MECHANISMS AND TREATMENT OF COPD PROGRESSION

描述(由申请人提供)： 慢性阻塞性肺疾病(COPD)是一种影响数百万人的致残性疾病，是美国和世界范围内的主要死亡原因。虽然戒烟可以阻止早期疾病的发展，但一旦疾病发展到晚期，即使戒烟也可能会进展。最近的证据表明，COPD的进展是肺内细胞维持过程的失调导致细胞凋亡导致肺气肿的结果。氧化应激、炎性细胞因子、生长因子和蛋白酶的复杂相互作用促进了这一过程，导致实质破坏和气道重塑。这份SCCOR的主题基础是，了解导致COPD结构进展的过程将导致能够阻止疾病临床进展的治疗。这项SCCOR中的项目探索了与COPD进展有关的关键途径--抗蛋白酶的新型抗凋亡特性、对氧化应激的遗传易感性、微粒吸入的促炎效应以及间歇性低氧的促炎应激。创新的临床治疗试验研究抗炎剂和生长因子抑制剂、环境控制和夜间机械支持-所有这些都是阻止COPD进展的有希望的治疗方法。高度集中的基础蛋白质组学研究解决了α-1抗胰蛋白酶的翻译后修饰，高度集中的基因组研究解决了抗氧化调节基因Nrf2的作用。霍普金斯SCCOR应用程序代表了一个具有多学科专业知识的研究人员联盟，其共同目标是将基础研究发现转化为COPD患者的直接利益。在四个交互核心(管理、成像、患者招募和数据管理以及分子病理生理学)的支持下，这五个人类和动物项目将使用最先进的分子方法和新的表型方法，这些方法不仅将提供迄今为止对COPD关键病理生物学过程的最深入了解，而且将定义与疾病易感性相关的关键途径，并发现新的治疗方法来改变这种疾病的进程 个别项目和核心单位 项目1：α1-抗胰蛋白酶新的保护性抗细胞凋亡作用 肺气肿 (鲁宾·图德尔) 描述(由申请人提供)： 肺泡细胞凋亡是肺气肿肺泡间隔消失和组织破坏的主要病理生物学过程之一。我们提出的SCCOR建议的总体理念是，慢性阻塞性肺疾病(COPD)肺细胞维持中断所导致的炎症和凋亡细胞破坏的相互作用决定了慢性阻塞性肺疾病(COPD)的肺破坏的程度。尽管α-1抗胰蛋白酶(A1AT)缺乏患者肺气肿的流行模式强调了A1AT作为弹性酶抑制剂的作用，但丝氨酸蛋白酶抑制剂(Serpins)，包括A1 AT，除了作为蛋白酶抑制剂的经典作用外，还具有更广泛的生物学效应。我们的目标是确定A1 AT的新的生物学作用，以增强我们对肺泡细胞损伤导致肺气肿的发病机制的理解。我们假设A1 AT通过结合和抑制活性的caspase-3来预防肺气肿，导致肺泡对细胞凋亡的保护，这是肺气肿破坏肺泡的关键步骤。这个基础科学项目依赖于一种综合的方法，涉及肺气肿的血管内皮生长因子受体阻断模型和腺相关病毒在体内转导人A1AT，以及使用细胞培养和无细胞系统来探索A1 AT和caspase-3的相互作用的重点机制研究。我们基于标准化的形态测量、肺成像、肺功能测试(在分子病理生理学核心D的支持下)以及与细胞凋亡、氧化应激和促凋亡脂质神经酰胺相关的终点，发展了对肺气肿肺的最先进的实验评估。我们的具体目标是(1)证明A1 AT通过阻断细胞凋亡，从而降低氧化应激和神经酰胺水平来预防小鼠肺气肿的发展。(2)确定A1 AT是否通过直接抑制caspase-3的激活而保护肺内皮细胞免于凋亡；以及(3)确定肺气肿患者A1AT翻译后的改变(氧化、亚硝化或聚合)是否削弱了A1 AT的抗凋亡作用。发现新的细胞内进入机制和α-1抗胰蛋白酶活性，并可能为改进我们治疗α1抗胰蛋白酶缺乏症和吸烟诱导的肺气肿的方法提供机会。我们将与项目4密切合作，以确定在发育中的肺生命中吸烟肺损伤是否损害A1AT的抗凋亡功能。我们计划将我们对A1AT新的抗凋亡作用的机械性见解转化为对COPD患者A1 AT的翻译后修饰(项目2)和暴露于环境颗粒物(项目5)可能使A1 AT对活性caspase-3无效的研究。

DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is a disabling disorder that affects millions of people and is a leading cause of death in the U.S. and worldwide. Although smoking cessation can halt progression of early disease, once the disease becomes advanced, it may progress even with smoking cessation. Recent evidence suggests that progression of COPD is the result of dysregulation of cellular maintenance processes in the lung that result in apoptosis leading to emphysema. The complex interplay of oxidative stress, inflammatory cytokines, growth factors, and proteases promote this process leading to parenchymal destruction and airway remodeling. The thematic underpinning of this SCCOR is that understanding the processes leading to structural progression of COPD will lead to treatments that can halt clinical progression of the disease. The projects in this SCCOR explore key pathways that are involved in progression of COPD - novel anti-apoptotic properties of anti-proteases, genetic susceptibility to oxidative stress, the pro-inflammatory effects of particulate inhalation, and the pro-inflammatory stress of intermittent hypoxia. Innovative clinical therapeutic trials investigate anti-inflammatory agents and growth factor inhibitors, environmental controls, and mechanical support of nocturnal ventilation - all of which are promising treatments to stop progression of COPD. Highly focused basic proteomic research addresses the post-translational modification of alpha-1 anti-trypsin and highly focused genomic research addresses the role of the anti-oxidant regulatory gene Nrf2. The Hopkins SCCOR application represents a consortium of investigators with multidisciplinary expertise, and the common goal to translate basic research discoveries into direct benefit for patients with COPD. Supported by four interactive cores (Administration, Imaging, Patient