Disarray of Injury/Regeneration Homeostasis in Smoking-Induced COPD

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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.