Alveolar and Airway Mechanisms for COPD

SCCOR项目的总体目标是确定对COPD的诊断、发病机制和治疗至关重要的肺泡和气道事件。选择肺泡/气道主题是为了体现我们的建议，即这两个组成部分对COPD至关重要，并利用我们在肺气肿和慢性气道疾病研究方面的长期专业知识。SCOR由五个相互关联的项目组成。项目I旨在利用肺移植患者的全肺以及肺成像和分析的新方法，检测COPD患者的肺泡对抗气道疾病。该项目特别针对T细胞和巨噬细胞的激活，但也采用了一种为其他项目目标提供底物的全局方法。其中一个目标是弹性分解活性，因此项目II在研究弹性蛋白的质量和数量时将重点放在肺气肿的遗传决定因素上。该项目利用易患肺气肿的弹性蛋白基因中自然发生的变异，并将这种方法扩展到新的遗传变异中。III项目继续在肺气肿研究中使用一种互补的方法，旨在研究额外的基质金属蛋白酶在肺气肿中的作用。该项目主要研究MTI-MMP与潜在诱导剂EMMPRIN之间新定义的相互作用，以及该途径如何影响香烟烟雾诱导的单核细胞/巨噬细胞激活、炎症和随之而来的肺泡破坏。项目IV在巨噬细胞活化的研究中延续了这一主题。本项目确定并探索了一种新的NKT细胞-巨噬细胞激活途径，该途径在香烟烟雾暴露的情况下驱动慢性IL-13产生和粘膜细胞化生。项目V继续这一策略，重点关注免疫系统的这一轴对糖皮质激素治疗的反应。该项目利用糖皮质激素受体生物学方面的专业知识来定义序列多态性和其他与治疗反应性相关的患者特征。因此，这些项目将从检测到发病机制到治疗的研究结合在一起，以解释COPD的基础；每一种方法都着重强调基于实验模型发展的临床研究。共同的科学目标创造了一个协同的计划，可以由一组共同的核心来支持：行政核心将执行行政职能，并将为电子通信和数据分析提供计算机支持。注册表和数据分析核心对所有临床研究材料进行编目，并确保临床方案的一致性。成像核心为高分辨率CT和氦核磁共振研究提供支持。形态学和显微镜核心提供组织处理和分析。小鼠核心开发转基因小鼠，并为烟雾暴露和生理测量提供设施。核心/项目的互动是基于项目合作的原则，将实验模型中的任何发现转化为COPD患者的研究。

The overall goal of this SCCOR program is to identify the alveolar and airway events that are critical to the diagnosis, pathogenesis, and treatment of COPD. This alveolar/airway theme was chosen to capture our proposal that both components are critical to COPD and to take advantage of our longstanding expertise in research on emphysema and chronic airway disease. The SCOR consists of five interrelated Projects. Project I aims at detection of alveolar versus airway disease in COPD by taking advantage of whole lungs from COPD patients undergoing lung transplantation and a new approach to lung imaging and profiling. This project takes special aim at T cell and macrophage activation, but also assumes a global approach that provides a substrate for other project targets. One of these targets is elastolytic activity, and Project II accordingly focuses on genetic determinants of emphysema in studies of the quality and quantity of elastin. This project capitalizes on a naturally occurring variation in the elastin gene that predisposes to emphysema and extends this approach to new genetic variations as well. Project III continues in emphysema studies using a complimentary approach aimed at the role of additional matrix metalloproteinases in emphysema. This project concentrates on a newly defined interaction between MTI-MMP and a potential inducer, i.e., EMMPRIN, and how this pathway influences cigarette smoke-induced monocyte/macrophage activation, inflammation, and consequent alveolar destruction. Project IV continues this theme in the study of macrophage activation. This project identifies and pursues a novel NKT cell-macrophage activation pathway that drives chronic IL-13 production and mucous cell metaplasia in the setting of cigarette smoke exposure. Project V continues on this tact, focusing on the responsiveness of this axis of the immune system to glucocorticoid treatment. The project capitalizes on expertise in glucocorticoid receptor biology to define sequence polymorphisms and other patient characteristics that are linked with responsiveness to treatment. The projects thereby weave studies from detection to pathogenesis to treatment together to explain the basis for COPD; and each provides for a predominant emphasis on clinical research based on development from experimental models. Common scientific goals create a synergistic program that can be supported by a common set of cores: the Administrative Core will perform administrative functions and will provide computer support for electronic communication and data analysis. The Registry and Data Analysis Core catalogues all clinical research materials and assures uniformity among clinical protocols. The Imaging Core provides support for high-resolution CT and helium-MRI studies. The Morphology & Microscopy Core provides for tissue processing and analysis. The Mouse Core develops transgenic mice and provides facilities for smoke exposure and physiologic measurements. Core/Project interactions are based on the principle that projects collaborate to translate any findings in experimental models to studies of patients with COPD.