Recovery of endothelial integrity after lung vascular injury is a poorly understood aspect of vascular homeostasis. Our long term goals using molecular, cellular, and in vivo approaches are to elucidate mechanisms of endothelial barrier repair following vascular injury and identify novel therapeutic targets to prevent persistent lung vascular injury and leaky microvessels associated with sepsis-induced acute lung injury. FoxM1 is a member of the Forkhead box (Fox) family of transcription factors essential for cell proliferation. FoxM1-null mutation in mice causes embryonic lethality due to improper execution of mitosis and the resulting polyploid cells in heart and liver. We will test the general HYPOTHESIS that FoxM1 is a critical determinant of endothelial repair following lung vascular injury. Our objective is to determine the essential role of FoxM1 in regulating endothelial cell proliferation and re-annealing endothelial junctions, thereby restoring endothelial integrity following lung vascular injury. The studies will address the following Specific Aims: 1. To determine the mechanisms of regulation of FoxM1 expression in response to lung vascular injury. We will dissect the signaling pathways that mediate FoxM1 induction in the pulmonary microvasculature following LPS-induced lung vascular injury. We will test the hypothesis that loss of endothelial cell-cell contact following lung vascular injury induces FoxM1 expression in endothelial cells through PI3K/Akt-dependent downregulation of p27Kip1, a key determinant of cell contact inhibition. 2. To elucidate the molecular mechanisms of FoxM1-regulated endothelial cell proliferation. We will characterize the defects in cell cycle progression of FoxM1 -deficient pulmonary endothelial cells and identify the FoxM1 transcriptional network of genes essential for endothelial cell proliferation. We will also dissect the mechanisms involved in FoxM1 regulation of p27Kip1. 3. To determine the role of FoxM1 in the mechanism of restoring endothelial integrity. We will address the possibility that FoxM1 plays an important role in re-organizing the endothelial cell-cell junctions following lung vascular injury. We will also examine following LPS-induced vascular injury the ultrastructural defects and the cellular nature of the leaks and repair failure of the pulmonary vasculature in mice with endothelial cell- restricted deficiency of FoxM1. ? ? ?
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