Endothelial Repair following Lung Vasc. Injury Regulated by FoxM1/p-Catenin Signa

肺血管损伤后内皮完整性的恢复是肺损伤的一个知之甚少的方面。项目4在项目背景下的重点是阐明肺血管损伤后内皮屏障修复的分子机制，从而确定预防或逆转与脓毒症诱导的肺损伤相关的肺血管损伤的新方法。研究将探讨FoxMI的作用，FoxMI是叉头盒（Fox）转录因子家族的成员，我们已经证明它是内皮细胞增殖所需的，并介导肺血管损伤后的后续内皮修复。我们新的支持性数据表明FoxMI也调节从头β-连环蛋白合成（一种粘附连接蛋白），因此可能诱导内皮粘附连接重新退火以改革 限制性内皮屏障。此外，我们的支持性数据表明，内皮损伤本身是一种 因子激活FoxMI的表达，继发于β-连环蛋白的核转位，以及LEF/TCF转录机制的激活。在项目4中，我们将检验这样的假设，即FoxMI诱导β-连环蛋白表达以及FoxMI的β-连环蛋白诱导都是肺血管损伤后肺内皮完整性恢复所必需的。这些研究将针对以下具体目标。在目的1中，我们将确定FoxMI诱导的β-连环蛋白表达在肺血管损伤后恢复内皮屏障功能中的作用。我们将确定FoxMI诱导β-连环蛋白表达和限制性肺内皮屏障形成的机制。在目标2中，我们将讨论β-连环蛋白在FoxMI表达机制中的作用，以及β-连环蛋白介导的FoxMI表达是否有助于肺血管损伤后内皮再生的机制。在目标3中，我们将描述β-连环蛋白通过GSK-3调节FoxMI表达的信号传导机制，以及其在介导肺内皮修复中的作用。随着这些研究的完成，我们将确定FoxMI和β-连环蛋白之间的串扰在肺血管修复机制中的关键作用，有了这种理解，我们认为我们将能够为急性肺损伤的治疗提供新的方法。

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.