The RAGE of COPD

慢性阻塞性肺病的愤怒

• 批准号: 8544152
• 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/8544152
• 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：确定COPD的致病机制并定义预防或治疗该疾病的新方法。假设：我们提出了一种新的范式，以在肺气肿发病机理中发挥高级糖基化最终产物（RAGE）及其配体的中心作用。我们假设愤怒及其配体通过包括NADPH氧化酶（S）（NOX）生成的活性氧（ROS）激活关键转录因子，包括NF-B和EGR-1，​​包括NF-B和EGR-1，​​以传播炎症，凋亡和肺部破坏导致肺炎的关键转录因子。背景：慢性阻塞性肺疾病（COPD）是一种毁灭性疾病，其特征是慢性气流限制。它是VA医院最常见的出院诊断之一，到2020年将是全球第三大死亡原因。部分由于导致COPD的机制仍然不足或未发现的机制，治疗方案非常有限。 COPD与慢性炎症，凋亡和肺气肿有关。该建议旨在定义炎症，凋亡和肺气肿的生化机制。目的：目标1将决定愤怒及其配体促进炎症，凋亡和肺部破坏的能力，从而导致肺气肿的发展。它将检验以下假设：高级糖基化终产物（年龄）或其他配体与愤怒相互作用，以扩增炎症反应和凋亡，从而介导肺部破坏，从而导致肺气肿的发展。 AIM 2将确定信号中间体在愤怒引起的肺部炎症，凋亡和破坏导致肺气肿发展的作用。它将检验以下假设：愤怒及其通过NOX（S）和NF-B或EGR-1作用的配体，导致促炎性细胞因子的合成和释放，以及其他rage配体，进一步使愤怒表达，炎症，氧化和/或蛋白酶的压力和蛋白酶的压力和凋亡与肺部销毁。 AIM 3将确定肺巨噬细胞愤怒或肺泡上皮细胞的愤怒主要负责传播炎症，凋亡和肺部破坏，从而导致肺气肿的发展。这些研究将利用具有单核或肺泡上皮细胞特异性rage的独特小鼠模型，以检验以下假设：肺巨噬细胞愤怒是愤怒介导的炎症和肺部破坏的主要效应因子。研究设计：我们将使用香烟烟雾暴露于小鼠的模型来研究肺气肿过程中愤怒及其配体的表达。暴露于香烟烟雾的突变小鼠将用于确定愤怒和特定信号通路在肺气肿发育中的重要性。暴露于香烟烟雾提取物的孤立细胞中的研究将补充小鼠模型中提议的辅助信号传导途径中提出的研究。特别的重点将是在肺巨噬细胞和肺泡上皮上表达的愤怒的作用，因为这些是吸烟者肺中愤怒表达的主要来源。意义：该提案的成功结果将通过专注于目前仅在讨论该疾病发展机制的讨论中切向提及的途径来改变对肺气肿的病理化学的基本理解。这将影响我们预防或减轻吸烟引起的巨大医疗负担的能力。在肺部疾病中，没有比在COPD中更重要的临床应用新方法的需要。