Lung development involves migration of epithelial cells into the surrounding mesoderm, resulting in the formation of the respiratory bronchioles and the terminal alveolar sacs with integrated endothelial capillary bed. However, relatively little is known of the genetic patterning and molecular events that are required to make a fully functional lung let alone the genetic basis of lung disorders such as asthma. Furthermore, airway remodeling that occurs in asthmatic patients involves cell interactions thought to be analogous to that which occurs during lung development.
In Aim 1, I will uncover critical genes involved in lung organogenesis by identifying the genetic defect in two mutant mouse lines generated through ENU induced mutagenesis that results in lobe septation defects.
In Aim 2, I will characterize the phenotype associated with mutations in these critical genes to determine the mechanism of protein action.
In Aim 3, I will test the hypothesis that genes that control embryonic lung organogenesis are abnormally expressed in mouse models of asthma. These studies will establish the key genetic, cellular and molecular events that regulate embryonic lung development and generate new animal models of lung development and disease as well as potential therapeutic targets for asthma treatment and repair of damaged lung tissue. ? ? ?
