# Project 3: Functional Genomic Mechanisms of Epithelial Dysfunction in Pulmonary Fibrosis

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $337,601

## Abstract

PROJECT SUMMARY
Using single-cell RNA-sequencing (scRNA-seq), we and others have demonstrated dramatic changes in
cellular identities, frequencies, and molecular programs that characterize late-stage pulmonary fibrosis (PF).
These advances have led to new questions regarding the timing, coordination, transcriptional regulatory
mechanisms, and impact of genetic variation on the evolution of the diverse cellular pathology seen in
advanced PF lungs. Utilizing transbronchial biopsy samples from subjects in our At-Risk for Familial PF (FPF)
cohort, we are now uniquely positioned to investigate these mechanisms through the critical phase of early
disease pathogenesis. Pilot studies in which we performed single-nucleus multiomic (RNA+ATAC)-sequencing
of archival flash frozen biopsies from At-Risk for FPF subjects suggest that changes in cell-type specific gene
expression (including alveolar niche factors) and chromatin accessibility (including key regulators of alveolar
epithelial cell fate/identity) are detectable and may develop prior to the appearance of interstitial lung
abnormalities or overt pulmonary fibrosis. Additional preliminary data reveal that a subset of genetic variants
that regulate gene expression (single-cell expression quantitative trait loci, sc-eQTL) exhibit significant
differences in effect size and/or direction in PF lungs compared to controls - we term these “disease-interacting
sc-eQTL.” In the distal lung epithelium, disease-interacting sc-eQTL are specifically enriched within the binding
motifs for a set of stress-induced transcription factors which also regulate top differentially expressed genes in
KRT5-/KRT17+ basal-like cells in PF lungs. This remarkable convergence suggests that genetic variation at
cell-type specific loci modulating activity of a set of stress-induced transcription factors regulates alveolar
epithelial repair. We hypothesize that activation of injury-response transcriptional programs in the distal lung
epithelium unmasks disease-interacting expression-quantitative-trait loci (eQTLs) to mediate dysfunctional
epithelial repair and promote initiation and early progression of FPF. Our specific aims are: 1) To define the
single-cell molecular programs of early interstitial lung abnormalities, 2) To determine the cell-type-specific
transcriptional regulatory mechanisms through which genetic risk for FPF mediates early ILA development and
progression, and 3) To examine the mechanisms through which PF-associated genetic variation regulates
distal airway and alveolar epithelial repair. Integrating single-cell multiomics of pre-disease lung biopsy
samples linked to future PF progression outcomes, genetic variation and patient-derived organoid models, we
will investigate the mechanisms through which genetic variation interacts with injury-response transcriptional
regulation to drive the early pathogenesis of PF.

## Key facts

- **NIH application ID:** 10846187
- **Project number:** 1P01HL172729-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jonathan Andrew Kropski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $337,601
- **Award type:** 1
- **Project period:** 2024-09-17 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846187

## Citation

> US National Institutes of Health, RePORTER application 10846187, Project 3: Functional Genomic Mechanisms of Epithelial Dysfunction in Pulmonary Fibrosis (1P01HL172729-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10846187. Licensed CC0.

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