# Understanding how alveolar epithelial cell stress drives aberrant repair in interstitial lung disease

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2021 · $167,940

## Abstract

PROJECT SUMMARY
Interstitial lung diseases (ILDs) are a class of pulmonary diseases pathologically defined by interstitial fibrosis
and inflammation. Owing to our limited understanding of the upstream initiators of pathogenesis, ILDs have poor
prognoses and limited therapeutics. Mutations in the Alveolar Epithelial Type 2 Cell (AEC2) restricted Surfactant
Protein C (SP-C) gene (SFTPC) in a subset of ILD patients supports a growing hypothesis that AEC2
dysfunction is a driver of disease. When we model these disease-related SFTPC mutations in vitro they
segregate into two major classes based upon how the mutated SP-C isoform stresses cellular pathways that
manage abnormal proteins: mutations that inhibit macroautophagy and mutations that cause endoplasmic
reticulum (ER) stress. However, how these AEC2 stress phenotypes, which have also been identified in ILD
patients without SFTPC mutations, relate to ILD development remains poorly understood.
To understand this relationship, we have generated two unique Sftpc mutation knock-in mouse models, one
expressing an SP-C isoform that induces AEC2 macroautophagy dysfunction (SP-CI73T) and the other inducing
ER stress (SP-CC121G). Each of these mutations when expressed in the adult mouse lung results in spontaneous
alveolitis and lung injury followed by aberrant repair with resultant fibrotic ILD. These models thus provide proof
of concept that AEC2 stress is capable of driving spontaneous lung pathology and are robust preclinical
platforms. These models also support a second emerging theory of ILD pathogenesis: that in ILD AEC2s, which
must act as critical facultative progenitor cells after lung injury by both proliferating and differentiating to repair
damaged epithelium, develop dysfunction in their progenitor cell capacity. We discovered that while similar lung
pathology develops in each of our Sftpc models, there are divergent AEC2 proliferation phenotypes following
lung injury: SP-CI73T AEC2s become hyperpoliferative and SP-CC121G AEC2s become apoptotic and
hypoproliferative. Thus, our models support the hypothesis that abnormal AEC2 progenitor cell function plays a
central role in ILD development, and also create a platform to develop a mechanistic understanding of how
discrete AEC2 stress signatures result in distinct defects in progenitor cell capacity.
This proposal has three interrelated aims that seek to understand the molecular and cellular mechanisms that
relate AEC2 cell stress, dysfunctional progenitor cell capacity, and ILD. Aim 1 uses bioinformatics and in vivo
linage-tracing to characterize the AEC2 stress signaling and progenitor function pathways involved in each
model. Aim 2 provides a mechanistic link between cell stress signaling and progenitor cell dysfunction through
ex vivo organoid culture and in vivo modeling. In Aim 3 we will generate the first ILD patient-derived iPSC
culture model of an ER stress associated SFTPC mutation as a humanized platform to study the pathways
identifi...

## Key facts

- **NIH application ID:** 10200141
- **Project number:** 5K08HL150226-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jeremy Binder Katzen
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $167,940
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200141

## Citation

> US National Institutes of Health, RePORTER application 10200141, Understanding how alveolar epithelial cell stress drives aberrant repair in interstitial lung disease (5K08HL150226-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10200141. Licensed CC0.

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