The RAGE of COPD

描述（由申请人提供）： 摘要：目的：探讨慢性阻塞性肺疾病（COPD）的发病机制，寻找防治COPD的新方法。假设：我们提出了一个新的范例，晚期糖基化终末产物（AGEs）受体及其配体在肺气肿发病机制中的核心作用。我们假设，NADPH及其配体通过不同的信号通路，包括NADPH氧化酶（Nox）产生的活性氧（ROS）激活关键的转录因子，包括NF-B和EGR-1传播炎症，细胞凋亡和肺破坏，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严重疾病。它是VA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。在某种程度上，由于导致COPD的机制仍然不清楚或未被发现，治疗选择非常有限。COPD与慢性炎症、细胞凋亡和肺气肿相关。该建议旨在确定炎症、细胞凋亡和肺气肿的生化机制。目的：目的1将确定肺气肿及其配体促进炎症、细胞凋亡和肺破坏的能力，从而导致肺气肿的发展。它将测试的假设，即晚期糖基化终末产物（AGEs）或其他配体与肺动脉粥样硬化相互作用，以放大炎症反应和细胞凋亡，介导肺破坏，导致肺气肿的发展。目的2将确定信号中间体在RAGE诱导的肺炎症、凋亡和破坏中的作用，从而导致肺气肿的发展。它将测试以下假设：通过Nox和NF-B或Egr-1起作用的TNF及其配体引起促炎细胞因子和另外的TNF配体的合成和释放，其进一步使TNF表达、炎症、氧化和/或蛋白酶应激和凋亡永久化，从而导致肺破坏。目的3将确定肺巨噬细胞增殖或肺泡上皮细胞增殖是否是导致肺气肿发展的炎症、凋亡和肺破坏的主要原因。这些研究将利用单核细胞或肺泡上皮细胞特异性缺失RAGE的独特小鼠模型来检验肺巨噬细胞RAGE是RAGE介导的炎症和肺破坏的主要效应子的假设。研究设计：我们将使用香烟烟雾暴露小鼠模型研究在肺气肿发展过程中，β-淀粉样蛋白及其配体的表达。暴露于香烟烟雾的突变小鼠将被用于确定肺气肿发展中的呼吸和特定信号通路的重要性。在暴露于香烟烟雾提取物的分离细胞中的研究将补充在小鼠模型中提出的研究，以帮助描绘信号通路。特别关注的是在肺巨噬细胞和肺泡上皮细胞上表达的α-淀粉酶的作用，因为这些是吸烟者肺中α-淀粉酶表达的主要来源。重要性：这一建议的成功结果将改变对肺气肿病理生物化学的基本理解，重点是目前在讨论这种疾病的发展机制时只提到的途径。它将影响我们预防或减少吸烟造成的巨大医疗负担的能力。在肺部疾病中，没有比COPD更需要具有临床应用的新方法。

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.