Negative regulators of endothelial regeneration in aging lungs and ARDS

衰老肺和 ARDS 中内皮再生的负调节因子

• 批准号: 10629328
• 负责人: YOU-YANG ZHAO
• 金额: $ 66.87万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629328
• 关键词: Acute; Acute Respiratory Distress Syndrome; Aging; Animals; Bilateral; Binding; Blood Vessels; Cells; Clinical; Complex; Data; Deacetylation; Dominant-Negative Mutation; Edema; Elderly; Endothelial Cells; Endothelium; Epigenetic Process; Extravasation; FOXM1 gene; FOXO1A gene; Family; Future; Genetic; Heart failure; Histone Deacetylase; Homeostasis; Human; Impairment; Incidence; Infiltration; Inflammation; Inflammatory; Injury; Left; Lipopolysaccharides; Lung; Mediating; Mediator; Microvascular Permeability; Modeling; Molecular; Outcome; Pathologic; Pathway interactions; Patients; Pneumonia; Proteins; Pulmonary Edema; Resolution; Role; SIRT1 gene; Sepsis; Severities; Syndrome; Therapeutic; Transcription Repressor; Transgenes; Translations; Vascular Permeabilities; Ventricular; acute hypoxemic respiratory failure; aged; cecal ligation puncture; effective therapy; endothelial regeneration; forkhead protein; gene therapy; improved; lung injury; lung vascular injury; member; mortality; nanoparticle; nanoparticle delivery; novel; novel strategies; novel therapeutic intervention; older patient; polymicrobial sepsis; pre-clinical; programs; promoter; regenerative; repaired; restoration; sepsis induced ARDS; therapeutically effective; translational potential; young adult

Negative regulators of endothelial regeneration in aging lungs and ARDS Acute respiratory distress syndrome (ARDS) is a complex, multi-factorial syndrome with a mortality rate as great as 30-40%. A fundamental pathological change found in ARDS that results from sepsis, and pneumonia is injury to the endothelial barrier, and, as a result, increased lung vascular permeability and intractable protein- rich edema. Compared to young adult patients, the incidence of ARDS resulting from sepsis and pneumonia in elderly patients is much higher and the mortality rate is 10-fold higher. However, the underlying causes of aging-related high incidence and mortality of ARDS are poorly understood. There is no effective treatment of ARDS. Employing genetic lineage tracing, our Supporting Data show that the endogenous endothelial regeneration program was severely impaired in aged lungs following sepsis challenge, and restoration of FOXM1 expression could normalize this regenerative and reparative program. Furthermore, our Supporting Data show that FOXO1 is a suppressor of FOXM1 expression in aged lungs. Sirtuin 1 (SIRT1) functions as an aging-regulated epigenetic regulator of FOXO1. Thus, we hypothesize that epigenetic dysregulation of endothelial FOXO1→FOXM1 expression by SIRT1 in aged lungs is responsible for the impaired endothelial regeneration and vascular repair and thereby reactivation of the FOXM1-dependent regenerative and reparative pathway through EC-targeted nanoparticle delivery of FOXM1 transgene may represent a novel therapeutic approach for restoring lung microvessel integrity and resolving inflammatory edema and thus improving survival of elderly ARDS patients. The proposed studies will address the following three Specific Aims. Studies in Aim1 will determine the role of endothelial FoxO1 in regulating endothelial regeneration and vascular repair in aged lungs following sepsis challenge and define FOXO1 as a transcriptional repressor of FOXM1 in endothelial cells. In Aim 2, we will define the epigenetic mechanism of aging activation of FOXO1 via SIRT1. We will characterize the unexpected role of endothelial SIRT1 in inhibiting endothelial regeneration and resolution of inflammatory injury in aged lungs through FOXO1-mediated suppression of FOXM1 expression. Studies in Aim 3 will develop novel biodegradable nanoparticles for endothelial delivery of FOXM1 transgene in aged lungs. This translational aim will explore the potential of novel nanoparticle delivery of FOXM1 as an EC-targeted gene therapy approach for treatment of ARDS in elderly patients. Successful completion of the proposed studies will provide novel understanding of the molecular mechanisms of impaired endothelial regeneration and vascular repair and thus high incidence and mortality of ARDS in elderly patients and provide fundamentally important preclinical data needed for future clinical and commercial translation of our discovery into ARDS therapy in elderly patients. Thus, the translation potential of the proposed studies is extremely high.

衰老肺和ARDS内皮再生的负调节剂 急性呼吸窘迫综合征（ARDS）是一种复杂的多因素综合征，死亡率为 高达30-40％。败血症和肺炎引起的ARDS中发现的基本病理变化 是内皮屏障的损伤，结果增加了肺血管渗透性和可怕的蛋白质 - 丰富的水肿。与年轻的成人患者相比，败血症和肺炎引起的ARDS事件 在古老的患者中，患者要高得多，死亡率高10倍。但是， 与衰老有关的高事件和ARD的死亡率知之甚少。没有有效的处理 ARDS。使用遗传谱系追踪，我们的支持数据表明内源性内皮 败血症挑战后，衰老的肺部再生计划严重受损，并恢复 FOXM1表达可以使该再生和修复程序归一化。此外，我们的支持 数据表明，FOXO1是老化肺FoxM1表达的抑制剂。 Sirtuin 1（SIRT1）充当 FOXO1的老化调节的表观遗传调节剂。这是我们假设的表观遗传失调 内皮FOXO1→FOXM1 SIRT1在老年肺中的表达是造成内皮受损的 再生和血管修复，从而重新激活FOXM1依赖性再生和 通过FOXM1转基因的EC靶向纳米颗粒传递的修复途径可能代表一种新颖 恢复肺微血管完整性和解决炎症性水肿的治疗方法，从而 改善了最古老的ARDS患者的存活率。拟议的研究将解决以下三个特定 目标。 AIM1的研究将确定内皮FOXO1在调节内皮再生和 败血症挑战后老化肺的血管修复，并将FOXO1定义为转录代表 内皮细胞中的FOXM1。在AIM 2中，我们将定义FOXO1衰老激活的表观遗传机制 通过SIRT1。我们将表征内皮SIRT1在抑制内皮再生中的意外作用 通过FOXO1介导的FOXM1的抑制，老化肺部炎症损伤的分辨率 表达。 AIM 3中的研究将开发新型可生物降解的纳米颗粒，用于FOXM1的内皮递送 老年肺的转基因。这种翻译目的将探索新颖的纳米颗粒输送的潜力 FOXM1是一种以EC靶向基因治疗方法，用于治疗古老的患者的ARDS。成功的 拟议研究的完成将提供对受损分子机制的新了解 内皮再生和血管修复，因此，老患者的ARDS的高入和死亡率很高 并提供根本重要的临床前数据，以使未来的临床和商业翻译所需 我们在老年患者中发现了ARDS治疗。那就是拟议研究的翻译潜力是 极高。