MECHANISMS AND TREATMENT OF COPD PROGRESSION

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。在四个互动核心(行政、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对COPD关键病理生物学过程的最深入了解，而且将确定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。

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.