Project 1: Initiation of Inflammation in Hemorrhagic Shock

项目1：失血性休克中炎症的启动

• 批准号: 7751460
• 负责人: TIMOTHY R BILLIAR
• 金额: $ 25.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751460
• 关键词: Age; Cause of Death; Cells; Exhibits; Genes; Goals; HMGB1 Protein; Hemorrhage; Hemorrhagic Shock; Hepatic; Hypoxia; Immune System Diseases; Immune system; Immunologic Receptors; Inflammation; Inflammatory; Inflammatory Response; Injury; Instruction; Invaded; Ischemia; Knockout Mice; Ligands; Mediating; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Nuclear Protein; Nuclear Proteins; Organ; Patients; Pattern; Pattern recognition receptor; Peripheral; Play; Production; Regulation; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; TLR4 gene; Therapeutic Intervention; Tissues; Trauma; Work; cell type; cytokine; improved; injured; macrophage; mortality; mouse model; neutralizing antibody; pathogen; response; response to injury; tissue trauma; toll-like receptor 4

Severe trauma leads to the activation a systemic inflammatory response that when excessive, contributes to both end-organ dysfunction and immune dysregulation. The goal of this project is to define molecular mechanisms for the initiation and propagation of inflammation following severe injury. We hypothesize that tissue damage and/or ischemia leads to the release of endogenous molecules that then trigger inflammatory signaling through pattern recognition receptors of the innate immune system. We have compelling evidence that two pattern recognition receptors, toll-like receptors 4 and 9 (TLR4 and 9) and the nuclear protein and TLR4 ligand, high mobility group box-1 (HMGB1), play critical roles in initiating inflammation following injury. We will more fully characterize the function of TLR4 and 9 and HMGB1 in the injury response in three Aims. Under Aim 1, we will define the relative roles of TLR4 and TLR9 to the systemic and organ-specific responses. We will also use a TLR4-loxP mouse recently developed in our lab to define cell-type specific roles for TLR4. Under Aim II, we will use gene knockout mice to establish the major TLR-dependent signaling pathways involved in trauma-induced inflammatory response. Under Aim 111, we will define the cell types that mobilize and release HMGB1 following systemic injury and the mechanisms leading to HMGB1 release. To accomplish these aims, we will utilize our well-characterized mouse models of hemorrhagic shock and peripheral tissue trauma. It is expected that the completion of this work will both advance our understanding of how the immune system becomes activated after injury and define potential targets for therapeutic intervention to limit the excessive inflammation in severely injured patients. RELEVANCE (See instructions): Trauma is the most common cause of death and morbidity in peopl under the age of 50 in the USA. Much of the morbidity and mortality are due to an excessive inflammatory response. The research described in this proposal is aimed at understanding how trauma induces an inflammatory response at the molecular level with the long-term goal identifying strategies to modify this response and improve survival.

严重创伤会导致全身炎症反应的激活，当过度时，会导致 终末器官功能障碍和免疫失调。该项目的目标是定义分子 严重损伤后炎症发生和传播的机制。我们假设 组织损伤和/或缺血导致内源性分子释放，进而引发炎症 通过先天免疫系统的模式识别受体发出信号。我们有令人信服的证据 两种模式识别受体，Toll 样受体 4 和 9（TLR4 和 9）以及核蛋白和 TLR4 配体高迁移率族蛋白 1 (HMGB1) 在损伤后引发炎症中发挥着关键作用。 我们将在三个目标中更全面地描述 TLR4 和 9 以及 HMGB1 在损伤反应中的功能。 在目标 1 下，我们将定义 TLR4 和 TLR9 对系统性和器官特异性的相对作用 回应。我们还将使用我们实验室最近开发的 TLR4-loxP 小鼠来定义细胞类型特异性 TLR4 的角色。在Aim II下，我们将使用基因敲除小鼠来建立主要的TLR依赖性 信号通路涉及创伤引起的炎症反应。在目标 111 下，我们将定义单元格 全身损伤后动员和释放 HMGB1 的类型以及导致 HMGB1 的机制 发布。为了实现这些目标，我们将利用我们充分表征的出血性小鼠模型 休克和周围组织损伤。预计这项工作的完成将促进我们的 了解免疫系统在受伤后如何被激活并确定潜在的目标 治疗干预以限制严重受伤患者的过度炎症。 相关性（参见说明）： 创伤是美国 50 岁以下人群最常见的死亡和发病原因。很多 发病率和死亡率是由于过度的炎症反应造成的。本文描述的研究 该提案旨在了解创伤如何在分子水平上诱发炎症反应 长期目标确定策略来改变这种反应并提高生存率。