PREDICTIVE MATHEMATICAL MODEL OF INFLAMMATION FOR SHOCK/TRAUMA

休克/创伤炎症的预测数学模型

• 批准号: 7094107
• 负责人: YORAM VODOVOTZ
• 金额: $ 25.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7094107
• 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。这个过程涉及白细胞的迁移和激活、细胞因子的分泌以及自由基的产生。这些变化共同可能导致严重的器官功能障碍和死亡。我们开发了一种数学模型来描述急性炎症的介质，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。该模型在人内毒素血症中得到了进一步校准。尽管受到循环介质的影响，该模型根据整体组织功能障碍方程表达了各个器官所经历的生理紊乱。炎症数学模型的输出与实验数据之间的密切相关性表明，常见的炎症反应 是不同休克状态的基础，提高了体内炎症过程建模的可能性。我们假设经过验证和校准的炎症及其病理后果的数学模型将有助于预测遭受创伤/失血性休克的患者的结果。我们将在两个具体目标中检验这一假设。在目标 1 中，我们将增强啮齿动物的数学模型，包括适应性免疫的要素，并模拟治疗干预。我们将修改我们的模型以包括自然杀伤 (NK) 细胞、NKT 细胞、肥大细胞、树突状细胞以及 TH1 和 TH2 细胞。我们将修改一氧化氮反应模型的方式，检查 HMG-B1 和透明质酸的促炎作用 警报分子，并模拟 MAP 激酶抑制剂的影响。此外，数学模型将告知项目 I-IV 中提出的假设，并且将受到项目 I-IV 中提出的假设的告知。为了 例如，我们假设我们可以预测休克/创伤啮齿动物模型中抗 IL-6、林格氏丙酮酸乙酯溶液和 NAD 的最佳时机和剂量。我们将在小鼠身上进行详细的时间过程研究，以验证和校准该模型和拟议的干预措施。在目标 2 中，我们将把创伤/出血引起的炎症的数学模型应用于人类，并创建一个整合到个体化临床决策中的平台。在一项针对500名创伤患者的前瞻性临床研究中，我们将获得数学模型所需的炎症和器官功能障碍的病程数据以及细胞因子基因多态性数据，以及用于构建一系列统计模型的临床数据。目标 1 中选定的干预措施将在模拟临床试验中进行测试。我们还将创建一个基于数学模型的平台，用于集成到个体化临床中 休克/创伤中的决策。本文提出的研究将影响休克/创伤炎症过程的基础和转化研究。