DETERMINANTS OF CELL FATE AND DIFFERENTIATION IN THE DEVELOPING LUNG

描述(由申请人提供)：这是一项计划项目资助的竞争性续签，目前已进入第16个年头，重点是肺发育的分子调控。该方案非常成功地汇集了一个由多学科研究人员组成的互动式团队来探索这一主题，并为该领域作出了重大贡献。这次更新包括五个互动项目，以研究发育中的肺中细胞命运和分化的决定因素。这些项目解决了关于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之间的关系的关键和鲜为人知的问题。项目1解决了在早期形态发生过程中最初的呼吸谱系是如何在空间上组织和扩展的问题，以及Notch和FGFs在这一过程中的作用。项目2将侧重于内源性microRNAs在肺近端-远端规范过程中控制动态基因活性的机制。项目3开发了探索小鼠ES细胞培养系统的新工具，以研究控制早期肺系特征的遗传机制。项目4侧重于染色质重塑和DNA甲基化在肺发育早期基因转录调控中的作用机制。项目5考察了血球来源的细胞如何对肺结构的发展和建立天然免疫作出贡献。除了这些项目外，还提出了三个核心。“行政核心”将处理该方案的总体管理和财务方面。“显微图像分析和FACS核心”将为组织学、通过标准或共聚焦显微镜分析基因/蛋白质表达和细胞分类提供资源：“小鼠核心”将支持研究人员维持各种现有的小鼠品系、育种、基因分型和设计新的小鼠品系结构。这些项目和核心的设计是高度互动的，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的机制提供相关的见解。

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.