Novel Signalings and Molecular Targets of Endothelial Regeneration in Aging Lung

衰老肺内皮再生的新信号传导和分子靶点

• 批准号: 8909182
• 负责人: YOU-YANG ZHAO
• 金额: $ 39.28万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909182
• 关键词: Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Aging; Animal Model; Animals; Blood Vessels; CXCR4 Receptors; CXCR4 gene; Cells; Complex; Data; Edema; Elderly; Endothelium; Extravasation; Fluid Balance; G Protein-Coupled Receptor Genes; Goals; Health; Homeostasis; Human; Hypoxemia; Hypoxia Inducible Factor; Incidence; Infiltration; Inflammatory; Injury; Ligation; Lung; Lung Inflammation; Mediator of activation protein; Molecular; Molecular Target; Mus; Natural regeneration; Outcome; Oxygen; Pathway interactions; Patients; Procollagen-Proline Dioxygenase; Protein Isoforms; Proteins; Pulmonary Edema; Puncture procedure; Recovery; Resolution; Role; Secondary to; Sepsis; Severities; Signal Transduction; Stromal Cell-Derived Factor 1; Syndrome; Therapeutic; Transcriptional Regulation; Ursidae Family; Vascular Endothelial Cell; Vascular Permeabilities; aged; clinically relevant; forkhead protein; improved; lung injury; lung vascular injury; mortality; novel; novel therapeutic intervention; novel therapeutics; older patient; programs; repaired; restoration; sensor; therapeutic target

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-1a is the critical mediator of FoxM1 expression through transcriptional control of SDF-1a 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- 1a->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-1a->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-1a 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-1a->FoxM1-dependent mechanisms to repair leaky lung microvessels for the treatment of ALI/ARDS in elderly patients.

描述（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通透性持续增加和顽固性富含蛋白质的水肿形成。与年轻患者相比，老年患者脓毒症引起的ALI/ARDS的发生率高出19倍，死亡率高出10倍。然而，人们对根本原因知之甚少。同样至关重要的是，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。我们最近发现 Forkhead 转录因子 FoxM1 是负责内皮再生的关键修复因子。然而，我们在此提供的新支持数据表明，在炎症性肺损伤后，衰老的肺部中 FoxM1 表达和内源性内皮再生程序严重受损。我们观察到，内皮缺氧诱导因子 HIF-1a 是 FoxM1 表达的关键介质，通过 SDF-1a 的转录控制激活 CXCR4 受体，从而激活 GPCR 依赖性的 PI3K p110gamma 亚型，并且抑制氧传感器 HIF 脯氨酰羟化酶 (PHD) 重新诱导 FoxM1 表达并激活 老化肺部的内皮再生程序。因此，我们假设老年肺中 PHD2 激活继发的 HIF-1a->FoxM1 信号受损是导致这些肺中严重缺陷的内皮再生的原因，并且通过 PHD2 抑制和 CXCR4 激活来激活这一基本修复途径是逆转肺微血管渗漏和改善老年人生存的潜在新治疗方法 ALI/ARDS 患者。拟议的研究涉及以下具体目标。在目标#1中，我们将探讨衰老肺部中受损的 HIF-1a->FoxM1 信号传导的作用，这是脓毒症挑战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，我们将描述脓毒症挑战后老化肺部严重缺陷的内皮再生的信号传导机制。在目标 3 中，我们将确定通过 PHD 抑制来稳定 HIF-1a 在激活老化肺部内皮再生中的作用。我们还将探讨我们在动物模型中的研究结果与人类的潜在临床相关性；从而确定抑制 PHD2 和激活 CXCR4 在治疗老年患者 ALI/ARDS 中的治疗意义。通过这些全面的研究，我们将描述老年肺部内皮再生受损的基本信号传导机制，并确定治疗靶点来激活这种基本的内在 HIF-1a->FoxM1 依赖性机制，以修复渗漏的肺微血管，从而治疗老年患者的 ALI/ARDS。