The overall goal of this revised application is to investigate mechanisms by which airway progenitor cells acquire and balance their different cell phenotypes during development and during regeneration in adult life. More specifically, we will focus on the role of Notch and its regulation by Ascl1 in the selection of cell fates in developing airways and when airways are repopulated after injury. We have recently reported that Notch signaling in the embryonic airway epithelium is essential for establishing the balance of secretory and non-secretory cell fates. Disruption of Notch signaling prevents Clara cells from forming and results in airways overpopulated by neuroendocrine and ciliated cells. How does Notch influence cell fate selection? Which ligands are critical for this process and do they drive any specific lineage program in the airways? Studies in adult mice injured by Naphthalene suggest that a population of Clara cells resistant to this compound is able to give rise to a balanced proportion of secretory and ciliated cells. How this is achieved is currently unknown. We have preliminary evidence that Notch may regulate this process. Here we propose to address these issues in three specific aims.
Aim 1 : Study mechanisms that balance epithelial cell phenotypes looking at the role of different Notch ligands in mouse genetic models in which Jagged or Delta ligands were inactivated;
Aim 2 : Characterize lineage and fate of Ascl1-expressing cells and their influence in the neighbor airway epithelium using in vivo and airway epithelial culture models, and, Aim 3: Investigate mechanisms of Notch-mediated cell fate choice in regenerating airways using a Naphthalene model of injury repair and pharmacologic and genetic approaches to inactivate Notch.

Public Health Relevance

The goal of this project is to study the mechanisms by which the Notch pathway and the transcription factor Ascl1 (Achaete-scute 1) control cell fate in the airway epithelium during development and regeneration in the adult lung. We will study specific aspects of these mechanisms using relevant mouse genetic models, primary airway epithelial culture systems and a model of lung injury-repair.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Blaisdell, Carol J
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Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
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Guha, Arjun; Deshpande, Aditya; Jain, Aradhya et al. (2017) Uroplakin 3a+ Cells Are a Distinctive Population of Epithelial Progenitors that Contribute to Airway Maintenance and Post-injury Repair. Cell Rep 19:246-254
Tsao, Po-Nien; Matsuoka, Chisa; Wei, Shu-Chen et al. (2016) Epithelial Notch signaling regulates lung alveolar morphogenesis and airway epithelial integrity. Proc Natl Acad Sci U S A 113:8242-7
Szymaniak, Aleksander D; Mahoney, John E; Cardoso, Wellington V et al. (2015) Crumbs3-Mediated Polarity Directs Airway Epithelial Cell Fate through the Hippo Pathway Effector Yap. Dev Cell 34:283-96
Mori, Munemasa; Mahoney, John E; Stupnikov, Maria R et al. (2015) Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development 142:258-67
Mahoney, John E; Mori, Munemasa; Szymaniak, Aleksander D et al. (2014) The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors. Dev Cell 30:137-50
Guha, Arjun; Vasconcelos, Michelle; Zhao, Rui et al. (2014) Analysis of Notch signaling-dependent gene expression in developing airways reveals diversity of Clara cells. PLoS One 9:e88848
Morrisey, Edward E; Cardoso, Wellington V; Lane, Robert H et al. (2013) Molecular determinants of lung development. Ann Am Thorac Soc 10:S12-6
Guha, Arjun; Vasconcelos, Michelle; Cai, Yan et al. (2012) Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways. Proc Natl Acad Sci U S A 109:12592-7
Golan-Gerstl, Regina; Wallach-Dayan, Shulamit B; Zisman, Philip et al. (2012) Cellular FLICE-like inhibitory protein deviates myofibroblast fas-induced apoptosis toward proliferation during lung fibrosis. Am J Respir Cell Mol Biol 47:271-9
Manoli, Sara E; Smith, Lacey A; Vyhlidal, Carrie A et al. (2012) Maternal smoking and the retinoid pathway in the developing lung. Respir Res 13:42

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