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 ainA/ay and alveolar epithelial cell progenitor biology is a crucial part of any effort to move the field of directed distal lung remodeling or repair toward the clinical arena. Toward that end, this application brings together investigative groups with different expertise but overiapplng 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 underiies 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 allows 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 biology to human lung disease.

Public Health Relevance

; This proposal brings together several investigators with overiapplng but distinct expertise in the field of epithelial cell biology with the 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL111054-03
Application #
8598931
Study Section
Special Emphasis Panel (ZHL1-CSR-H (O1))
Program Officer
Blaisdell, Carol J
Project Start
2012-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$581,920
Indirect Cost
$205,273
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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