Pulmonary alveolar homeostasis is dependent upon balanced airway and tissue surfactant pools. Quantitative and qualitative alterations in alveolar surfactant pools are associated with inflammation and tissue destruction in severe lung diseases including infant respiratory distress syndrome, many forms of acute lung injury and pulmonary alveolar proteinosis. Identification of a physiologically-dominant molecular pathway within alveolar epithelial cells that senses and regulates endogenous alveolar surfactant pools, coupled with the ability to pharmacologically modulate it both positively and negatively, would be a major therapeutic advance for patients with lung diseases associated with pulmonary surfactant disorders. Preliminary data supporting this application strongly implicate an alveolar epithelial cell-centric, G protein-dependent pathway driven by GPR116 as a druggable molecular target to modulate endogenous alveolar surfactant pools. We demonstrate that GPR116 is abundantly expressed in human and mouse lung, and pulmonary epithelium-specific deletion of GPR116 in mice results in early and progressive accumulation of alveolar surfactant associated with phospholipid peroxidation, neutrophilia and alveolar remodeling, culminating in respiratory failure. We have identified a novel synthetic peptide that is sufficient to activate G protein-dependent signaling downstream of mouse and human GPR116 in vitro and suppress alveolar surfactant levels in mice in vivo, providing proof-of- concept that GPR116 is a plausible therapeutic target to modulate endogenous alveolar surfactant pools in humans. Our central hypothesis is that epithelial GPR116 regulates alveolar surfactant homeostasis via Gq/11- driven modulation of actin cytoskeletal dynamics in alveolar type II cells. Our goal in this projec is to systematically define the signaling pathways by which GPR116 controls surfactant homeostasis using cell-based assays and mouse genetics through completion of three integrated aims. In the first aim, we will test the hypothesis that GPR116-dependent activation of a Gq/G11-PKC?-dependent pathway induces cortical F-actin assembly to suppress surfactant secretion and/or decrease surfactant uptake in alveolar type II cells. In the second aim, we will test the hypothesis that activation of epithelial GPR116 is sufficient to restore surfactant homeostasis in two established mouse models of alveolar surfactant overload, Csf2rb-/- and Sftpd-/- mice. In the third aim, we will test the hypothesis that increased alveolar surfactant pools initiate alveolar macrophage oxidative stress and subsequent alveolar simplification in Gpr116-/- mice. Successful completion of these specific aims will delineate the signaling pathways by which GPR116 senses and regulates surfactant and alveolar homeostasis. The long-term goal of this work is to identify potential therapeutic targets, including GPR116 itself, that will permit modulation of endogenous surfactant levels to treat human lung diseases associated with surfactant dysfunction.
Pulmonary surfactant is essential for gas exchange in the lung and changes in the amount, or composition, of surfactant are associated with severe lung diseases in children and adults. Studies proposed in this application will provide insight into the mechanisms by which an orphan G protein-coupled receptor, GPR116, regulates the amount of surfactant in the lung to support breathing. The long-term goal of this work is to identify potentil therapeutic targets, including GPR116 itself, for modulating endogenous surfactant levels in the treatment of lung diseases associated with surfactant dysfunction
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