Fstl1通过调节肺上皮细胞分裂方向参与气管形状决定的作用

在肺发育的早期，肺芽以分支形态发生的方式形成复杂的支气管立体网络-支气管树，这是进一步肺泡发育和肺气体交换功能建立的结构基础。伴随着分支发生，气管的形状在不停的改变，但决定其形状改变的细胞机制尚不清楚。其他器官（如：肾）的研究结果提示气管形状改变与上皮细胞有丝分裂方向改变相关。分泌型糖蛋白Ftsl1在肺的发育过程中起重要作用，以往的研究表明Fstl1基因缺失抑制肺泡发育，导致小鼠出生后呼吸衰竭而死。研究还发现Fstl1基因敲除小鼠的气管异常粗大。我们推测在肺发育早期Fstl1参与气管形状的决定。本项目将结合动物遗传模型和体外细胞三维培养的研究体系，深入研究Fstl1通过调控肺上皮细胞有丝分裂方向参与气管形状决定的作用，阐明其发挥作用的信号调控机制。本项目的开展将深化我们对肺发育的细胞和分子机制的认知，还可为类似病理过程的肺疾病（如慢性气管炎）的病理机制研究提供理论基础及新型动物模型。

During the early developmental stage, lung buds undergo repetitive outgrowth and branching, and generate a complex tree-like structure-bronchiole tree. Branching morphogenesis is critical for further alveologenesis. Lung tubes change shape during branching. Surprisingly, we still know little about the cellular mechanisms underlying. Clues about the potential mechanism come from studies on kidney morphogenesis, in which changes in the orientation of cell division are used to modulate the shape of epithelial tubes. We have reported the role of Fstl1 during lung development. Target deletion of Fstl1 in mouse inhibits the maturation of alveolar, resulting in the neonatal death of respiratory failure. Histological examination of sections of Fstl1－/－ pups also revealed a striking increase of the diameter of the tracheal lumen compared to wild-type littermates, suggesting the role of Fstl1 in the lung tube shape determination. The goal of this project is to study the role of Fstl1 in the lung tube shape determination. Using the mouse genetic model and in vitro three-dimension cell cultures system, we will demonstrate that the regulation of mitotic spindle angel by Fstl1 determines lung tube shape. Our study will extend the knowledge of branching morphogenesis in lung development, and facilitate the pathological study of related lung diseases.