UNIVERSITY OF ILLINOIS
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 the mechanisms of endothelial barrier repair following lung vascular injury and identify novel therapeutic targets to prevent and treat persistent lung vascular injury and leaky microvessels associated with sepsis-induced acute lung injury. Our published studies have demonstrated FoxM1, a forkhead transcriptional factor plays an essential role in endothelial repair following inflammatory lung vascular injury, suggesting promotion of FoxM1-mediated endothelial regenration is a novel therapeutic strategy for acute lung injury. Thus, the overall objective of the parent grant is to determine the essential role of FoxM1 in regulating endothelial cell proliferation and re-annealing the endothelial junctions, thereby restoring endothelial integrity following lung vascular injury. The studies have been designed to address: i) the mechanisms of regulation of FoxM1 expression in response to lung vascular injury; ii) the molecular basis of FoxM1-regulated endothelial cell proliferation; iii) the role of FoxM1 in the mechanism of restoring endothelail integrity. To accelerate the research proposed in the parent grant, the REQUESTED SUPPLEMENT will address the following Specific Aims: in Aim 1, we will determine the role of PI3K/Akt signaling pathway in regulating FoxM1 expression following lung vascular injury, and identify the specific isoform of PI3K mediating FoxM1 induction; in Aim 2, we will test the possibility that beta-catenin is the downstream transcriptional target of FoxM1 responsible for FoxM1-regulated endothelial cell proliferation. Accomplishment of these studies is critical for us to achieve our long term goals. Importantly, identification of the specific isoform of PI3K mediating FoxM1 induction following lung vascular injury may provide a rational and safer therapeutic strategy for ALI.