The research in our laboratory is aimed at identifying the molecular and cellular mechanisms important for lung development, particularly for pulmonary alveolar formation. We are also interested in identifying conditions that promote lung repair and regeneration in the adults.
The lungs consist of airways, which include the trachea and bronchi that function as air conduits, and alveoli, which form the gas exchange area of the lungs and are tiny air sacs composed of a lining of epithelial cells surrounded by capillaries within a very thin wall. The close apposition of epithelial cells and capillaries is necessary for the exchange of oxygen and carbon dioxide between air and blood. Many lung diseases of impaired lung development, of lung destruction, or of abnormal lung repair result in nonfunctional alveoli that cause inefficient gas exchange, poor lung function and significant morbidity. These diseases have no effective treatments currently, and the ability to stimulate formation of new alveoli would provide a good therapeutic option.
Our current areas of focus are: 1) The role of the vasculature in lung organogenesis. We are interested in the molecular mechanisms of tissue vascularization and the role of the vasculature in tissue morphogenesis. The precise anatomical relationship between airways, airspaces, and pulmonary vessels is critical for lung function and suggests that there must be reciprocal inductive interactions between lung epithelial and endothelial cells during their development. We found that the angiogenic factor VEGF produced by lung epithelium regulates the formation of the surrounding blood vessels, and that the pulmonary capillaries in turn produce paracrine factors that influence the development of the surrounding cells, including epithelial cells, fibroblasts, and myofibroblasts. We are characterizing these endothelium-derived factors and determining their function. 2) The development of pulmonary alveoli. Since the formation of alveoli occurs in a defined period, we speculate that genes regulating alveolar morphogenesis must be differentially expressed between periods of active and inactive alveolar formation. In a differential screen, we identified a novel gene, P311, which is highly differentially expressed during the period of alveogenesis. This gene encodes a small protein with no known function. It has been implicated in diverse biological processes, including interestingly, in myofibroblast development. Lung myofibroblasts are interstitial smooth muscle-like cells that are essential for alveolar development. They are also implicated in the pathogenesis of many lung diseases including pulmonary fibrosis. The regulation of myofibroblast development and function is not well understood. We are investigating the function of P311 using biochemical and genetic methods. 3) The identification of adult stem cell populations that can participate in lung repair and regeneration. As a rule the adult lungs do not regenerate and the response to lung injury in many cases is destruction or fibrosis. We are employing in vitro and in vivo assays to determine the capacities of adult stem cells to differentiate into lung cell types and to participate in the formation of new lung structures in the adult.