# Defining PRC2 complex epigenomic control in alveolar progenitor cells

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $569,920

## Abstract

PROJECT SUMMARY
The alveolar region of the mammalian lung is a complex, precisely structured tissue required for the primary
functions of the respiratory system, gas exchange and tissue oxygenation. Damage to the alveolar epithelium
plays a central role in human lung diseases including Acute Respiratory Distress Syndrome (ARDS), a
prevalent, high impact clinical disorder that affects up to 5% of mechanically ventilated patients in the
developed world. The mortality rate of ARDS approaches 40%, and the recovery for ARDS survivors is
arduous, with a substantial burden of multi-system disability continuing 5 or more years following
hospitalization. Critically, while many ARDS survivors recover lung function, a subset of patients develops
persistently abnormal pulmonary function, imaging evidence of pulmonary scarring, and pulmonary symptoms
even years after ARDS. To date, no data exists regarding the mechanisms that guide ARDS recovery. These
challenges have been made more acute by the coronavirus pandemic, which has exposed a large proportion
of the human population to acute lung injury. An enormous population of patients is at risk of both acute and
chronic lung consequences of lung injury following coronavirus infection, emphasizing the clear and urgent
need for new regenerative therapies to promote recovery from acute lung disease.
Regeneration in many organs is driven by adult facultative progenitor cells. We recently discovered a facultative
progenitor cell in the mouse and human lung which participates in regeneration after viral injury we call alveolar
epithelial progenitors (AEPs). Progenitor cells control their chromatin carefully, as they must maintain more broad
potential than fully differentiated cells, and so a hallmark of progenitor chromatin state is regions of active
regulation between fully open and fully closed states, so called poised chromatin. Unique preliminary data from
our laboratory and review of the literature support the idea that the chromatin modifying complex PRC2 is a
critical regulator of the progenitor chromatin state of AEPs. In this application, using a combination of advanced
lung organoids and genetic mouse injury models, we will identify the temporal and functional requirements for
PRC2 function in lung progenitors, define the key binding partners and targets of the PRC2 complex in
maintenance of AEP progenitor state, and evaluate the genomic loci regulated by PRC2 complex activity
necessary for AEP-mediated alveolar regeneration. Understanding these fundamental mechanisms will provide
the framework needed to understand alveolar regenerative biology at a granular level and develop therapeutic
strategies to maintain and restore AT2 progenitor function to drive repair following infection and environmental
stress.

## Key facts

- **NIH application ID:** 10752611
- **Project number:** 5R01HL166245-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** William John Zacharias
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $569,920
- **Award type:** 5
- **Project period:** 2022-12-15 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752611

## Citation

> US National Institutes of Health, RePORTER application 10752611, Defining PRC2 complex epigenomic control in alveolar progenitor cells (5R01HL166245-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10752611. Licensed CC0.

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