The devastating mortality associate with acute lung injury (ALI) is intimately related to profound vascular permeability and alveolar flooding with effectible therapy not currentiy available. Project 2 investigators were the first to demonstrate that the multifunctional lipid mediator, sphingosine 1-phosphate (SIP) potently enhances endothelial cell (EC) monolayer integrity and reduces vascular permeability via ligation of the G potein-coupled SIP receptor, S1PR1. We subsequently showed that S1PR1 ligation induces Rac GTPase signaling to the EC cytoskeleton and reduces LPS, ischemia/reperfusion, ventilator and radiation-induced increases in lung vascular permeability. S1PR1 is also critical to hepatocyte growth factor and activated protein C-mediated barrier enhancement via S1PR1 transactivation. In contrast, ligation of a related SIP receptor, S1PR3, induced Rho GTPase signaling, disrupts cell-cell junctions and increases lung permeability and alveolar flooding. These conflicting roles for specific SIPRs potentially limit utilization of SI Pas a therapeutic strategy for vascular barrier dysfunction in inflammatory lung syndromes. Project 2 will integrate translational SI P-S1 PR insights into strategies which limit ALI pathobiology. SA #1 will assess the dose and delivery route-dependent (intratracheal vs intravenous) effects of SIP and selective S1PR1 &S1PR3 agonists/antagonists on vascular leakage in genetically-engineered mice (S1P1+/-, S1P3-/-) in murine ALL SA#2 will detail regulation of S1PR1, S1PR1 and S1PR3 gene promoter activities by inflammatory stimuli and extend preliminary data evaluating SI PR promoter SNP effects on luciferase promoter activity. SA #3 will assess potential novel biomarkers in ALI focusing on levels of circulating SIP, S1PR3 shed from the EC surface and SIP pathway-related gene expression signatures. Finally, SA #4 will conduct association studies in Caucasian and African ALI cohorts to further link novel SNPs in SI P-related target genes to ALI susceptibility. In summary, Project #2 will clarify the key roles of SIP receptors in ALI pathobiology, and facilitate development of pharmacogenomic assays and SI P-based therapies for the critically ill.
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