# Patient-specific iPSCs to model and treat the inception of pulmonary fibrosis

> **NIH HL P01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2026 · $464,118

## Abstract

Project Summary
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis leading to disruption of the gas
exchange unit and death within an average of four years from the time of diagnosis. A poor understanding of IPF
pathogenesis, in part due to a lack of reliable human disease models, has been a major hurdle to developing
effective therapies. With the advent of genome wide association studies and intensive study of familial forms of
pulmonary fibrosis, dysfunction of the distal lung epithelium and in particular dysfunction of alveolar epithelial
type 2 (AT2) cells has been implicated as a potential proximal disease driver. Using patient-specific induced
pluripotent stem cell (iPSC)-derived AT2 cells (iAT2s) our group recently described how the inception of
interstitial lung disease may result from a dysfunctional AT2 cell phenotype characterized by diminished
progenitor capacity, perturbed proteostasis, mitochondrial dysfunction, and NF-κB pathway activation. Despite
the progress made, critical information remains to be elucidated to allow for the development of effective
mechanistic IPF therapies. This proposal aims to: 1) advance our understanding of the role of mitochondrial
dysfunction in eliciting a pro-fibrotic AT2 cell phenotype, 2) understand how disease-relevant environmental
insults, such as cigarette smoke exposure, contribute to this dysfunction, and 3) test its reversibility. Specifically,
the role of insufficient adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation in driving
the AT2 cell mitochondrial dysfunction, suggested by our preliminary data, will be investigated and the potential
of AMPK activators as IPF therapeutics will be tested both in vitro and in vivo. We test the hypothesis that
mitochondrial dysfunction in genetically susceptible human AT2 cells results from insufficient AMPK activity and
is exaggerated by environmental insults leading to diminished alveolar progenitor capacity, inflammatory
ac

## Key facts

- **NIH application ID:** 11309146
- **Project number:** 5P01HL170952-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Konstantinos  Alysandratos
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** HL
- **Fiscal year:** 2026
- **Award amount:** $464,118
- **Award type:** 5
- **Project period:** 2024-03-01T00:00:00 → 2029-02-28T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11309146

## Citation

> US National Institutes of Health, RePORTER application 11309146, Patient-specific iPSCs to model and treat the inception of pulmonary fibrosis (5P01HL170952-03). Retrieved via AI Analytics 2026-07-12 from https://api.ai-analytics.org/grant/nih/11309146. Licensed CC0.

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