The major goal of our research is to study the role of the Na,K-ATPase subunits in the regulation of alveolar epithelial function in normal and hypoxic conditions. We will shift the emphasis from the transport function of the Na,K-ATPase to its important role in stabilizing intercellular junctions and hence in alveolar epithelial integrity. Hypoxemia and injury of the alveolar-capillary barrier might result not only in a decrease in Na,K-ATPase activity but also in weakening interactions between the Na,K-ATPase ß1 subunits in neighboring cells. We will determine the molecular mechanisms regulating these ß1:ß1 interactions and design strategies to strengthen them as a way to enhance the function of the alveolar epithelial barrier. We are also interested in the role of FXYD5, which regulates cell-cell adhesion and the integrity of the alveolar epithelium by inhibiting the intercellular interaction between the Na,K-ATPase ß1 subunits of neighboring cells in a competitive mode. Given the fact that FXYD proteins are expressed and interact with the Na,K-ATPase in a tissue-specific way, understanding the molecular mechanisms of FXYD5-mediated regulation of ß1:ß1 interactions and thus alveolar epithelial barrier function may lead to novel, more effective treatment of acute lung injury.