Novel Signalings and Molecular Targets of Endothelial Regeneration in Aging Lung

描述（由申请人提供）：急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的一个重要组成部分是肺微血管内皮屏障的损伤导致肺血管对蛋白质的渗透性持续增加和难治性富蛋白水肿形成。与年轻患者相比，老年患者中脓毒症导致的ALI/ARDS的发生率高达19倍，死亡率高达10倍。然而，人们对根本原因知之甚少。同样重要的是，人们对衰老如何影响脓毒症后内皮再生和血管稳态恢复的机制知之甚少。我们最近表明，叉头转录因子FoxM1是一个关键的修复因子负责内皮再生。然而，我们的新的支持性数据表明，FoxM1的表达和内源性内皮再生程序严重受损，在老年肺炎症性肺损伤。我们观察到，内皮缺氧诱导因子HIF-1 α是FoxM1表达的关键介质，通过转录控制SDF-1 α激活CXCR4受体，导致GPCR依赖性PI3K的p110 γ亚型的激活，并且抑制氧传感器HIF脯氨酰羟化酶（PHDs）重新诱导FoxM1表达并激活老年肺中的内皮再生程序。因此，我们假设继发于老年肺中PHD 2激活的受损的HIF-1 α-> FoxM1信号传导是这些肺中严重缺陷的内皮再生的原因，并且通过PHD 2抑制和CXCR 4激活激活这一基本修复途径是逆转肺微血管渗漏和改善老年ALI/ARDS患者存活率的潜在新治疗方法。拟议的研究涉及以下具体目标。在目标#1中，我们将讨论受损的HIF-1 α-> FoxM1信号传导在老年肺中的作用，作为脓毒症激发后严重受损的内皮再生和肺血管稳态恢复的关键因素。在目标#2中，我们将描述脓毒症激发后老年肺中严重缺陷的内皮再生的信号机制。在目标#3中，我们将通过PHD抑制来确定HIF-1 α稳定在激活老年肺内皮再生中的作用。我们还将讨论我们在动物模型中的发现与人类的潜在临床相关性;从而确定抑制PHD 2和激活CXCR 4在治疗老年患者ALI/ARDS中的治疗意义。通过这些全面的研究，我们将描绘老年肺内皮再生受损的基本信号机制，并确定治疗靶点，以激活这种基本的内源性HIF-1 α-> FoxM1依赖性机制，修复老年患者ALI/ARDS的肺微血管渗漏。

DESCRIPTION (provided by applicant): An essential component of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is that injury of the endothelial barrier of pulmonary microvessels results in persistent increase in lung vascular permeability to protein and intractable protein-rich edema formation. Compared to young patients, the incidence of ALI/ARDS resulting from sepsis in elderly patients is as much as 19-fold greater and the mortality rate is up to 10-fold greater. However, the underlying causes are poorly understood. Also crucially little is known how aging influences mechanisms of endothelial regeneration and restoration of vascular homeostasis following sepsis challenge. We have recently shown that the Forkhead transcription factor FoxM1 is a key reparative factor responsible for endothelial regeneration. However, our new Supporting Data presented here show that FoxM1 expression and the endogenous endothelial regeneration program were severely impaired in aged lungs following inflammatory lung injury. We observed that endothelial hypoxia-inducible factor HIF-1α is the critical mediator of FoxM1 expression through transcriptional control of SDF-1α which activates CXCR4 receptor leading to activation of the GPCR-dependent p110gamma isoform of PI3K, and that inhibition of the oxygen sensors HIF prolyl hydroxylase (PHDs) re-induced FoxM1 expression and activated the endothelial regeneration program in aged lungs. Thus, we hypothesize that impaired HIF- 1α->FoxM1 signaling secondary to activation of PHD2 in aged lungs is responsible for the severely defective endothelial regeneration in these lungs, and activation of this fundamental reparative pathway through PHD2 inhibition and CXCR4 activation is a potential novel therapeutic approach for reversing lung microvessel leakiness and improving survival of elderly ALI/ARDS patients. The proposed studies address the following Specific Aims. In Aim #1, we will address the role of impaired HIF-1α->FoxM1 signaling in aged lungs as a crucial factor responsible for severely impaired endothelial regeneration and restoration of lung vascular homeostasis following sepsis challenge. In Aim #2, we will delineate the signaling mechanisms underlying severely defective endothelial regeneration in aged lungs following sepsis challenge. In Aim #3, we will determine the role of HIF-1α stabilization through PHD inhibition in activating endothelial regeneration in aged lungs. We will also address the potential clinical relevance of our findings in animal models to humans; thereby determine the therapeutic implications of inhibition of PHD2 and activation of CXCR4 in treatment of ALI/ARDS of elderly patients. With these comprehensive studies, we will delineate the fundamental signaling mechanisms of impaired endothelial regeneration in aged lungs, and identify therapeutic targets to activate this fundamental intrinsic HIF-1α->FoxM1-dependent mechanisms to repair leaky lung microvessels for the treatment of ALI/ARDS in elderly patients.