Recruitment and Data Management, and Molecular Pathophysiology), the five human and animal projects will use state-of-the-art molecular approaches and novel phenotyping methods that will not only provide the deepest understanding of critical pathobiologic processes in COPD to date, but will define key pathways relevant to disease susceptibility and uncover new therapeutic approaches to modify the course of this disease INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: Novel Protective Antiapoptotic Action of Alpha 1-Antitrypsin In Emphysema (Tuder, Rubin) DESCRIPTION (provided by applicant): Alveolar cell apoptosis represents one of the major pathobiological processes that account for the loss of alveolar septae and tissue destruction in emphysema. Our overall concept underlying this SCCOR proposal is that the interaction of inflammation and apoptotic cell destruction due to disruption of lung cellular maintenance determines the magnitude of lung destruction in chronic obstructive pulmonary disease (COPD). Although the prevailing paradigm of emphysema development in patients with alpha-1 antitrypsin (A1AT) deficiency emphasizes the role of A1AT as an elastase inhibitor, serine protease inhibitors (Serpins), including A1 AT, have broader biological effects beyond their classical action as protease inhibitors. It is our goal to identify novel biological roles of A1 AT that might enhance our understanding of the pathogenesis of alveolar cell injury leading to emphysema. We hypothesize that A1 AT prevents emphysema by binding to and inhibiting active caspase-3, leading to alveolar protection against apoptosis, a critical step of alveolar destruction in emphysema. This basic science project relies on an integrated approach involving the VEGF receptor blockade model of emphysema and adeno-associated virus transduction of human A1AT in vivo, and on focused mechanistic studies using cell cultures and cellfree systems to probe for the interaction of A1 AT and caspase-3. We have developed state of the art experimental assessment of emphysema lungs, based on standardized morphometry, lung imaging, pulmonary function tests (with the support of Molecular Pathophysiology Core D), and end points related to apoptosis, oxidative stress, and the proapoptotic lipid ceramide. Our specific aims are (1) To demonstrate that A1 AT prevents the development of emphysema in mice by blocking apoptosis, and thus reducing oxidative stress and ceramide levels. (2) To determine whether A1 AT protects pulmonary endothelial cells from apoptosis by a direct intracellular inhibition of caspase-3 activation; and (3) To identify whether in patients with emphysema, post-translational alterations in A1AT (oxidation, nitrosylation, or polymerization) impair the anti-apoptotic effect of A1 AT. Discovery of novel mechanisms of intracellular entry and activity of alpha-1 antritrypsin and may provide an opportunity improve our therapeutic approaches in alpha 1 antitrypsin deficiency- and smoking-induced emphysema. We will collaborate closely with Project 4 to determine whether cigarette smoke lung injury in the developing lung life impairs antiapoptotic functions of A1AT. We plan to translate our mechanistic insights of the novel antiapoptotic actions of A1AT in the investigation of posttranslational modifications of A1 AT in patients with COPD (with Project 2) and exposure to environmental particulates (with Project 5) that may render A1 AT inactive against active caspase-3.