# Negative regulators of endothelial regeneration in aging lungs and ARDS

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2022 · $668,687

## Abstract

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 tran...

## Key facts

- **NIH application ID:** 10467781
- **Project number:** 1R01HL164014-01
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** YOU-YANG ZHAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $668,687
- **Award type:** 1
- **Project period:** 2022-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467781

## Citation

> US National Institutes of Health, RePORTER application 10467781, Negative regulators of endothelial regeneration in aging lungs and ARDS (1R01HL164014-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10467781. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*