# Mechanistic evaluation of a novel Wnt-responsive adult alveolar epithelial progenitor population during regeneration after diffuse alveolar damage

> **NIH NIH K08** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $163,080

## 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.
A key requirement for developing strategies to improve recovery after ARDS and promote lung regeneration is
to understand progenitor populations in the lung, and their specific roles in the complex, regionalized nature of
regeneration after injury. We have found a distinct group of Wnt-responsive AT2 cells. These cells comprise a
distinct progenitor sublineage, which we call AEPs (Axin2+ Alveolar Epithelial Progenitors). AEPs are capable
of generating both AT1 and AT2 cells in vivo and in vitro, are stable for 9 months during alveolar homeostasis,
and expand rapidly to regenerate a majority of the alveolar epithelium after diffuse alveolar damage.
Importantly, we have identified an AEP-enriched cell surface receptor that marks AEPs in both mouse and
human lung, which has allowed functional validation of human AEPs as a progenitor lineage.
The ability to directly compare AEPs from mouse and human has provided specific insight into possible
upstream signals and downstream effectors required for AEP function. The scientific objective of this proposal
is to directly evaluate the requirement and role for several such candidate factors in AEP biology during lung
regeneration, with a specific emphasis on the combinatorial role of Wnt and Fgf signals in promoting AEP
function. The Aims of the proposal are 1) Define the requirement for Wnt signaling in AEP biology during
alveolar regeneration and 2) Determine the function of FGFR2 signaling and ETS transcription factors in AEPs.
The other crucial objective of this proposal is to provide for a structured, focused training plan to allow the
primary investigator to develop an advanced armamentarium of research techniques in regenerative biology
and allow for a successful transition to independence.

## Key facts

- **NIH application ID:** 10241459
- **Project number:** 5K08HL140178-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** William John Zacharias
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $163,080
- **Award type:** 5
- **Project period:** 2018-07-21 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241459

## Citation

> US National Institutes of Health, RePORTER application 10241459, Mechanistic evaluation of a novel Wnt-responsive adult alveolar epithelial progenitor population during regeneration after diffuse alveolar damage (5K08HL140178-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241459. Licensed CC0.

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