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: 10467781
• 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/10467781
• 关键词: Acute; Acute Respiratory Distress Syndrome; Address; 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; Foxes; Future; Genetic; Heart failure; Histone Deacetylase; Homeostasis; Human; Impairment; Incidence; Inflammation; Inflammatory; Injury; Left; Lipopolysaccharides; Lung; Mediating; Mediator of activation protein; 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; 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.

老化肺和ARDS中内皮再生的负调节因子 急性呼吸窘迫综合征（ARDS）是一种复杂的多因素综合征， 30%-40%。一种在ARDS中发现的由败血症和肺炎引起的基本病理变化 是对内皮屏障的损伤，结果是肺血管通透性增加和顽固性蛋白质- 丰富水肿。与年轻成人患者相比，脓毒症和肺炎导致的ARDS发生率 老年患者的死亡率要高得多，死亡率高出10倍。然而， 与年龄相关的ARDS高发病率和死亡率知之甚少。没有有效的治疗方法 ARDS。采用遗传谱系追踪，我们的支持数据表明，内源性内皮细胞 在脓毒症攻击后，老年肺的再生程序严重受损， FOXM 1表达可以使这种再生和修复程序正常化。此外，我们的支持 数据显示FOXO 1是老年肺中FOXM 1表达的抑制剂。Sirtuin 1（SIRT 1）是一种 FOXO 1的衰老调节表观遗传调节因子。因此，我们假设，表观遗传失调， 老年肺组织中SIRT 1表达的内皮FOXO 1 → FOXM 1是导致内皮损伤的原因 再生和血管修复，从而重新激活FOXM 1依赖性再生和 通过EC靶向纳米颗粒递送FOXM 1转基因的修复途径可能代表了一种新的 用于恢复肺微血管完整性和解决炎性水肿的治疗方法 提高老年ARDS患者的生存率。拟议的研究将涉及以下三个具体问题： 目标。对Aim 1的研究将确定内皮FoxO 1在调节内皮再生中的作用， 脓毒症激发后老年肺血管修复，并将FOXO 1定义为 内皮细胞中的FOXM 1。在目的2中，我们将定义FOXO 1老化激活的表观遗传机制 通过SIRT 1。我们将描述内皮SIRT 1在抑制内皮再生中意想不到的作用， 通过FOXO 1介导的FOXM 1抑制来缓解老年肺的炎症损伤 表情目标3中的研究将开发用于内皮递送FOXM 1的新型生物可降解纳米颗粒 老年肺中的转基因。这一翻译目标将探索新的纳米颗粒递送的潜力， FOXM 1作为治疗老年患者ARDS的EC靶向基因治疗方法。成功 这些研究的完成将为我们提供新的理解， 内皮再生和血管修复，因此老年患者的ARDS发生率和死亡率较高 并提供未来临床和商业翻译所需的基本重要的临床前数据， 我们在老年患者ARDS治疗中的发现。因此，拟议研究的翻译潜力是 极高