Role of the SFTA2/ADGRF5 signaling axis in alveolar homeostasis - PROJECT SUMMARY Pulmonary alveolar homeostasis is dependent upon balanced airway and tissue surfactant pools. Alterations in alveolar surfactant pools are associated with inflammation and tissue destruction in severe lung diseases including acute respiratory distress syndrome, pulmonary alveolar proteinosis and genetic disorders of surfactant dysfunction. We have previously shown that the orphan G-protein coupled receptor ADGRF5 is a physiologically dominant molecular pathway within alveolar epithelial cells that regulates endogenous alveolar surfactant pools. The ability to pharmacologically modulate the ADGRF5 pathway, both positively and negatively, would be a major therapeutic advance for patients with lung diseases associated with pulmonary surfactant disorders. However, the endogenous ligand for ADGRF5 has not been identified, representing a critical knowledge gap in our understanding of this key surfactant homeostasis mechanism. Preliminary data within this application strongly implicate a novel secreted protein from alveolar type II cells, Surfactant Associated Protein 2 (SFTA2), as a druggable molecular target to modulate endogenous alveolar surfactant pools. We demonstrate that SFTA2 is abundantly expressed in human and mouse lung, and pulmonary epithelium-specific deletion of SFTA2 in mice results in early and progressive accumulation of alveolar surfactant. Our central hypothesis is that SFTA2 regulates alveolar surfactant levels via binding to the extracellular domain of ADGRF5 to decrease surfactant secretion and/or increase surfactant uptake in AT2 cells. The goal of this project is to systematically define the signaling pathways by which SFTA2 interacts with ADGRF5 to control surfactant homeostasis using cell-based assays and mouse genetics through completion of three integrated aims. In the first aim, we will test the hypothesis test the hypothesis that SFTA2 regulates alveolar surfactant levels via binding and activation of ADGRF5 signaling in AT2 cells. In the second aim we will test the hypothesis that transient amplification of alveolar surfactant levels via inhibition of the SFTA2/ADGRF5 signaling axis is sufficient to prevent and/or reverse acute lung injury. In the third aim we will define the role of glycosylation in the trafficking and function of SFTA2 in homeostasis and in the context of acute lung injury. Successful completion of these specific aims will delineate the signaling pathways by which SFTA2/ADGRF5 senses and regulates surfactant and alveolar homeostasis. The long-term goal of this work is to identify potential therapeutic targets, including SFTA2 itself, that will permit modulation of endogenous surfactant levels to treat human lung diseases associated with surfactant dysfunction including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).
