# Transcriptional Regulation of Endothelial Cells after Acute Lung Injury

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $524,323

## Abstract

PROJECT SUMMARY. Capillary endothelial cells (ECs) play a key role in alveolar gas exchange and actively
participate in lung repair after acute lung injury (ALI). Acute Respiratory Distress Syndrome (ARDS) is a life-
threatening complication of ALI with high mortality rate. Given the lack of major improvements in ALI/ ARDS
clinical management, there is a compelling need for innovative molecular approaches to complement existing
ALI/ ARDS therapies. My laboratory previously demonstrated that FOXF1 transcription factor is a critical
regulator of lung vascular development in mice and humans. Global deletion of Foxf1 gene in mice is
embryonic lethal, whereas mice heterozygous for the Foxf1 null allele (Foxf1+/-) had reduced numbers of
pulmonary capillaries and increased mortality during the early neonatal period. Inactivating mutations in
FOXF1 gene locus were found in >50% of patients with Alveolar Capillary Dysplasia (ACD), a rare congenital
disorder with high mortality rate due to severe reduction in pulmonary capillaries. While these studies indicate
an important role for FOXF1 in development of pulmonary vasculature, FOXF1 function in adult lung/ injury
repair remains unknown. In this proposal, we provide preliminary data demonstrating that FOXF1 levels are
reduced after lung injury in mice and humans. Endothelial-specific deletion of both Foxf1 alleles causes
respiratory failure and mortality due to loss of endothelial integrity, disruption of adherens junctions and
reduced expression of genes critical for EC barrier function. Deletion of only one Foxf1 allele from ECs inhibits
lung repair and increases mortality in mouse ALI models. Knockdown of FOXF1 in cultured ECs delays cell
entry into S phase, increases levels of cell cycle inhibitors p21cip1 and p15ink4b, and reduces phosphorylation of
STAT3, a key transcriptional mediator of endothelial proliferation. FOXF1 physically binds to the STAT3
protein, and mutations in STAT3-binding region of the FOXF1 protein were recently found in ACD patients,
emphasizing the importance of FOXF1-STAT3 protein interactions in ECs. In this grant proposal, we will
identify molecular mechanisms regulated by FOXF1 during endothelial repair using mouse and rat ALI models.
We will test the hypothesis that FOXF1 promotes lung repair after acute lung injury. In Aim 1, we will use
cultured ECs and unique mouse models with gain-of-function and loss-of-function of FOXF1 to determine the
role of FOXF1 in EC barrier function and identify direct FOXF1 target genes. We will also use nanoparticles
(specifically targeting ECs in vivo) and a small molecule FOXF1-activating compound (recently discovered in
my laboratory) to restore FOXF1 expression after lung injury and determine whether pharmacological targeting
of FOXF1 will promote endothelial repair. In Aim 2, we will examine the importance of FOXF1-STAT3
interactions and FOXF1-mediated repression of p21cip1 and p15ink4b for EC proliferation in vitro and in vivo.
Completio...

## Key facts

- **NIH application ID:** 9900064
- **Project number:** 5R01HL141174-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Vladimir Kalinichenko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $524,323
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900064

## Citation

> US National Institutes of Health, RePORTER application 9900064, Transcriptional Regulation of Endothelial Cells after Acute Lung Injury (5R01HL141174-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9900064. Licensed CC0.

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