This application proposes to continue multidisciplinary studies of development, control and disorders of the pulmonary parenchyma. The objectives of this proposal are to examine some of the mechanisms involved in the formation and stabilization of the pulmonary parenchyma, during development and post-natal life, and in states of health and disease. As in our past studies, we propose to emphasize investigations of lung branching and growth, alveolar epithelial cell development and functions, functions of the lung surfactant system, and alveolar disease processes leading to inflammation and fibrosis. The broad goals of the four inter-related projects proposed are: Project 1: Structure and function of surfactant proteins: To study the relationship between the structure of the surfactant apoproteins and their functions in regulating surfactant homeostasis and the immune milieu of the alveolus. Project 2: Tenascins and lung injury: To study the role of the tenascin proteins in acute lung injury and the development of pulmonary fibrosis. Project 3: Molecular mechanisms of lung branching morpho-genesis: To study epithelial-mesenchymal interactions during lung development with a specific emphasis on fibroblast growth factor and sonic hedgehog signaling and interactions. Project 4: Regulation of alveolar epithelial cell phenotype: To elucidate mechanisms responsible for the regulation of alveolar epithelial cell phenotypic expression during development. The overall purpose of these studies is to deepen our understanding of the processes underlying lung parenchymal stability and to contribute to new concepts and treatments for lung diseases associated with disorders of alveolar stability, growth, maturation, and repair after injury.
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