The pulmonary bronchiolar and alveolar epithelia are involved prominently in a number of important human diseases associated with loss of alveolar integrity, including emphysema and pulmonary fibrosis. In each of these conditions the capacity to generate new alveolar epithelium, and its associated vascular bed, would be of great potential therapeutic value, but such capacity remains beyond the reach of current technology. This application is predicated on the idea that better understanding of distal airway and alveolar epithelial cell progenitor biology is a crucial part of any effort to move the field of directed dital lung remodeling or repair toward the clinical arena. Toward that end, this application brings together investigative groups with different expertise but overlapping interests in epithelial progenitor cell biology to advance the understanding of distal lung development, maintenance, and repair. The major objectives are (1) to define the transcriptional program of heretofore uncharacterized distal airway and alveolar progenitors and test the hypothesis that differential expression of adhesion receptors underlies the capacity of epithelial subtypes to self-organize and promote repair. (2) Define the requirement for neuroendocrine cells (PNECS) and alveolar progenitor cells in maintenance and reconstitution of distal airway and alveolar cells following lung injury. (3) Analyze and further develop a novel, single cell in vivo lung organoid assay in kidney capsules in order to optimize the capacity of adult epithelial progenitor cells to generate functional respiratory units de novo. Important tools and approaches developed to achieve these aims include mice with inducible cre activity knocked into lineage-defining genomic loci, flow cytometry-based techniques to isolate and transcriptionally profile mouse and human embryonic and adult epithelial progenitors, and innovative imaging that allow real time capture of stable images of lung and lung organoids over time. We anticipate that by the completion of these studies we should be able to adapt our in vivo assay toward orthotopic transplantation of cellular units capable of lung development. Overall, these studies should provide crucial conceptual and technological infrastructure for the clinical translation of progenitor cell biologyto human lung disease.

Public Health Relevance

;This proposal brings together several investigators with overlapping but distinct expertise in the field of epithelial cell biology with he goal of generating the conceptual biological infrastructure as well as technology for creating distal lung tissue de novo from a source of progenitor cells. The projects should empower translation of new concepts to the treatment of lung diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHL1-CSR-H (O1))
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Blaisdell, Carol J
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Vaughan, Andrew E; Brumwell, Alexis N; Xi, Ying et al. (2015) Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517:621-5
Lin, Chuwen; Chen, Miao-Hsueh; Yao, Erica et al. (2014) Differential regulation of Gli proteins by Sufu in the lung affects PDGF signaling and myofibroblast development. Dev Biol 392:324-33
Lelkes, Efrat; Headley, Mark B; Thornton, Emily E et al. (2014) The spatiotemporal cellular dynamics of lung immunity. Trends Immunol 35:379-86
Vaughan, Andrew E; Chapman, Harold A (2013) Regenerative activity of the lung after epithelial injury. Biochim Biophys Acta 1832:922-30