Negative regulators of endothelial regeneration in aging lungs and ARDS

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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.