The RAGE of COPD

慢性阻塞性肺病的愤怒

• 批准号: 8669718
• 负责人: John R Hoidal
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669718
• 关键词: Ablation; Address; Advanced Glycosylation End Products; Alveolar; Alveolar Macrophages; Animal Model; Apoptosis; Biochemical; Cause of Death; Cells; Chronic; Chronic Obstructive Airway Disease; Cigarette Smoker; Complement; Data; Development; Diagnosis; Disease; Epithelial Cells; Epithelial Receptor Cell; Exposure to; Family; Generations; Genetic; HMGB1 Protein; Hospitals; Inflammation; Inflammatory; Inflammatory Response; Lead; Leukocyte L1 Antigen Complex; Ligands; Lung; Lung Inflammation; Lung diseases; Mediating; Medical; Modeling; Mononuclear; Mus; Mutant Strains Mice; NADPH Oxidase; Outcome; Pathogenesis; Pathway interactions; Peptide Hydrolases; Publications; Pulmonary Emphysema; Reactive Oxygen Species; Receptor Inhibition; Relative (related person); Research Design; Role; Signal Pathway; Signal Transduction; Source; Stress; Testing; Validation; abstracting; alveolar epithelium; base; cigarette smoking; cigarette smoking; clinical application; cytokine; macrophage; member; mouse model; novel strategies; oxidant stress; prevent; public health relevance; receptor; receptor expression; transcription factor

DESCRIPTION (provided by applicant): Abstract: Objective: To determine the pathogenic mechanisms of COPD and to define new ways to prevent or treat the disorder. Hypotheses: We propose a new paradigm for a central role of the receptor for advanced glycation end products (RAGE) and its ligands in the emphysema pathogenesis. We hypothesize that RAGE and its ligands through distinct signaling pathways that include NADPH oxidase(s) (Nox)-generated reactive oxygen species (ROS) activate key transcription factors including NF-B and EGR-1 to propagate the inflammation, apoptosis and lung destruction leading to emphysema. Background: Chronic obstructive pulmonary disease (COPD) is a devastating disorder characterized by chronic airflow limitation. It is among the most common discharge diagnoses from VA hospitals and will be the third leading cause of death worldwide by the year 2020. In part, due to the still poorly elucidated or undiscovered mechanisms causing COPD, treatment options are very limited. COPD is associated with chronic inflammation, apoptosis and emphysema. This proposal is aimed at defining the biochemical mechanisms for the inflammation, apoptosis and emphysema. Aims: Aim 1 will determine the ability of RAGE and its ligands to promote inflammation, apoptosis and lung destruction leading to the development of emphysema. It will test the hypothesis that advanced glycation end products (AGEs) or other ligands interact with RAGE to amplify the inflammatory response and apoptosis that mediate the lung destruction leading to the development of emphysema. Aim 2 will determine the role of signaling intermediates in RAGE-induced lung inflammation, apoptosis and destruction leading to the development of emphysema. It will test the hypothesis that RAGE and its ligands acting through Nox(s) and NF-B or Egr-1, cause synthesis and release of pro-inflammatory cytokines and additional RAGE ligands, which further perpetuate RAGE expression, inflammation, oxidative and/or proteinase stress and apoptosis with resulting lung destruction. Aim 3 will determine whether lung macrophage RAGE or alveolar epithelial cell RAGE is primarily responsible for propagating inflammation, apoptosis and lung destruction leading to the development of emphysema. These studies will take advantage of unique mouse models with mononuclear or alveolar epithelial cell specific deletion of RAGE to test the hypothesis that lung macrophage RAGE is the primary effector of RAGE-mediated inflammation and lung destruction. Research Design: We will study the expression of RAGE and its ligands during the development of emphysema using a model of cigarette smoke exposure to mice. Mutant mice exposed to cigarette smoke will be used to determine the importance of RAGE and specific signaling pathways in emphysema development. Studies in isolated cells exposed to cigarette smoke extract will complement those proposed in mouse models to aide in delineating signaling pathways. A particular focus will be the role(s) of RAGE expressed on lung macrophages and alveolar epithelium since these are the primary sources of RAGE expression in the lungs of cigarette smokers. Significance: Successful outcome of this proposal will transform basic understanding of the pathobiochemistry of emphysema by focusing on pathways currently only tangentially mentioned in discussions of the mechanisms for development of the disorder. It will impact our ability to prevent or reduce the enormous medical burden caused by cigarette smoking. Nowhere is the need for new approaches with clinical application more important in pulmonary diseases than in COPD.

描述（由申请人提供）： 【摘要】：目的:明确慢性阻塞性肺病(COPD)的发病机制,并寻找预防或治疗该疾病的新方法。假设：我们提出了晚期糖基化终末产物受体（RAGE）及其配体在肺气肿发病机制中的核心作用的新范例。我们假设 RAGE 及其配体通过不同的信号传导途径，包括 NADPH 氧化酶 (Nox) 产生的活性氧 (ROS) 激活关键转录因子，包括 NF-B 和 EGR-1，​​从而传播炎症、细胞凋亡和肺部破坏，导致肺气肿。背景：慢性阻塞性肺疾病（COPD）是一种以慢性气流受限为特征的破坏性疾病。它是退伍军人管理局医院最常见的出院诊断之一，到 2020 年将成为全球第三大死亡原因。部分原因是慢性阻塞性肺病的致病机制尚未阐明或尚未发现，治疗选择非常有限。 COPD 与慢性炎症、细胞凋亡和肺气肿有关。该提案旨在明确炎症、细胞凋亡和肺气肿的生化机制。目标：目标 1 将确定 RAGE 及其配体促进炎症、细胞凋亡和肺部破坏从而导致肺气肿发展的能力。它将检验以下假设：晚期糖基化终末产物 (AGE) 或其他配体与 RAGE 相互作用，放大炎症反应和细胞凋亡，介导肺部破坏，导致肺气肿的发展。目标 2 将确定信号中间体在 RAGE 诱导的肺部炎症、细胞凋亡和破坏（导致肺气肿发展）中的作用。它将检验以下假设：RAGE 及其配体通过 Nox 和 NF-B 或 Egr-1 起作用，导致促炎细胞因子和其他 RAGE 配体的合成和释放，从而进一步维持 RAGE 表达、炎症、氧化和/或蛋白酶应激和细胞凋亡，从而导致肺破坏。目标 3 将确定肺巨噬细胞 RAGE 或肺泡上皮细胞 RAGE 是否主要负责传播炎症、细胞凋亡和肺部破坏，从而导致肺气肿的发展。这些研究将利用单核或肺泡上皮细胞特异性删除 RAGE 的独特小鼠模型来检验肺巨噬细胞 RAGE 是 RAGE 介导的炎症和肺部破坏的主要效应器的假设。研究设计：我们将使用小鼠吸烟模型来研究肺气肿发展过程中 RAGE 及其配体的表达。暴露于香烟烟雾的突变小鼠将被用来确定 RAGE 和特定信号通路在肺气肿发展中的重要性。对暴露于香烟烟雾提取物的分离细胞进行的研究将补充小鼠模型中提出的研究，以帮助描绘信号通路。特别关注的是肺巨噬细胞和肺泡上皮表达的 RAGE 的作用，因为这些是吸烟者肺部 RAGE 表达的主要来源。意义：该提案的成功结果将通过关注目前在疾病发展机制的讨论中仅间接提及的途径，将改变对肺气肿病理生物化学的基本理解。它将影响我们预防或减轻吸烟造成的巨大医疗负担的能力。在肺部疾病中，没有什么比慢性阻塞性肺病更需要临床应用的新方法了。