The long-term goal of this study is to understand how undifferentiated epithelial cells generate specialized cell types in the postnatal lung and elucidate the molecular mechanisms by which specific lung cell types control lung regeneration and development of lung diseases. In this project, we focus on pulmonary neuroendocrine cells (PNECs). PNECs are associated with a number of lung diseases;perhaps the most important clinical connection comes from the speculation that PNECs constitute the cells of origin for small cell lung cancer. PNECs have been proposed to control multiple aspects of lung function including airway oxygen sensing, regulating pulmonary blood flow, controlling bronchial tonus and modulating immune responses. Prior work has also implicated PNECs in maintaining a stem cell niche essential for Clara cell regeneration during lung injury. Progress on these central issues has been hindered by the lack of a fundamental understanding of PNEC specification and function. Furthermore, the major physiological functions of PNECs in lung homeostasis and injury have not been rigorously tested in a genetic system. To answer these critical questions, we developed a new genetic tool in mice that allows conditional manipulation of gene expression in PNECs and enables isolation of a pure population of PNECs. This would allow us to elucidate the molecular mechanisms of PNEC specification and define the signaling pathways that control these processes. These investigations will also pinpoint the physiological functions of PNECs during normal homeostasis and in lung injury and disease.

Public Health Relevance

Pulmonary neuroendocrine cells (PNECs) control multiple aspects of lung function and also underlie several lung diseases. A fundamental understanding of PNEC specification and function will provide key insights into the roles of PNEC in normal homeostasis, lung injury and disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL115207-02
Application #
8693010
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143