The vasculature is an integral part of the lungs and develops in parallel with the airways. The precise alignment of the airways and the vasculature requires the coordinated growth and differentiation of epithelial and endothelial cell populations during lung development. The complex cellular and molecular interactions that must exist to regulate the parallel development of lung components are poorly understood. This knowledge is fundamental to understand the pathogenesis of and to develop treatment for developmental lung diseases that are caused by malformation and misalignment of the vasculature and lung structural components such as bronchopulmonary dysplasia and alveolar-capillary dysplasia. Knowledge of the factors that coordinate lung vascularization and development would also be necessary to the design of therapeutic approaches to lung injury repair. We hypothesize that the Notch signaling pathway plays a critical role in the cellular interactions that coordinate the development of the lungs and its vasculature. The Notch signaling pathway mediates local cell interactions that determine cell fate choices among neighboring cells in many tissues, and many Notch receptors and ligands are expressed in the developing lungs. Notch receptors and ligands are cell surface molecules, necessitating either cell autonomous signaling or interactions between adjacent cells. Ligand-mediated activation of the receptors leads to cellular responses through transcriptional activation of downstream target genes. We propose to study the function of the Notch signaling pathway in the coordinated development of lung epithelium and vasculature by determining in a comprehensive manner the expression of Notch receptors and ligands in the developing lungs, and by determining the function of this signaling pathway in specific lung cell populations using a loss of function approach. We will inhibit the Notch signaling pathway selectively in epithelial or endothelial cells using conditional and tissue-specific expression of a dominant-negative transcriptional regulator protein in the Notch signaling pathway. Knowledge of the cellular expression of the Notch receptors and ligands and the function of Notch signaling in specific cell populations will lead to better understanding of how the growth and differentiation of lung epithelial and endothelial cells might be regulated through cellular interactions using this pathway.
