FoxM1 regulates endothelial repair following lung vascular injury

描述(由申请人提供)：内皮屏障的完整性是肺液平衡生理调节的关键要求。炎症性肺血管损伤损害内皮细胞屏障后，内皮再生和屏障重建是生存所必需的。调控这些过程的分子机制仍然知之甚少，因此目前还没有有效的选择来预防或治疗持续渗漏的肺微血管，这是人类急性肺损伤的标志。我们使用分子、细胞和体内方法的长期目标是阐明肺血管损伤后内皮细胞再生和屏障修复的机制，并寻找新的治疗靶点来预防或逆转肺血管损伤和渗漏的微血管。我们的研究从这笔赠款的第一个周期开始 已证实FOXM1在调节内皮细胞-细胞接触的内皮再生和重新退火，从而在炎症性肺血管损伤后内皮屏障完整性的恢复中发挥重要作用。我们提供的支持数据表明，缺氧诱导因子HIF-1的内皮特异性缺失导致肺血管中FOXM1诱导的完全抑制，以及炎症损伤反应中内皮屏障修复的缺陷。因此，我们将验证这样一个假设，即肺血管损伤后，通过转录调控FOXM1表达，HIF-1的稳定是内皮屏障修复所必需的。拟议研究涉及下文所述的具体目标。在AIM#1中，我们将确定HIF-1在脓毒症诱导的肺血管损伤后内皮细胞屏障修复中的核心作用。在AIM#2中，我们将描述HIF-1介导的内皮屏障修复的信号机制。我们将讨论FOXM1作为HIF-1的关键效应器的作用。在AIM#3中，我们将通过抑制氧感受器脯氨酸羟基酶(PhDS)激活肺内皮屏障修复来解决HIF-1的稳定作用。我们还将讨论我们在动物模型中的发现与ARDS患者发病机制的潜在临床相关性。通过这些综合性研究的数据，我们将勾勒出肺血管损伤后激活内皮再生和屏障修复的内在程序的基本机制。我们寻求寻找新的治疗方法，以靶向渗漏的微血管来预防和治疗急性肺损伤及其严重形式--急性呼吸窘迫综合征。

DESCRIPTION (provided by applicant): Endothelial barrier integrity is a critical requirement for physiological regulation of lung fluid balance. Following inflammatory lung vascular injury that compromises the endothelial barrier, endothelial regeneration and barrier restoration are requisite for survival. The molecular mechanisms that regulate these processes remain poorly understood, hence there currently is no efficacious option to prevent or treat persistently leaky lung microvessels, the hallmark of human acute lung injury. Our long term goal using molecular, cellular, and in vivo approaches is to elucidate the mechanisms of endothelial regeneration and barrier repair following lung vascular injury and identify novel therapeutic targets to prevent or reverse lung vascular injury and leaky microvessels. Our studies from the first cycle of this grant have demonstrated the essential role of FoxM1 in regulating endothelial regeneration and re-annealing of endothelial cell-cell contacts and thereby the recovery of endothelial barrier integrity following inflammatory lung vascular injury. Our Supporting Data presented here show that the endothelial-specific loss of the hypoxia-inducible factor HIF-1¿ results in complete inhibition of FoxM1 induction in the pulmonary vasculature and defective endothelial barrier repair in response to inflammatory injury. Thus, we will test the hypothesis that stabilization of HIF-1¿ is required for endothelial barrier repair through transcriptional regulation of FoxM1 expression following lung vascular injury. The proposed studies address the Specific Aims described below. In AIM #1, we will determine the central role of endothelial expression of HIF-1¿ in mediating endothelial barrier repair following sepsis-induced lung vascular injury. In AIM #2, we will delineate signaling mechanisms of HIF-1¿-mediated endothelial barrier repair. We will address the role of FoxM1 as the key effector of HIF-1¿. In AIM #3, we will address the role of HIF-1¿ stabilization by inhibiting the oxygen sensor prolyl hydroxylases (PHDs) in activating lung endothelial barrier repair. We will also address the potential clinical relevance of our findings in animal models to the pathogenesis of ARDS in patients. With the data from these comprehensive studies, we will delineate the fundamental mechanisms of activation of the intrinsic program for endothelial regeneration and barrier repair following lung vascular injury. We seek to identify novel therapeutic approaches to target leaky microvessels for the prevention and treatment of acute lung injury and its severe form, the acute respiratory distress syndrome.