Viral respiratory infections, such as influenza and SARS-CoV2, frequently lead to acute respiratory distress syndrome (ARDS), a condition with a mortality up to 46%. Endothelial injury, dysfunction and the resultant vascular hyperpermeability contribute to the severity of ARDS, persistence of lung injury, and dysregulated repair with the development of fibrosis. While sphingosine-1-phosphate receptor 1 (S1PR1) is a key protective signaling axis on endothelial cells, the role of S1PR1 signaling in the resolution of lung injury in post-viral ARDS has not been well explored. The objective of this application is to define endothelial S1PR1-dependant pathways which promote the re-alveolarization of the post-viral lung needed to prevent morbid fibrotic outcomes. We hypothesize that endothelial S1PR1 signaling promotes productive lung repair after viral infection via BMP2 mediated support of the epithelial niche. These preliminary findings a new facet to the pleotropic benefits of EC S1PR1 beyond its established role in limiting vascular hyperpermeability and highlight a need to comprehensively validate the therapeutic potential of augmenting S1PR1 expression to limit post-viral pulmonary fibrosis. We will test this hypothesis via two specific aims: 1) determine the mechanism of endothelial S1PR1 mediated epithelial repair after viral-induced ARDS, and 2) determine how EC S1PR1 regulation can be therapeutically augmented to attenuate post-viral fibrosis. The proposed research will reveal novel links between EC S1PR1 and epithelial regeneration and differentiation after viral infection and identify regulators of endothelial function which can be therapeutically targeted to attenuate post- viral fibrosis. Dr. Brazee’s long-term goal is to be an independent basic and translational investigator with a research program aimed at understanding the contributions of the endothelium in supporting productive lung repair pathways. The proposed K01 research aims utilize prior training in mouse models of influenza virus infection, fibrotic lung disease, and fundamental molecular biology techniques. In addition, the project will necessitate advanced training in vascular and epithelial biology, G-protein coupled receptor (GPCR) signaling, and translational modeling of human disease using human derived 3D organoids and precision cut lung slices. Successful completion of these aims, together with continued professional development, will provide the proficiencies necessary to establish a productive research program and an impactful career as an independent R01-funded investigator.