DETERMINANTS OF CELL FATE AND DIFFERENTIATION IN THE DEVELOPING LUNG

描述（由申请人提供）：这是一个竞争性的计划项目赠款的更新，目前在其第16年，重点是肺发育的分子调控。该计划非常成功地汇集了一个互动的多学科研究团队来探索这一主题，并为该领域做出了重大贡献。这次更新包括五个互动项目，以研究发育中的肺细胞命运和分化的决定因素。这些项目解决了关键的和知之甚少的问题，建立肺细胞谱系的机制，以及这与形态发生和获得分化的细胞表型的关系。项目1解决了与最初的呼吸谱系在早期形态发生过程中如何在空间上组织和扩展以及Notch和Fgfs在此过程中的作用有关的问题。项目2将重点关注内源性microRNA在肺近端-远端特化过程中控制动态基因活性的机制。项目3开发了新的工具，探索小鼠ES细胞培养系统，以研究控制早期肺谱系特化的遗传机制。项目4的重点是早期肺发育过程中染色质重塑和DNA甲基化在基因转录调控中的机制。 项目5研究了造血干细胞如何促进肺结构的发育和天然免疫的建立。 除了这些项目，还提出了三个核心。“行政核心”将处理方案的总体管理和财务问题。“显微镜图像分析和流式细胞仪核心”将提供组织学资源，通过标准或共聚焦显微镜分析基因/蛋白质表达和细胞分选：“小鼠核心”将支持研究人员维持各种现有的小鼠品系，育种，基因分型和设计新小鼠品系的构建体。这些项目和核心被设计成高度互动的，广泛分享专业知识，试剂和模型系统。这些研究的结果将为肺发育和干细胞生物学机制提供相关见解。

DESCRIPTION (provided by applicant): This is a competing renewal of a Program Project Grant, currently in its 16th year, which focuses on the molecular regulation of lung development. The program has been highly successful in bringing together an interactive multidisciplinary team of investigators to explore this theme, and has resulted in significant contributions to the field. This renewal consists of five interactive projects to study determinants of cell fate and differentiation in the developing lung. These projects address critical and poorly understood issues on the mechanisms of establishment of lung cell lineages, and on how this relates to morphogenesis and acquisition of differentiated cellular phenotypes. Project 1 addresses questions related to how the initial respiratory lineages are spatially organized and expanded during early morphogenesis, and the role of Notch and Fgfs in this process. Project 2 will focus on the mechanisms by which endogenous microRNAs control dynamic gene activity during proximal-distal specification of the lung. Project 3 develops new tools exploring a mouse ES cell culture system to study the genetic mechanisms that control early lung lineage specification. Project 4 focuses on mechanisms of chromatin remodeling and DNA methylation in the regulation of gene transcription during early lung development. Project 5 examines how hematopoletic-derived cells contribute to the development of lung structure and to the establishment of native immunity. Besides these projects, three cores are proposed. The "Administrative Core" will deal with the overall management and financial aspects of the Program. The "Microscopy-Image Analysis and FACS Core" will provide resources for histology, analysis of gene/protein expression by standard or confocal microscopy and for cell sorting: The "Mouse Core" will support the investigators in maintaining the various existing mouse lines, breeding, genotyping, and for designing constructs of new mouse lines. The projects and cores are designed to be highly interactive, with extensive sharing of expertise, reagents and model systems. Results from these studies will provide relevant insights into mechanisms of lung development and stem cell biology.