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

创伤和出血会引起急性炎症反应。这个复杂的过程是在细胞内观察到的， 组织、器官和整个生物体的水平。现在人们认识到，损伤相关的分子模式 (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 调节这种炎症反应的中心方面。尽管乍一看令人望而生畏，但 可以研究炎症，可以使用开创性的计算模拟来预测结果 被我们这群人。我们假设，一个经过验证和校准的炎症数学模型及其 多个级别的病理结果将有助于预测患者的预后 创伤性/失血性休克。我们将在三个具体目标上检验这一假设。在目标1中，我们将利用基因- 改良的小鼠和细胞，多路分析数据，统计方法，以及对 炎症反应，以便辨别潮湿驱动的主开关，这些开关可能会在治疗上进行修改。 预适应(预先暴露于给定刺激将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，它对初始条件和其他系统状态的依赖使预适应成为首要条件 炎症是一个复杂系统的例子。在目标2中，我们将在电子显微镜下观察其在体外和体内的作用 预适应现象中的DAMP及其受体。在目标3中，我们将创建特定于患者的 包括两种血浆分析物的创伤后人类炎症反应的总体模拟 动力学和细胞因子单核苷酸多态，结合使用新的电子临床试验 计算洞察力和方法。本文提出的研究将对基础研究和翻译研究产生影响 休克/创伤炎症过程的研究。 相关性(请参阅说明)： 本文提出的工作将导致创建一系列计算模拟 炎症，测试对受损组织的反应作为中央媒介的假设， 整合者，在创伤/出血的背景下可能的治疗目标。这项工作将包括 创建特定于患者的诊断以及模拟临床试验，因此是翻译的。 PROJECJ/

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/