# Mechanisms of alveolar homeostasis and repair.

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

PROJECT SUMMARY
Chronic respiratory diseases including pulmonary fibrosis (PF) are substantial causes of morbidity and
mortality among veteran populations. Most patients with progressive PF die of respiratory failure or require
lung transplantation within 5 years of diagnosis, and currently available therapies only modestly slow disease
progression, underscoring an urgent need for new and more effective therapies that halt disease progression
and/or promote functional lung regeneration. Dysfunctional repair of the alveolar epithelium following
recurrent/chronic injury has been hypothesized as central to PF pathogenesis, and our prior work and
preliminary data demonstrate that that lung epithelium in PF is characterized by accumulation of cells in
abnormal differentiation states similar to regeneration-associated transitional cells observed in mice,
suggesting that persistence of typically transient cell-states may be driver of disease pathogenesis. Using
single-cell transcriptomics, genetic lineage-tracing studies, recurrent injury-models together with human and
mouse organoid models, our preliminary data demonstrate that there is aberrant and persistent activation of
hypoxia-inducible-factor-2 (Hif2) in the distal lung epithelium following recurrent injury. Preventing or blocking
Hif2 activity protects against proximal-like epithelial metaplasia and experimental lung fibrosis and enhances
alveolar epithelial cell maturation. We hypothesize that recurrent injury to regenerating airway-derived
progenitor cells prevents AEC maturation via persistent activation of HIF2, which cooperates with the
ETS family of transcription factors to direct ectopic “proximal-like” cell fates and potentiate local
profibrotic signaling. Our specific aims are: 1) To test whether targeted Hif-inhibition can ameliorate
experimental lung fibrosis, 2) To investigate the mechanisms through which localized Hif-activation regulates
niche-specific profibrotic signaling, and 3) To determine whether HIF2:ETS interactions mediate HIF-regulation
of regenerating epithelial cell fate and profibrotic signaling. Integrating transgenic mouse models, human and
mouse organoid studies, and state-of-the-art spatial-transcriptomic and multiomic approaches, these studies
will determine whether hypoxia or non-hypoxic mechanisms drive Hif activation following recurrent injury, test
whether targeted inhibition/deletion of Hif1α/Hif2α or both can prevent and/or enhance resolution of lung
fibrosis, determine the mediators through which epithelial Hif2 promotes local fibroblast activation, and define
the interacting partners by which Hif2 regulates fate and function of regenerating AECs. Together, these
experiments will determine crucial insights into the “upstream” mechanisms linking dysfunctional alveolar repair
to lung fibrosis, and establish HIF2 as a novel therapeutic target to interrupt the PF pathobiology and promote
functional alveolar regeneration.

## Key facts

- **NIH application ID:** 10803576
- **Project number:** 1I01BX006121-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Jonathan Andrew Kropski
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803576

## Citation

> US National Institutes of Health, RePORTER application 10803576, Mechanisms of alveolar homeostasis and repair. (1I01BX006121-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10803576. Licensed CC0.

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