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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Program Officer
Punturieri, Antonello
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
Strulovici-Barel, Yael; Staudt, Michelle R; Krause, Anja et al. (2016) Persistence of circulating endothelial microparticles in COPD despite smoking cessation. Thorax 71:1137-1144
Barjaktarevic, Igor Z; Crystal, Ronald G; Kaner, Robert J (2016) The Role of Interleukin-23 in the Early Development of Emphysema in HIV1(+) Smokers. J Immunol Res 2016:3463104
Harvey, Ben-Gary; Strulovici-Barel, Yael; Kaner, Robert J et al. (2015) Risk of COPD with obstruction in active smokers with normal spirometry and reduced diffusion capacity. Eur Respir J 46:1589-1597
Gomi, Kazunori; Arbelaez, Vanessa; Crystal, Ronald G et al. (2015) Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway. PLoS One 10:e0116507
Wang, Guoqing; Wang, Rui; Strulovici-Barel, Yael et al. (2015) Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation. PLoS One 10:e0120824
Walters, Matthew S; De, Bishnu P; Salit, Jacqueline et al. (2014) Smoking accelerates aging of the small airway epithelium. Respir Res 15:94
Hessel, Justina; Heldrich, Jonna; Fuller, Jennifer et al. (2014) Intraflagellar transport gene expression associated with short cilia in smoking and COPD. PLoS One 9:e85453
Shaykhiev, Renat; Crystal, Ronald G (2014) Early events in the pathogenesis of chronic obstructive pulmonary disease. Smoking-induced reprogramming of airway epithelial basal progenitor cells. Ann Am Thorac Soc 11 Suppl 5:S252-8
Brekman, Angelika; Walters, Matthew S; Tilley, Ann E et al. (2014) FOXJ1 prevents cilia growth inhibition by cigarette smoke in human airway epithelium in vitro. Am J Respir Cell Mol Biol 51:688-700
Gao, Chuan; Tignor, Nicole L; Salit, Jacqueline et al. (2014) HEFT: eQTL analysis of many thousands of expressed genes while simultaneously controlling for hidden factors. Bioinformatics 30:369-76

Showing the most recent 10 out of 75 publications