Negative regulators of endothelial regeneration in aging lungs and ARDS

衰老肺和ARDS中内皮细胞再生的负调控因子 急性呼吸窘迫综合征(ARDS)是一种复杂的、多因素的综合征，死亡率为 高达30%-40%。败血症和肺炎引起的急性呼吸窘迫综合征的基本病理改变 是对内皮屏障的损伤，结果是增加了肺血管的通透性和难处理的蛋白质- 重度水肿症。与青壮年患者相比，脓毒症和肺炎引起的ARDS的发生率 老年患者的死亡率要高得多，死亡率高出10倍。然而，潜在的原因是 与衰老相关的ARDS的高发病率和死亡率目前还知之甚少。目前还没有有效的治疗方法 阿兹。利用遗传谱系追踪，我们的支持数据表明，内源性内皮细胞 在脓毒症挑战后，老年肺再生计划严重受损，并恢复 FOXM1的表达可以使这种再生和修复程序正常化。此外，我们的支持 有资料表明，FOXO1是老年肺组织中FOXM1表达的抑制因子。Sirtuin 1(SIRT1)作为一种 FOXO1衰老调控的表观遗传调控因子因此，我们假设表观遗传失调 内皮细胞FOXO_1、→、FOX_1在老年肺组织中的表达与内皮损伤的关系 再生和血管修复，从而重新激活FOXM1依赖的再生和 通过EC靶向纳米颗粒递送FOXM1转基因修复途径可能是一种新的途径 恢复肺微血管完整性和消融炎性水肿的治疗途径 提高老年ARDS患者的存活率。拟议的研究将涉及以下三个具体问题 目标。对Aim1的研究将确定内皮FoxO1在调节内皮再生和 脓毒症后老年肺血管修复与FOXO1转录抑制因子的关系 内皮细胞中的FOXM1。在目标2中，我们将定义FOXO1老化激活的表观遗传学机制 通过SIRT1。我们将描述内皮细胞SIRT1在抑制内皮再生中的意外作用 FOXO1介导的FOXM1抑制老年肺炎性损伤 表情。AIM 3的研究将开发用于内皮递送FOXM1的新型可生物降解纳米颗粒 在老年肺中进行转基因。这一翻译目标将探索新型纳米颗粒递送的潜力 FOXM1作为EC靶向基因治疗老年ARDS的方法。成功 拟议研究的完成将提供对受损的分子机制的新的理解 血管内皮细胞再生和血管修复与老年ARDS的高发病率和死亡率 并为未来的临床和商业翻译提供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 非常高。

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.