# Derivation of lung epithelia from iPS cells for advanced disease modeling

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $471,114

## Abstract

Project Summary/Abstract
Diseases affecting the lung parenchyma or alveoli cause significant morbidity and
mortality in the US today. Treatments for these diseases are often ineffective and the
development of novel therapeutics is hampered by an incomplete understanding of
disease pathogenesis due in part to an inability to access living alveolar cells from
patients. The derivation of an inexhaustible supply of patient-specific alveolar epithelial
cells would allow studies of disease pathogenesis in primary cells carrying each patient’s
entire genetic background, and consequently the development of new therapeutics. This
application proposes to renew a long-standing project focused on the in vitro derivation
of lung epithelial lineages from patient-specific induced pluripotent stem cells (iPSCs). In
this renewal we generate an inexhaustible source of functionally mature alveolar
epithelial type 2 cells (AEC2s) from iPSCs that we have engineered by reprogramming
patient blood or skin specimens. Employing iPSCs generated from children and adults
with interstitial lung diseases that arise from heterozygous mutations in surfactant genes,
we propose to model the onset of a currently untreatable parenchymal lung disease at
its inception, an event that likely begins with AEC2 dysfunction initiated by toxic-gain-of
function effects of misfolded proteins. Through three aims we test the hypothesis that
AEC2s generated from patient specific iPSCs carrying surfactant pathway mutations
exhibit surfactant protein mistrafficking which leads to disrupted proteostasis, a late
block in autophagy, broad alveolar progenitor dysfunction, and inflammatory activation.

## Key facts

- **NIH application ID:** 9922331
- **Project number:** 5R01HL095993-11
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Darrell N. Kotton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $471,114
- **Award type:** 5
- **Project period:** 2009-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922331

## Citation

> US National Institutes of Health, RePORTER application 9922331, Derivation of lung epithelia from iPS cells for advanced disease modeling (5R01HL095993-11). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9922331. Licensed CC0.

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