Disarray of Injury/Regeneration Homeostasis in Smoking-Induced COPD

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）是导致肺残疾和死亡的主要原因，主要由吸烟引起。最初的病理变化是在小气道和中央小叶肺泡，慢性炎症和伴随的蛋白酶，氧化剂，凋亡和其他炎症介质的局部表达能够损伤气道和肺泡。Weill Cornell COPD SCCOR的基本主题是，当肺的再生过程不再能够在由吸烟引起的气道/肺泡的持续损伤和对吸烟的炎症性宿主反应下维持正常的肺结构和功能时，COPD的临床表型演变。在这一主题下，拟议的SCCOR有5个项目，由6个核心支持。四个项目是临床项目（项目1，2，4，5），都集中在COPD患者肺部特定成分的基因表达。一个项目是临床前（项目3），重点是肺再生。核心A、B提供支持人类受试者研究的服务，核心C、D提供生物材料分析服务，核心E专注于培养临床研究技能的教育，核心F提供行政支持。所有的项目都使用新颖的策略来评估潜在的主题。项目1基于HIV-1+吸烟者在早期和有限吸烟史时肺气肿发病率高的临床观察，提出研究肺泡巨噬细胞中的基因表达，以帮助了解哪些介质在介导肺破坏中最重要。项目2利用了果蝇和发育中的小鼠胚胎研究的知识，即Notch通路是分化的“看门人”，以帮助解开在COPD气道上皮中观察到的异常分化模式。项目3应用于肺切除术后快速肺再生的小鼠模型，以解读CXCR 4 + VEGFR 1+血管生成前体对肺血管重建的作用。项目4研究了在创伤诱导的气道上皮再生后稳态和随时间推移用于纤毛发生的基因，以评估COPD中异常纤毛功能中基因表达紊乱的作用。项目5利用一种新开发的策略，对人类小气道上皮细胞进行重复采样，以确定与COPD发病机制有关的多种基因的异常表达，并使用这种异常的“小气道分子特征”来评估戒烟、气雾剂皮质类固醇治疗或白三烯途径抑制剂治疗对COPD相关分子途径的影响。 个别项目和核心单位 项目1：肺泡巨噬细胞在加速肺气肿中的作用 HIV-1阳性吸烟者 （Kaner，Robert） 描述（由申请人提供）： 随着高效抗逆转录病毒疗法（HAART）的出现，HIV-1感染者的存活率大大提高。然而，最近认识到肺气肿的显着加速发展，在这个人群中，在很小的年龄和最低限度的吸烟史提供了一个机会，研究这个问题的分子基础。在这种情况下，肺气肿的HIV-1/艾滋病加入α 1-抗胰蛋白酶缺乏症作为一个临床模型的一种加速形式的肺破坏，因此，HIV-1 +个人吸烟可以作为一个模型，以了解肺气肿的发病机制。基于肺泡巨噬细胞（AM）是慢性感染HIV-1的肺的主要细胞类型，以及AM在释放介导吸烟引起的肺气肿中肺破坏的介质中起核心作用的知识，我们假设HIV-1和香烟烟雾协同激活AM表达对肺实质高度危险的转录组。它的评价将有助于确定激活途径，这是最关键的肺气肿的发展，并代表药理学目标。基于这一背景，我们建议评估3个具体目标。目标1.检验以下假设：HIV-1感染和吸烟共同作用，产生AM基因表达模式，表明与肺气肿发病机制相关的基因表达上调，并且这些变化超过或补充吸烟或HIV-1单独诱导的变化。目标2.基于HIV-1感染与肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）的全身和肺水平升高相关，以及实验动物肺中TNF-α或IFN-γ的表达与肺气肿的发展相关的知识，我们将检验这样的假设，即HIV-1 +吸烟者AM表达的肺气肿相关介质的过度表达与TNF-α的过度表达有关。a和/或IFN-γ。目标3。为了检验以下假设：虽然HAART疗法有效地抑制了AM中HIV-1的复制，但它并不完全抑制与肺气肿发病机制相关的AM的基因表达模式，并且AM中上调基因子集的持续存在与肺泡环境中的TNF-α或INF-γ相关。

DESCRIPTION (provided by applicant): Chronic obstructive lung disease (COPD), a leading cause of pulmonary disability and death, is caused mainly by cigarette smoking. The initial pathologic changes are in the small airways and central lobular alveoli, with chronic inflammation and concomitant local expression of protease, oxidant, apoptotic and other inflammatory mediators capable of injuring the airways and alveoli. The theme underlying the Weill Cornell COPD SCCOR is that the clinical phenotype of COPD evolves when the regenerative process of the lung are no longer capable of maintaining normal lung structure and.function under the persistent injury to airways/alveoli caused by smoking and the inflammatory host response to smoking. With this theme, the proposed SCCOR has 5 projects supported by 6 cores. Four projects are clinical (Projects 1, 2, 4, 5), all focused on gene expression of specific components of the lung in patients with COPD. One project is pre-clinical (Project 3), focused on lung regeneration. Cores A, B provide services to support the study of human subjects, Cores C, D provide services for analysis of biologic materials, Core E is focused on education for developing clinical research skills, and Core F provides administrative support. All of the projects use novel strategies to assess the underlying theme. Project 1, based on the clinical observation that smokers that are HIV-1+ have a high incidence of emphysema at an early age and limited smoking history, proposes to study gene expression in alveolar macrophages to help understand which mediators are the most important in mediating lung destruction. Project 2 exploits the knowledge from studies of Drosophila and the developing murine embryo that the Notch pathway is a "gatekeeper" for differentiation to help unravel the