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.

严重的创伤会激活全身炎症反应，当过度时，会导致 终末器官功能障碍和免疫失调。这个项目的目标是定义分子 严重损伤后炎症的启动和传播机制。我们假设 组织损伤和/或局部缺血导致内源性分子的释放 通过先天免疫系统的模式识别受体进行信号传导。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（TLR 4和9）和核蛋白， TLR 4配体，高迁移率族蛋白1（HMGB 1），在损伤后引发炎症中起关键作用。 我们将在三个目标中更全面地描述TLR 4和9以及HMGB 1在损伤反应中的功能。 在目标1中，我们将定义TLR 4和TLR 9在全身性和器官特异性免疫应答中的相对作用。 应答我们还将使用我们实验室最近开发的TLR 4-loxP小鼠来定义细胞类型特异性 TLR 4的作用在目标II中，我们将使用基因敲除小鼠来建立主要的TLR依赖性 参与创伤诱导的炎症反应的信号通路。在目标111下，我们将定义单元格 全身性损伤后动员和释放HMGB 1的类型以及导致HMGB 1的机制 release.为了实现这些目标，我们将利用我们的良好表征的出血性小鼠模型， 休克和周围组织创伤。预计这项工作的完成将促进我们的 了解损伤后免疫系统如何被激活，并确定潜在的靶点， 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岁以下人群死亡和发病的最常见原因。大部分 发病率和死亡率是由于过度的炎症反应。本文中描述的研究 该提案旨在了解创伤如何在分子水平上诱导炎症反应， 长期目标是确定改变这种反应和提高生存率的策略。