This K08 proposal outlines a 5-year training program design to develop an academic career in translational research. This program will promote the command of vascular physiology specifically as it applies in the pulmonary vasculature in the acutely injured state. Research activities will focus on modulation of pulmonary vascular tone and barrier function both in in vitro models and in vivo models of inflammatory lung injury. Recent work identified sphingosine 1-phosphate (S1P) as a biologically active sphingolipid produced by activated platelets with potent endothelial barrier-enhancing properties downstream of profound cytoskeletal reorganization. Further investigation demonstrated the ability of S1P to attenuate lung edema formation in rodent and mechanically relevant large animal models of inflammatory lung injury. The proposed experiments probe the mechanisms of SIP-induced lung edema prevention using a variety of physiological, cellular, molecular, and imaging techniques. SA#1 examines the pulmonary vascular effects of exogenous sphingosine 1-phosphate administration in vitro. SA#2 explores the mechanisms underlying the pulmonary vascular effects of exogenous sphingosine 1-phosphate in normal and injured perfused mouse lungs using sophisticated functional optical imaging techniques. SA#3 explores sphingosine 1-phosphate effects on regional lung mechanics and ventilation/perfusion matching using sophisticated functional CT imaging techniques in a canine model of inflammatory ALL SA#4 establishes sphingosine 1-phosphate as a therapeutic strategy in a canine model of inflammatory ALL These experiments represent the first mechanistic evaluation of biologically active sphingolipids in vivo and serve as an essential step in the translation of basic scientific discovery into clinical application in the intensive care unit.
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