abnormal pattern of differentiation observed in the airway epithelium in COPD. Project 3 applies to the murine model of rapid postpneumonectomy lung regeneration to decipher the role of CXCR4+VEGFR1 + hemangiogenic precursor to lung revascularization. Project 4 studies genes used for ciliogenesis in the steady state and over time after wounding-induced airway epithelial regeneration to assess the role of deranged gene expression in abnormal cilia function in COPD. Project 5 utilizes a newly developed strategy to repetitively sample the human small airway epithelium to define abnormal expression of multiple categories of genes implicated in the pathogenesis of COPD, and uses this abnormal "small airway molecular signature" to assess the impact of smoking cessation, aerosol corticosteroid therapy, or leukotriene pathway inhibitor therapy on molecular pathways relevant to COPD. INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: Role of Alveolar Macrophages in the Accelerated Emphysema Of HIV-1 Positive Cigarette Smokers (Kaner, Robert) DESCRIPTION (provided by applicant): With the advent of highly active antiretroviral therapy (HAART), the survival of individuals infected with HIV-1 has dramatically improved. However, recent recognition of the markedly accelerated development of emphysema in this population at an early age and with a minimal smoking history provides an opportunity to study the molecular basis for this problem. In this context, the emphysema of HIV-1/AIDS joins a1-antitrypsin deficiency as a clinical model of an accelerated form of lung destruction, and thus HIV-1 + individuals that smoke can serve as a model to understand the pathogenesis of emphysema. Based on the knowledge that the alveolar macrophage (AM) is the primary cell type of the lung that is chronically infected by HIV-1, and that the AM plays a central role in releasing mediators that mediate the lung destruction in smoking-ind.uced emphysema, we hypothesize that HIV-1 and cigarette smoke synergize to activate AM to express a transcriptome that is highly dangerous to the lung parenchyma. Its evaluation will help to identify the activation pathways that are most critical in the development of emphysema and represent pharmacologic targets. Based on this background, we propose to assess 3 specific aims. Aim 1. To test the hypothesis that HIV-1 infection and cigarette smoking act in concert to create a pattern of AM gene expression indicative of up-regulated expression of genes relevant to the pathogenesis of emphysema and that these changes are in excess of, or in addition to, that induced by smoking or HIV-1 alone. Aim 2. Based on the knowledge that HIV-1 infection is associated with elevated systemic and lung levels of tumor necrosis factor-a (TNF-a) and interferon-Y (IFN-v), and that expression of TNF-a or IFN-v in the lungs of experimental animals is associated with the development of emphysema, we will examine the hypothesis that the exaggerated program of emphysema-related mediators expressed by AM of HIV-1 + smokers is linked to the overexpression of TNF-a and/or IFN-y in the lung. Aim 3. To examine the hypothesis that while HAART therapy effectively suppresses replication of HIV-1 in the AM, it does not entirely suppress the pattern of gene expression of the AM relevant to the pathogenesis of emphysema, and that the persistence of the subset of up-regulated genes in the AM is linked to TNF-a or INF-v in the milieu of the alveolus.