# Targeting Lung Fibrosis Using Epigenetic Therapy

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $698,070

## Abstract

PROJECT SUMMARY
 Pulmonary fibrosis is a complex disease that limits lung function through development of collagen-rich
scar tissue. Although there are currently two FDA-approved therapies for fibrosis patients, these drugs are
capable of extending life only months and do not reverse the progression of the disease. The research described
in this proposal would build upon evidence that reprogramming cellular fate through modulation of the
epigenetic enzyme EZH2 can ameliorate several phenotypes of pulmonary fibrosis, including aberrant
alveolar cell fate and pro-fibrotic cytokine signaling. Specifically, the aims will test if the FDA-approved EZH2
inhibitor, tazemetostat, will allow for prevention or reversion of these cellular phenotypes. The model systems to
be used include both human and mouse organotypic cell cultures and two established in vivo models of
pulmonary fibrosis, namely lung instillation of the chemotherapy bleomycin or adeno-associated virus (AAV)
expressing TGFβ. For Aim 1, we will quantify the extent of aberrant basaloid/alveolar transition cells in lung
epithelial cultures that are depleted for EZH2 activity genetically or pharmacologically, and assess rescue of this
phenotype by deletion of the transcription factor FOXP2. FOXP2 deletion and knock-down will also be used to
understand this important transcription factor’s role alveolar cell fate. We will also assess the down-regulation of
IL1β by EZH2 inhibition, and its effects on both murine and human epithelial and fibroblast cells. The influence
of TGFβ on fibroblasts and epithelial cells in the presence of EZH2 inhibitor will be tested. In Aim 2 in vivo lung
injury models will be used to examine both prevention and treatment of lung fibrosis, and to characterize specific
changes to the epithelial, fibroblast, and myeloid cell populations driven by EZH2 inhibition. Lung function
testing, histology, scRNA-seq and flow cytometry will be used to characterize the lung phenotypes. Patient
tissues will be used to understand if EZH2 activity is high and FOXP2 expression is low in aberrant
basaloid/alveolar transition cells in vivo. We expect that this research could validate the use of EZH2 inhibition
as a treatment for pulmonary fibrosis, and will expand our knowledge in the field of lung epigenetics and stem
cell biology.

## Key facts

- **NIH application ID:** 10990721
- **Project number:** 1R01HL170193-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Christine Fillmore Brainson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $698,070
- **Award type:** 1
- **Project period:** 2024-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990721

## Citation

> US National Institutes of Health, RePORTER application 10990721, Targeting Lung Fibrosis Using Epigenetic Therapy (1R01HL170193-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10990721. Licensed CC0.

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