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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的重要组成部分是，肺部微丝的内皮屏障的损伤导致肺血管通透性持续增加对蛋白质和可怕的蛋白质含量蛋白质富含蛋白质含量。与年轻患者相比，老年患者败血症引起的ALI/ARD的发生率高达19倍，死亡率高达10倍。但是，基本原因知之甚少。同样至关重要的是，衰老挑战挑战后，衰老如何影响内皮再生的机制和血管稳态的恢复。我们最近表明，叉状转录因子FOXM1是负责内皮再生的关键修复因子。但是，我们在此提供的新支持数据表明，在炎症肺损伤后，FOXM1表达和内源性内皮再生计划在老年肺部受到严重损害。 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老年肺的内皮再生计划。因此，我们假设在老年肺中激活PHD2继发的HIF-1A-> FOXM1信号受损是这些肺中严重缺陷的内皮再生的原因，并且通过PHD2抑制作用和CXCR4激活的一种基本修复途径的激活是一种潜在的新型频率，用于泄漏的频率且频率的范围差异，差异是差异的，该方法的差异是差异的范围。 ALI/ARDS患者。拟议的研究针对以下特定目的。在AIM＃1中，我们将解决HIF-1A-> FOXM1信号在老年肺中受损的作用，这是导致败血症挑战后肺血管稳态严重受损的至关重要因素。在AIM＃2中，我们将描述败血症挑战后老化肺部严重缺陷内皮再生的信号传导机制。在AIM＃3中，我们将通过抑制PHD抑制HIF-1A稳定在激活老年肺的内皮再生中的作用。我们还将解决动物模型中我们发现与人类的潜在临床相关性；从而确定抑制PHD2的治疗意义和CXCR4在治疗老年患者ALI/ARD中的激活。通过这些全面的研究，我们将描述老年肺内皮再生受损的基本信号传导机制，并鉴定治疗靶标，以激活这种基本的内在HIF-1A-> FOXM1依赖性机制，以修复漏水的肺微病房，以治疗ALI/ARD患者的ALI/ARD患者。