Alveolar and Airway Mechanisms for COPD

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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.