The alveolar type II cell plays a pivotal role in lung development and in the maintenance of the alveolar epithelial air-capillary interface. The type II cell is the progenitor of the alveolar epithelium and terminally differentiates into the type l cell following injury to restore normal alveolar structure and function. Homotypic cell-cell adhesion, a function primarily ascribed to a class of calcium-dependent transmembrane glycoproteins called cadherins, almost certainly play a central role in these processes. Because of the unique architecture of the alveolus and because so much is known about the biology of the type Il cell, the lung is particularly suited to the study of cadherin function. We propose to apply fetal lung explant culture, isolated type Il cell culture, and adult lung injury models to the study of these important molecules and their function in the fetal and adult rat lung, with specific reference to the distal alveolar epithelium. Specifically, we will 1) identify, clone, sequence, and develop antibodies to cadherins expressed in rat lung, 2) determine the role of cadherins in proliferation and differentiation in the fetal lung, and 3) determine the role of cadherins in proliferation and differentiation in the adult lung in vitro and in vivo. The use of these three systems will allow testing of hypotheses on cadherin function in fetal and adult lung. The principal investigator in this research proposal will be a junior faculty member committed to basic research on lung biology. She will investigate basic mechanisms of homotypic cell-cell adhesion and apply these concepts to a better understanding of the nature of perturbation of cadherin function in diverse lung diseases such as fetal and adult respiratory distress syndrome, lung malignancies, and a spectrum of interstitial lung diseases.
