The Role of Wnt7b in Pulmonary Organogenesis

描述(由申请人提供)： 这项建议描述了一项为期5年的研究计划，以获得哺乳动物肺器官发生领域的专业知识。哺乳动物的肺是一种精致的结构，由呼吸道组成，形成纸一样薄的肺泡组成的蜂窝状网络，允许高效的气体交换。两个小的肺芽从肠道中分离出来，经历了一个显着的分支过程，这一过程受到精细的调节，最终形成了成人肺的复杂结构。在这个过程中，肺部不同区域的细胞被指定为在呼吸道和肺泡产生不同的细胞群。了解肺的正常发育不仅有助于了解肺的发育异常，而且有助于了解与许多肺部疾病相关的有缺陷的修复和生长状态。 对分支形态发生的调控仍然缺乏精确的了解，特别是因为参与肺器官发生的许多途径还没有被确定。本研究旨在阐明Wnt信号通路的一个组成部分，即Wnt7b，在肺器官发生中的作用。众所周知，WNTs可以促进细胞分化和增殖，最近的研究表明，WNTs可以影响干细胞更新。本研究旨在阐明WNT7b在肺器官发生过程中调节这些过程中的作用。特别是，带有条件非活性Wnt7b基因的小鼠将被用来评估Wnt7b信号在小鼠肺中的作用。在不同的时间和在气管和远端肺中分别控制Wnt7b的消除，应该可以更详细地了解Wnt7b在肺形成中的作用及其与肺中其他关键信号级联的关系。正常和突变的胚胎肺芽的体外培养系统的开发应该可以进一步详细地分析Wnt7b的功能。 最终，希望对正常肺发育控制的详细了解可以作为努力在受损肺(如被肺气肿或囊性纤维化破坏的肺)诱导新肺生长的基础。最后，对肺发育的更全面的了解应该有助于从胚胎干细胞产生肺组织，这可以为体外研究肺功能提供组织，或者作为组织替代治疗的平台。

DESCRIPTION (provided by applicant): This proposal describes a 5-year research program to acquire expertise in the field of mammalian lung organogenesis. The mammalian lung is an exquisite structure that is comprised of airways which lead to a honeycomb network of paper-thin alveoli that allow for efficient gas exchange. Two small lung buds separate from the gut and undergo a remarkable process of branching which is finely regulated to ultimately form the intricate structure of the adult lung. During this process, the cells in different regions of the lung are specified to produce different cell populations in the airways and alveoli. An understanding of normal lung development should contribute to an understanding not only of developmental anomalies of the lung, but also of the faulty repair and growth states associated with many pulmonary diseases. A precise understanding of the regulation of branching morphogenesis is still lacking, in particular because many of the pathways involved in lung organogenesis have not yet been identified. This study is undertaken to elucidate the role of a component of the Wnt signaling pathway, namely Wnt7b, during pulmonary organogenesis. Wnts are known to promote cell differentiation, proliferation, and have most recently been shown to affect stem cell renewal. This study seeks to elucidate the role of Wnt7b in regulating these processes during pulmonary organogenesis. In particular, a mouse with a conditionally inactive Wnt7b gene will be used to assess the role of Wnt7b signaling in mouse lung. The controlled elimination of Wnt7b at various times and separately in the trachea and the distal lung should provide a more detailed understanding of the role of Wnt7b in lung formation and its relationship to other critical signaling cascades in the lung. The development of an in vitro culture system for normal and mutant embryonic lung buds should permit further detailed assays of Wnt7b function. Eventually, it is hoped that a detailed understanding of the control of normal lung development could be used as a basis for efforts to induce new lung growth in damaged lung, such as lung destroyed by emphysema or cystic fibrosis. Finally, a more complete understanding of lung development should aid in the generation of lung tissue from embryonic stem cells which could provide tissue for the study of lung function in vitro or serve as a platform for tissue replacement therapies.