangement experienced by individual organs in terms of a global tissue dysfunction equation. The close correlation between the output of the mathematical model of inflammation and experimental data suggests that a common inflammatory response underlies diverse shock states, raising the possibility of modeling the inflammatory process in vivo. We hypothesize that a validated and calibrated mathematical model of inflammation and its pathologic consequences will be useful for predicting outcome in patients suffering from traumatic/hemorrhagic shock. We will test this hypothesis in two Specific Aims. In Aim 1, we will augment our mathematical model in rodents, including elements of adaptive immunity, and simulate therapeutic interventions. We will modify our model to include natural killer (NK) cells, NKT cells, mast cells, dendritic cells, and TH1 and TH2 cells. We will modify how we model reactions of nitric oxide, examine the roles of HMG-B1 and hyaluronic acid as pro-inflammatory alarm molecules, and model the impact of MAP kinase inhibitors. Furthermore, the mathematical model will inform and will be informed by the hypotheses presented in Projects I-IV. For example, we hypothesize that we can predict the optimal timing and dosage of anti-lL-6, Ringer's Ethyl Pyruvate solution, and NAD in rodent models of shock/trauma. We will carry out detailed time course studies in mice to validate and calibrate this model and the proposed interventions. In Aim 2, we will adapt the mathematical model of trauma/hemorrhage-induced inflammation to humans and create a platform for integration into individualized clinical decision-making. In a prospective clinical study of 500 trauma patients, we will obtain data on the course of inflammation and organ dysfunction as well as cytokine gene polymorphisms needed for our mathematical model, in addition to clinical data that will be used to construct a series of statistical models. Selected interventions from Aim 1 will be tested in simulated clinical trials. We will also create a platform, based on the mathematical model, for integration into individualized clinical decision-making in shock/trauma. The research proposed herein will impact both basic and translational research on the inflammatory process of shock/trauma.

创伤和出血引起急性炎症反应。这一过程包括白细胞的迁移和活化、细胞因子的分泌和自由基的产生。总之，这些变化可能导致严重的器官功能障碍和死亡。我们已经开发了一个描述急性炎症介质的数学模型，并在遭受内毒素血症、手术创伤和失血性休克的小鼠中进行了校准。该模型在人类内毒素血症中进一步校准。虽然有循环介质的影响，但该模型根据整体组织功能障碍方程表达了个体器官所经历的生理紊乱。炎症数学模型的输出与实验数据的密切相关表明，一种常见的炎症反应