# Bronchiolar Dysplasia in COPD is Governed by Loss of Polycomb Repressive Complex 2

> **NIH NIH F31** · UNIVERSITY OF KENTUCKY · 2021 · $23,605

## Abstract

PROJECT SUMMARY
Future Research Questions
As a graduate student in the Toxicology and Cancer Biology Department of University of Kentucky, I seek to
understand the complex molecular processes that drive development of lung diseases. The goal of my
dissertation research is to determine how the role of Polycomb Repressive Complex 2 (PRC2) directs proper
lung stem cell fate, and how this process is dysregulated in lung disease. My central hypothesis is that PRC2
normally represses basal and goblet cell fates in bronchiolar epithelium, and that loss of PRC2-mediated
repression of these lineages leads to phenotypes observed in bronchiolar epithelium of Chronic Obstructive
Pulmonary disease (COPD), including basal cell and goblet cell metaplasia.
Background and Methodology
Polycomb Repressive Complex 2 (PRC2) modulates gene expression through histone modification. Recent
unpublished data from the Brainson lab suggests that PRC2 activity is dysregulated in chronic obstructive
pulmonary disease (COPD). These findings fit with others in the field that demonstrated loss of PRC2 in
developing lung causes aberrant expression of basal cell markers including KRT5 and p63 in distal lung airways
in mice. Together these data suggest that improper PRC2 activity is important for cell development, fate, and
function. They also warrant further investigation into PRC2's role in disease development and propagation,
particularly those involving lung functions.
Methodology
The Aims of my proposal are to: 1) Elucidate the cellular changes in bronchiolar epithelial cells observed in in
vitro and in vivo after genetic modulation of the PRC2 complex and 2) Confirm that loss of proper PRC2 gene
silencing leads to expansion of basal cell and goblet cell fates in human bronchiolar epithelial cells. For Aim 1,
I am knocking out one or two alleles of Ezh2, the gene encoding the enzyme for PRC2, in adult mouse lung for
four months, and challenging the mice with ovalbumin to induce goblet cell metaplasia. My hypothesis that loss
of PRC2 will prevent cells from resolving allergic response will be tested by lung histology. In parallel, I will use
lung organoid cultures and single cell RNA-sequencing to examine lung cell fates when PRC2 is dysregulated
in mouse lung cells. For Aim 2, I will use an EZH2 inhibitor, short hairpin RNAs against PRC2 components, and
cigarette smoke extract on human bronchial epithelial cells in air-liquid interphase cultures to examine how
perturbation of PRC2 changes lung cell fate decisions. I will also establish new cultures from COPD patients,
and finally explore the transcriptional changes in these cultures and how PRC2 influences these changes by
chromatin immunoprecipitation experiments.
Career Potential
My ultimate goal is to influence national and global health policy by effectively investigating the physiological
changes that are currently taking and have taken place as a result of environmental changes. My personal
interest in stem cell biology a...

## Key facts

- **NIH application ID:** 10271240
- **Project number:** 5F31HL151111-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Aria Byrd
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $23,605
- **Award type:** 5
- **Project period:** 2020-03-15 → 2021-10-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271240

## Citation

> US National Institutes of Health, RePORTER application 10271240, Bronchiolar Dysplasia in COPD is Governed by Loss of Polycomb Repressive Complex 2 (5F31HL151111-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10271240. Licensed CC0.

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