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

项目5：休克/创伤炎症预测数学模型

基本信息

批准号：
8294841
负责人：
YORAM VODOVOTZ
金额：
$ 29.72万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
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/8294841
关键词：
Accounting Acute Address Anti-Inflammatory Agents Anti-inflammatory Basic Science Behavior Biological Phenomena Blushing Cells Cessation of life Clinical Trials Collaborations Complex Computer Simulation Coupled Data Dependence Diagnostic Disease Doctor of Medicine Doctor of Philosophy Equation Exposure to Factor V Free Radicals Functional disorder Funding Gene-Modified Genes Genetic Polymorphism Goals HMGB1 gene Healed Health Status Hemorrhage Hemorrhagic Shock Human In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Instruction Lead Ligands Mediating Mediator of activation protein Methods Modeling Molecular Molecular Biology Morbidity - disease rate Mus Organ Organism Outcome Outcome Study Pathologic Pathology Pathway interactions Patients Pattern Physiological Plasma Play Population Principal Investigator Process Property Quantum Mechanics Research Research Infrastructure Research Personnel Research Project Grants Rodent Role Series Shock Signal Pathway Signal Transduction Signaling Molecule Simulate Single Nucleotide Polymorphism Solid Statistical Methods Sterility Stimulus System Systems Biology Testing Therapeutic Time Tissues Toll-Like Receptor Pathway Transforming Growth Factors Translational Research Trauma Tumor Necrosis Factor-alpha Universities Validation Whole Organism Work base cell type clinically relevant cytokine design experience healing in vivo insight mathematical model mortality novel novel strategies pathogen preconditioning programs receptor regenerative response simulation success therapeutic target tissue trauma

项目摘要

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/

创伤和出血引起急性炎症反应。这个复杂的过程是在细胞中观察到的，组织、器官和整个生物体水平。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介导和诱导的信号级联调节这种炎症反应的核心方面。尽管乍一看令人望而生畏，但其复杂性使用开创性的计算模拟可以研究炎症并预测结果由我们小组。我们假设有一个经过验证和校准的炎症数学模型及其多种尺度的病理后果将有助于预测患有以下疾病的患者的结果外伤/失血性休克。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、多重分析物数据、统计方法和多尺度模拟炎症反应，以便识别可能在治疗上修改的 DAMP 驱动的主开关。预处理（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）是非线性炎症轨迹和创伤结果的核心特征患者及其对初始条件和其他系统状态的依赖性使得预处理成为首要条件炎症作为一个复杂系统的例子。在目标 2 中，我们将通过计算机定义以下物质的体外和体内作用： DAMP'S 及其受体的预处理现象。在目标 3 中，我们将创建针对患者的特定和人类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，结合使用新颖的计算机临床试验计算见解和方法。本文提出的研究将影响基础和转化休克/创伤炎症过程的研究。相关性（参见说明）：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心介质的假设，积分器，以及创伤/出血情况下可能的治疗目标。这项工作将包括创建针对患者的诊断以及模拟临床试验，因此具有转化性。项目/