Mechanisms of early tracheal specification and morphogenesis

项目概要 气管先天性异常，包括气管食管瘘 (TEF)，很常见，影响周围 1:3000 活产。 TEF 被定义为气管和气管之间的连接维护不当。 食道，并且是由于这些结构与其共同结构未能完全分离而产生的 起源，前肠内胚层管。通常，腹侧前肠内胚层呼吸特性的诱导 肺芽生长开始后，立即发生腹侧的形态发生分离 气管来自背侧食管。尽管 TEF 很常见，但我们对 TEF 的理解 控制这一发育过程的途径是不完整的，并且几乎不存在关于该发育过程的知识。 分离的分子效应器。此外，气管与气管分离的细胞生物学机制 食道目前尚不清楚。我们的提案结合了包括 RNA 在内的全基因组方法 测序和染色质免疫沉淀测序，并将其与小鼠遗传学相结合 成像方法可以更好地了解气管细胞命运规范的控制如何与细胞耦合 分离的生物驱动因素。这项工作将为早期气管发育提供新的见解 监管，提高我们对 TEF 的理解，并为未来的再生和组织提供资源 需要详细了解早期气管基因调控网络的工程方法。

Project summary Congenital anomalies of the trachea, including tracheoesophageal fistula (TEF), are common, affecting around 1:3000 live births. TEF is defined as the inappropriate maintenance of a connection between the trachea and esophagus, and arises as a result of a failure of the complete separation of these structures from their common origin, the foregut endoderm tube. Normally, induction of respiratory identity in the ventral foregut endoderm and initiation of lung bud outgrowth is followed immediately by a morphogenetic separation of the ventral trachea from the dorsal esophagus. Despite the common occurrence of TEF, our understanding of the pathways that control this developmental process is incomplete, and almost no knowledge exists regarding the molecular effectors of separation. Further, the cell biological mechanisms by which the trachea separates from the esophagus are currently not known. Our proposal incorporates genome-wide approaches including RNA sequencing and chromatin immunoprecipitation sequencing, and integrates them with mouse genetics and imaging approaches to better understand how control of tracheal cell fate specification is coupled to the cell biological drivers of separation. This work will provide new insights into how early tracheal development is regulated, improve our understanding of TEF, and provide a resource for future regenerative and tissue engineering approaches that require a detailed understanding of early tracheal gene regulatory networks.