# Developing a patient-specific organoid model of pulmonary fibrosis using iPSCs

> **NIH NIH U01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $508,550

## Abstract

Project Summary/Abstract
Idiopathic pulmonary fibrosis (IPF) remains a deadly interstitial lung disease (ILD) with treatment
options limited by an incomplete understanding of the mechanisms that initiate and perpetuate
disease. A growing literature now implicates lung epithelial dysfunction as playing a role in the events
that lead to downstream fibroblast activation, culminating in relentless fibrosis. These studies,
together with the observation that lung epithelial cells in all forms of IPF display shortened telomeres,
suggests that lung epithelial dysfunction may initiate IPF, and accelerated aging phenotypes or
telomerase pathway abnormalities likely contribute to this pathogenesis. However, without access to
patient-specific human epithelial-mesenchymal model systems, there are limited options for testing
hypotheses of how epithelial changes induced by gene polymorphisms or telomerase perturbations
might mechanistically contribute to IPF. Here we propose to develop a human organoid-based in vitro
model system for the study of IPF. We have established a biorepository of induced pluripotent stem
cells (iPSCs) generated from individuals with sporadic or familial pulmonary fibrosis. In aim 1 we
apply this repository by directing the in vitro differentiation of banked IPF iPSCs carrying telomerase
mutations (vs normal iPSCs) into various airway and alveolar lung epithelial cells for the purpose of
generating a reductionist, epithelial-only 3D culture model of the intrinsic epithelial dysfunction that
we posit may initiate pulmonary fibrosis. In aim 2 we augment the complexity of this model by
introducing human organoids composed of iPSC-derived lung epithelia juxtaposed with human
mesenchymal lineages in order to model the epithelial-mesenchymal interactions hypothesized to
perpetuate IPF. Finally, in aim 3 we test the hypothesis that different telomerase pathway mutations
result in shared lung epithelial perturbations, including short telomeres and p53 activation, that then
leads to downstream mesenchymal activation.

## Key facts

- **NIH application ID:** 10026360
- **Project number:** 1U01HL152976-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Darrell N. Kotton
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,550
- **Award type:** 1
- **Project period:** 2020-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026360

## Citation

> US National Institutes of Health, RePORTER application 10026360, Developing a patient-specific organoid model of pulmonary fibrosis using iPSCs (1U01HL152976-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10026360. Licensed CC0.

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