The lineage and function of neuroendocrine cells in lung homeostasis and injury

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DESCRIPTION (provided by applicant): 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.