Recovery of endothelial integrity after lung vascular injury is a pooriy understood aspect of lung injury. The focus of Project 4 in the context of the Program Project is to elucidate the molecular mechanisms of endothelial barrier repair following lung vascular injury, and thereby to identify novel approaches that prevent or reverse lung vascular injury associated with sepsis-induced lung injury. Studies will address the role of FoxMI, a member of the Forkhead box (Fox) transcription factor family, which we have demonstrated to be required for proliferation of endothelial cells, and to mediate subsequent endothelial repair following lung vascular injury. Our novel Supporting Data show that FoxMI also regulates de novo beta-catenin synthesis (an adherens junction protein) and may thus induce the re-annealing of endothelial adherens junctions to reform a restrictive endothelial barrier. In addition, our Supporting Data show that endothelial injury itself is a factor activating expression of FoxMI secondary to nuclear translocation of beta-catenin, and activation of the LEF/TCF transcriptional machinery. In Project 4, we will test the hypothesis that FoxMI induction of beta-catenin expression as well as beta-catenin induction of FoxMI are both required for restoration of lung endothelial integrity following lung vascular injury. The studies will address the following Specific Aims.
In Aim 1 we will determine the role of FoxMI-induced beta-catenin expression in restoring endothelial barrier function following lung vascular injury. We will define mechanisms by which FoxMI induces the expression of beta-catenin and resultant formation of the restrictive lung endothelial barrier.
In Aim 2 we will address the role of beta-catenin in the mechanism of FoxMI expression and whether beta-catenin-mediated FoxMI expression contributes to the mechanism of endothelial regeneration following lung vascular injury.
In Aim 3 we will delineate the signaling mechanism of beta-catenin regulation of FoxMI expression through GSK-3, and its role in mediating lung endothelial repair. With the completion of these studies, we will have identified the critical role of the cross-talk between FoxMI and beta-catenin in the mechanism of lung vascular repair, and with this understanding we think that we will be able to provide novel approaches for the treatment of acute lung injury.
The overall objective of the proposed studies of Project 4 is to elucidate the molecular mechanisms of endothelial barrier repair following lung vascular injury, and thereby to identify novel approaches that prevent or reverse lung vascular injury associated with sepsis-induced lung injury.
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