End-stage lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are devastating human conditions for which there are no effective treatments. There is increasing evidence that the inability to maintain epithelial integrity or recovery from sustained injury likely reflects a failure of the stem cell compartment to mount an effective regenerative response. Tissue-specific stem cells are crucial for homeostasis and integrity of adult organs. In the airway epithelium these functions have been attributed largely to multipotent p63-dependent basal cells. However, this role is shared by additional progenitors, particularly by a sizable population of uncommitted p63-negative progenitors which occupy a parabasal location interfacing both basal and luminal differentiating cells. Changes in the size or function of the pool of uncommitted airway epithelial progenitors (basal, parabasal cells) are often accompanied by disruption of the microarchitectural organization seen in hyperplasias and metaplasias of end-stage lung conditions In spite of recent progress, there are still major gaps of knowledge on what collectively the airway endogenous progenitors represent; their origin, diversity, and contribution to plasticity in development, regeneration and disease states. Here we propose to address these gaps of knowledge in our research program to: a) study the molecular and cellular events that control the organization and behavior of the stem cell compartment in the airways, and b) investigate the impact of the disruption of these mechanisms in pulmonary disease pathogenesis. Results from these studies will provide crucial insights currently lacking in the field about how tissue- specific stem cells contribute to normal and disease processes in the lung.

Public Health Relevance

In spite of the recent advances in pulmonary medicine, still little is known about how lung stem cells are maintained and how they behave in response to injury and in disease states. This proposal will explore the mechanisms that control the behavior of these stem cells during development and allow the airway epithelium to regenerate. This knowledge will provide insights about mechanisms of pulmonary diseases and can inform about potential new treatments. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Unknown (R35)
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Special Emphasis Panel (ZHL1)
Program Officer
Lin, Sara
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Smith, Benjamin M; Traboulsi, Hussein; Austin, John H M et al. (2018) Human airway branch variation and chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A 115:E974-E981
de Barros Mendes Lopes, Thais; Groth, Espen E; Veras, Mariana et al. (2018) Pre- and postnatal exposure of mice to concentrated urban PM2.5 decreases the number of alveoli and leads to altered lung function at an early stage of life. Environ Pollut 241:511-520
Zhang, Yongchun; Yang, Ying; Jiang, Ming et al. (2018) 3D Modeling of Esophageal Development using Human PSC-Derived Basal Progenitors Reveals a Critical Role for Notch Signaling. Cell Stem Cell 23:516-529.e5
Yang, Ying; Cardoso, Wellington V (2018) Stem Cells Sheltered from Air-Raids Repair Airways. Cell Stem Cell 22:613-614
Yang, Ying; Riccio, Paul; Schotsaert, Michael et al. (2018) Spatial-Temporal Lineage Restrictions of Embryonic p63+ Progenitors Establish Distinct Stem Cell Pools in Adult Airways. Dev Cell 44:752-761.e4
Stupnikov, Maria R; Cardoso, Wellington V (2017) Sensing oxygen inside and out. Elife 6:
Mori, Munemasa; Hazan, Renin; Danielian, Paul S et al. (2017) Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis. Nat Commun 8:15857