# Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $666,067

## Abstract

ABSTRACT
Idiopathic Pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) characterized by disruption of
distal lung architecture that results in scar formation, abnormal gas exchange, and respiratory failure. Barriers
to better IPF outcomes have included an incomplete understanding of its pathophysiologic underpinnings and
a dearth of translationally relevant preclinical models. However, identification of rare genetic variants in the
alveolar epithelial type 2 (AT2) cell-restricted Surfactant Protein C (SP-C) gene (SFTPC) in subsets of PF
patients has been part of a paradigm shift in which dysfunctional AT2 cells serve as a proximal driver of IPF.
Coupled with the recent identification of a population of “reprogrammed” AT2 cells in human IPF lungs deficient
in classic AT2 transcriptional programs and enriched in profibrotic mediators, new opportunities are emerging
for therapeutic discovery for IPF. Our prior in vitro modeling demonstrated that IPF-associated SFTPC
mutations produce aberrant SP-C proprotein isoforms that functionally disrupt epithelial cell quality control
(QC) yielding 2 phenotypes: “ER stressed” from misfolding (“BRICHOS”) mutant with activation of all 3
signaling arms (ATF6, IRE1, PERK) of the unfolded protein response (UPR) or impaired autophagy /
mitophagy secondary to proSP-C mistrafficking (“Non-BRICHOS”) mutants. The prior funding period provided
proof of concept for a seminal role for disrupted AT2 QC showing that expression of either non-BRICHOS
(SftpcI73T) or BRICHOS (SftpcC121G) mutants in mouse lung epithelia are each sufficient to evoke a spontaneous
fibrotic phenotype with recapitulation of IPF defining elements. We also showed that SftpcC121G mice develop
marked activation of AT2 UPR with emergence of a reprogrammed transition state. Our Preliminary Data show
that mutant SftpcI73T expression in vivo causes AT2 glycolytic reprogramming, altered mitochondrial dynamics
(biogenesis, fission, and respiration) and emergence of the aberrant AT2 transition state. Thus, this renewal
application now seeks to mechanistically understand how imbalanced UPR signaling and metabolism each
contribute to AT2 reprogramming and promotion of a fibrotic niche. Leveraging our Sftpc mouse PF models,
we will first use mutant SftpcC121G as a model substrate for disruption of proteostasis while genetically and
pharmacologically interrogating UPR signaling focusing on IRE1α and ATF6 to define their impact on AT2
proteostasis, cell states, and progenitor function [Specific Aim 1]. Then using SftpcI73T mice we will define
downstream consequences of disrupted AT2 organellar QC for metabolic reprogramming and mitochondrial
dynamics with contextualization of their impact on pathological AT2 endophenotypes and fibrotic remodeling
[Specific Aim 2]. Proof of concept studies for each Aim using patient derived human induced Pluripotent Stem
Cell AT2 (iPSC-AT2) expressing these mutants will provide translation of preclinical data t...

## Key facts

- **NIH application ID:** 10979693
- **Project number:** 2R01HL145408-05A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MICHAEL FRANCIS BEERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $666,067
- **Award type:** 2
- **Project period:** 2019-07-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979693

## Citation

> US National Institutes of Health, RePORTER application 10979693, Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets (2R01HL145408-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10979693. Licensed CC0.

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