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Pulmonary Neuroendocrine Cells as a Sensor in Tobacco Induced Lung Diseases

Institution: University of California, San Diego
Investigator(s): Xin Sun,
Award Cycle: 2019 (Cycle 29) Grant #: T29IR0475 Award: $937,500
Subject Area: Pulmonary Disease
Award Type: High Impact Research Project Award

Initial Award Abstract
With the lung as a primary organ exposed to cigarette smoke, the impact of tobacco on respiratory health is profound. Much of the research has focused on cigarette smoke induced airway injury and inflammatory responses. Relatively little is known about the upstream sensors of tobacco smoke. In this study, we will investigate a fascinating group of cells in the lung called pulmonary neuroendocrine cells (PNECs). They have been overlooked in the past as they are rare, and thereby dismissed as not likely being of consequence. Recently, we found that PNECs are absolutely essential for allergen-induced asthmatic responses, challenging the dogma and demonstrating a cardinal role of these cells as key airway sensors despite their rarity. PNECs express nicotine receptors, and can be activated by nicotine when grown in a cell culture dish. Furthermore, PNECs are the cancer cell of origin for small cell lung cancer, which is one of the deadliest among lung cancers, and almost all small cell lung cancer patients have a smoking history. These findings support the important hypothesis that PNECs are key sensors for cigarette smoke and e-cigarette vapor, and are responsible for relaying the detrimental effects on lung. We will use cutting-edge single-cell genomic and epigenomic technologies to systematically define, for the first time, the impact of cigarette smoke and e-cigarette vapor on PNECs. As PNEC products are secreted and therefore easy to target, knowledge of PNEC function would open new therapeutic options for diseases such as chronic obstructive pulmonary disease and small cell lung cancer.