Project 5: Predictive Mathematical Model of Inflammation for Shock/Trauma

创伤和出血引起急性炎症反应。这个复杂的过程在细胞中观察到， 组织、器官和整个生物体水平。现在认识到，损伤相关分子模式 （DAMP）分子及其受体在多种细胞类型上诱导的信号级联介导和 调节炎症反应的中心环节虽然乍一看令人生畏， 可以研究炎症，并可以使用开创性的计算模拟来预测结果。 我们的团队。我们假设经过验证和校准的炎症及其数学模型 多尺度的病理结果将有助于预测患有 创伤性/出血性休克。我们将在三个具体目标中检验这一假设。在目标1中，我们将利用基因- 修饰的小鼠和细胞，多路复用的分析物数据，统计方法，和多尺度模拟， 炎症反应，以便辨别DAMP驱动的主开关，可以在治疗上进行修改。 预适应（预先暴露于给定刺激会改变对特定刺激的反应的现象）。 随后的刺激）是创伤的非线性炎症轨迹和结果的中心特征 患者，其对初始条件和其他系统状态的依赖性使预处理成为一个主要的 炎症是一个复杂的系统。在目标2中，我们将在计算机上定义的体外和体内的作用， DAMP及其受体在预适应现象中的作用。在目标3中，我们将创建患者特异性和 人对创伤的炎症反应的群体模拟，包括血浆分析物 动力学和细胞因子单核苷酸多态性，结合使用新的 计算的洞察力和方法。本文提出的研究将影响基础和翻译 研究休克/创伤的炎症过程。 相关性（参见说明）： 本文提出的工作将导致创建一系列的计算模拟， 炎症，测试对受损组织的反应作为中央介质的假设， 整合剂和创伤/出血背景下可能的治疗靶点。这项工作将包括 创建患者特异性诊断以及模拟临床试验，因此是转化的。 项目J/

Trauma and hemorrhage elicit an acute inflammatory response. This complex process is observed at the cellular, tissue, organ, and whole-organism levels. It is now appreciated that Damage-Associated Molecular Pattern (DAMP) molecules and the signaling cascades induced by their receptors on multiple cell types mediate and modulate central aspects of this inflammatory response. Though daunting at first blush, the complexity of inflammation can be studied and outcomes can be predicted using pioneering computational simulations created by our group. We hypothesize that a validated and calibrated mathematical model of inflammation and its pathologic consequences at the multiple scales will be useful for predicting outcome in patients suffering from traumatic/hemorrhagic shock. We will test this hypothesis in three Specific Aims. In Aim 1, we will utilize gene- modified mice and cells, multiplexed analyte data, statistical methods, and multi-scale simulations of the inflammatory response in order to discern DAMP-driven master switches that might be modified therapeutically. Preconditioning (the phenomenon in which prior exposure to a given stimulus will modify the response to a subsequent stimulus) is a central feature of the non-linear Inflammatory trajectories and outcomes of trauma patients, and its dependence on initial conditions and other system states makes preconditioning a prime example of inflammation as a complex system. In Aim 2, we will deflne in silico the in vitro and in vivo roles of DAMP'S and their receptors in the phenomenon of preconditioning. In Aim 3, we will create patient-specific and population simulations of the human inflammatory response to trauma that include both plasma analyte dynamics and cytokine single nucleotide polymorphisms, coupled to in silico clinical trials using novel computational insights and methods. The research proposed herein will impact both basic and translational research on the inflammatory process of shock/trauma. RELEVANCE (See instructions): The work proposed herein would lead to the creation of a series of computational simulations of inflammation, testing the hypothesis that the response to damaged tissue acts as a central mediator, integrator, and possible therapeutic target in the setting of trauma/hemorrhage. This work would include the creation of patient-specific diagnostics as well as simulated clinical trials, and thus is translational. PROJECJ/