# Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $573,748

## Abstract

PROJECT SUMMARY. COPD is a severe chronic respiratory disease, which is associated with smoking and
characterized by chronic lung inflammation, emphysema, airway remodeling and goblet cell metaplasia.
Identification of new molecular targets is needed to improve therapeutic outcomes in COPD patients. Our grant
application will explore the role of Forkhead transcription factor FOXM1 as a potential therapeutic target in
mouse and rat COPD models. FOXM1 is an embryonic transcription factor, which is not expressed in
quiescent lungs but aberrantly induced during lung carcinogenesis. We provide preliminary data demonstrating
that FOXM1 is activated in airway epithelial cells, macrophages and type II cells of COPD patients and mice
exposed to cigarette smoke (CS). Increased expression of FOXM1 in mouse and human lungs is associated
with emphysema and goblet cell metaplasia. Transgenic overexpression of FOXM1 in alveolar type II cells
exacerbated lung inflammation, leading to emphysema. Genetic deletion of Foxm1 gene from myeloid cells,
including macrophages and monocytes, decreased pulmonary inflammation after acute lung injury. Genetic
ablation of Foxm1 from airway club cells decreased goblet cell metaplasia caused by house dust mite
allergens. While FOXM1 is increased in human COPD and mouse genetic data suggest that FOXM1 is critical
goblet cell metaplasia, pulmonary inflammation and alveolar remodeling, molecular mechanisms regulated by
FOXM1 in COPD remain unknown. We propose to test the hypothesis that FOXM1 increases goblet cell
metaplasia and emphysema in COPD by transcriptionally activating distinct sets of pro-inflammatory and
mucinous genes in alveolar type II cells, airway club cells and macrophages. We will also test the therapeutic
efficacy of novel FOXM1 inhibitor RCM-1 in mouse and rat COPD models. Chronic CS exposure and a
combination of CS and Influenza infection will be used to induce pulmonary inflammation, emphysema and
goblet cell metaplasia. In Aim 1, we will identify molecular mechanisms regulated by FOXM1 in alveolar type II
cells (Aim 1A) and macrophages (Aim 1B) using purified cells and mice with specific ablation of Foxm1 gene
from these cell types. FOXM1 targets will be validated using de-identified human COPD lungs. In Aim 2A, we
will use mice with specific deletion of Foxm1 from airway club cells, to identify FOXM1 target genes critical for
differentiation of club cells into goblet cells in COPD model. In Aim 2B, we will test therapeutic potential of
novel, non-toxic FOXM1-inhibiting small molecule compound, RCM-1, which has been recently discovered in
my lab using a high throughput screen. Altogether, these studies will identify novel molecular mechanisms
critical for COPD pathogenesis and test therapeutic potential of FOXM1 inhibitors in animal COPD models.

## Key facts

- **NIH application ID:** 10055005
- **Project number:** 1R01HL149631-01A1
- **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:** $573,748
- **Award type:** 1
- **Project period:** 2020-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055005

## Citation

> US National Institutes of Health, RePORTER application 10055005, Molecular Mechanisms Regulated by FOXM1 in Chronic Lung Remodeling (1R01HL149631-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10055005. Licensed CC0.

---

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