Genetic Basis of Normal and Pathological Alveologenesis in Lung Development

项目摘要 肺泡形成是肺成熟的最后一步，产生约95%的气体， 通过形成新的隔膜交换表面积。破坏肺泡形成， 例如支气管肺发育不良（BPD），导致肺泡简化、气体缺乏 交换和其他呼吸系统缺陷。肌成纤维细胞代表了 细胞类型。在常规的二维分析中，肌成纤维细胞是 被描绘为手指状间隔嵴尖端的点，并被假定为驱动新的 通过迁移到管腔中形成隔膜。我们从三维空间中发现 肌成纤维细胞相互连接成环，环相互连接 成网。我们假设，正是这种肌成纤维细胞网络的拉伸特性， 形成新的隔膜。在人类肺部发育和疾病的小鼠模型中， 我们将使用遗传工具来研究肌成纤维细胞在正常人中的作用， 肺泡发生，BPD中的肺泡简化，以及 早产和BPD

PROJECT SUMMARY Alveologenesis is the last step of lung maturation and generates ~95% of the gas- exchange surface area through formation of new septa. Disruption of alveologenesis, such as in bronchopulmonary dysplasia (BPD), leads to simplified alveoli, poor gas exchange and other respiratory deficiencies later in life. Myofibroblasts represents a key cell type in alveologenesis. In conventional two-dimensional analysis, myofibroblasts are depicted as dots at the tip of the finger-like septal crest, and are postulated to drive new septa formation by migrating into the lumen. We have found from three-dimensional analysis, that myofibroblasts are interconnected into rings, and rings are interconnected into nets. We postulate that it is the tensile property of this network of myofibroblasts that drive new septa formation. In mouse models of human lung development and disease, we will use genetic tools to investigate the role of myofibroblasts in normal alveologenesis, in alveolar simplification in BPD, and in regeneration of new septa after premature birth and BPD.