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

描述(申请人提供)：本研究的长期目标是了解未分化上皮细胞如何在出生后的肺中产生特定的细胞类型，并阐明特定的肺细胞类型控制肺再生和肺部疾病发展的分子机制。本课题主要研究肺神经内分泌细胞(PNECs)。PNECs与许多肺部疾病有关；也许最重要的临床联系来自PNECs构成小细胞肺癌起源细胞的推测。PNECs被认为可以控制肺功能的多个方面，包括呼吸道氧气感应、调节肺血流、控制支气管张力和调节免疫反应。先前的工作还表明，PNECs在肺损伤期间维持对Clara细胞再生至关重要的干细胞生态位。这些中心的进展 由于缺乏对PNEC规范和功能的基本了解，这些问题一直受到阻碍。此外，PNECs在肺内稳态和损伤中的主要生理功能还没有在遗传系统中得到严格的测试。为了回答这些关键问题，我们在小鼠身上开发了一种新的遗传工具，可以有条件地操纵PNEC中的基因表达，并能够分离出纯PNEC群体。这将使我们能够阐明PNEC的分子机制，并定义控制这些过程的信号通路。这些研究还将明确PNECs在正常内稳态以及在肺损伤和疾病中的生理功能。

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.