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.
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