# Mechanisms of epithelial repair and remodeling in pulmonary fibrosis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $610,399

## Abstract

Abstract
 Pulmonary fibrosis (PF) is a clinical syndrome that represents the end-stage of chronic parenchymal
lung diseases. Dysfunctional repair of the distal lung epithelium has been hypothesized as central to PF
pathogenesis, but the mechanisms governing epithelial repair following injury remain incompletely understood.
In order to comprehensively profile the cell types and gene expression programs driving PF, we performed
single-cell RNA-sequencing (scRNA-seq) of peripheral tissue from PF and control lungs and identified dramatic
changes in cell types, states, and expression programs in PF lung epithelium including a previously
undescribed KRT5-/KRT17+ “distal basal cell” (DBC) population that produces pathologic extracellular matrix.
Independently, using whole-exome sequencing for genetic discovery in families with pulmonary fibrosis
(Familial Interstitial Pneumonia, FIP), we identified rare mutations in an orphan G-protein coupled receptor
(GPR87) that segregate with disease, implicating GPR87 as a novel FIP risk gene. Our preliminary data
indicate that GPR87 gene expression is dramatically increased in lung tissue from patients with sporadic cases
of IPF, and localizes specifically to these newly described pathologic ECM-producing DBCs. In mice, as in
humans, Gpr87 expression was low in the peripheral lung; however, expression increases substantially after
following bleomycin injury, where it localized to distal basal cells. We generated mice expressing an FIP-
associated mutant form of Gpr87 using a CRISPR-Cas9 gene editing strategy and found that mice carrying a
single-copy of the mutation (Gpr87mut/wt) had increased lung fibrosis compared to control mice following a
single-dose bleomycin. Unchallenged mice carrying biallelic mutations (Gpr87mut/mut) develop spontaneous
airway epithelial remodeling and striking atypical hyperplasia in vivo. Consistent with these findings, culture of
Gpr87mut/mut mouse tracheal epithelial cells (MTECs) in air-liquid interface (ALI) and 3D organoid systems
resulted in aberrant epithelial differentiation. Together, our preliminary data implicate DBCs in PF pathogenesis
and suggest that GPR87 regulates the fate and function of these cells. Our hypothesis is that GPR87
regulates proliferation and differentiation of distal basal cells, which are required for efficient repair of alveolar
epithelium after severe or repetitive injury. Our specific aims are: 1) Determine the role of Gpr87-
expressing distal basal cells in promoting lung fibrosis. 2) Identify mechanisms regulating distal
basal cell fate and function in severe and chronic alveolar injury. 3) Investigate GPR87-dependent
regulation of basal cell function and differentiation. In studies proposed below, we will use innovative
transgenic mouse, organoid and inducible pluripotent stem cell (iPSC)-based models to investigate the
mechanisms through which GPR87 contributes to fibrotic susceptibility and adaptive versus pathologic lung
epithelial repair.

## Key facts

- **NIH application ID:** 10030370
- **Project number:** 1R01HL153246-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jonathan Andrew Kropski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $610,399
- **Award type:** 1
- **Project period:** 2020-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10030370

## Citation

> US National Institutes of Health, RePORTER application 10030370, Mechanisms of epithelial repair and remodeling in pulmonary fibrosis (1R01HL153246-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10030370. Licensed CC0.

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