# Surfactant Protein C Mutations and Interstitial Lung Disease

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## Abstract

ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring interstitial lung disease (ILD) that affects mainly
older adults for which there remains a significant unmet therapeutic need. While the pathophysiologic
underpinnings of IPF remain incompletely understood, an additional critical barrier to developing better
therapeutic outcomes for IPF has been a dearth of translationally relevant preclinical models. Based on a recent
paradigm shift wherein the concepts of repetitive injury to a dysfunctional, vulnerable, alveolar epithelium coupled
with an abnormal wound healing response are postulated as disease “drivers”, new opportunities are emerging
for therapeutic discovery in IPF. Over 60 mutations in the alveolar type 2 cell (AT2) restricted, Surfactant Protein
C [SP-C] gene [SFTPC], have been found in sporadic and familial IPF and provide important clues for
understanding IPF pathogenesis. To address the unmet need for veterans with IPF, this proposal builds upon
on a strong foundation of our prior work funded by this Merit Review program characterizing the cell biology of
SP-C biosynthesis that culminated in generation of two novel knock-in mouse models of spontaneous lung
fibrosis already in hand which express clinical SP-C mutants in AT2 cells in an allelic and inducible fashion. Our
Published Data has demonstrated that clinical, IPF-associated SFTPC mutations produce aberrant SP-C
proprotein isoforms that functionally segregate into 2 AT2 cell stress phenotypes: ER stress induced by
intracellular SP-C misfolding (“BRICHOS”) or impaired autophagy/mitophagy secondary to proSP-C
mistrafficking to non-native organelles (“Non-BRICHOS”). When expressed in the lung epithelium in vivo, both
the non-BRICHOS mutant (SftpcI73T) and the BRICHOS mutant (SftpcC121G) are extremely toxic to the lung and
each is sufficient to evoke a time-dependent, physiologically restrictive peripheral fibrotic lung phenotype that
elaborates translationally relevant biomarkers reported in human IPF. Building on this, our Merit Review renewal
will now leverage these Sftpc mutant mice to map distal lung cell populations in IPF while also identifying and
translating molecular mechanisms linking the disrupted cellular quality control, epithelial dysfunction, and
pathophysiology of IPF/ILDs. In 3 specific aims, our experimental approach will be to exploit the unique features
of these genetic models combined with tools and reagents available in our program designed to interogate cell
quality control and integrated stress responses to first define key alveolar niche cell populations emerging during
initiation, injury amplification, and fibrosis stages induced by SP-C mutations in vivo [Specific Aim 1]. Then
armed with this functional map we will couple Sftpc mice with reductionist models such as AT2 organoids to
define the role of endogenous endoplasmic reticulum (ER) stress in AT2 dysfunction and the aberrant
injury/repair pathways found in IPF [Specific Aim 2]. Fin...

## Key facts

- **NIH application ID:** 10771003
- **Project number:** 5I01BX001176-12
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** MICHAEL FRANCIS BEERS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-07-01 → 2029-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771003

## Citation

> US National Institutes of Health, RePORTER application 10771003, Surfactant Protein C Mutations and Interstitial Lung Disease (5I01BX001176-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10771003. Licensed CC0.

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