# Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $616,340

## Abstract

ABSTRACT
Idiopathic Pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) of older adults characterized
by disruption of distal lung architecture that ultimately leads to scar formation, abnormal gas exchange, and
respiratory failure. A key 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. 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 IPF patients, this proposal builds upon on a strong foundation of our prior work 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 phenotypes: ER stress
induced by intracellular SP-C misfolding (BRICHOS) or autophagy/mitophagy impaired from 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. This proposal will leverage these unique
models for Discovery, Target ID/ Validation, and Proof of Concept studies aimed at mapping cell
subpopulations and uncovering novel pathways driving lung fibrosis whilst providing a compelling translational
platform to interface with other preclinical/translational platforms in this U01 consortium to accelerate IPF
therapeutic development. In 3 specific aims, we propose to utilize Sftpc mutant mice to map cell populations,
transcriptomic profiles, and cell-cell crosstalk repertoires arising during evolution of spontaneous fibrotic lung
phenotypes [Specific Aim 1], identify novel disease relevant biomarker candidates elaborated during the
aberrant injury-repair process [Specific Aim 2], and assess the important contributions of and mechanisms by
which aging and sex impact IPF phenotypes [Specific Aim 3]. Importantly, many of the endpoints defined in
Sftpc models will be cross-validated and contextualized using lung tissue and serum from a well-phenotyped
human IPF biorepository. When completed, the impactful deliverables produced from th...

## Key facts

- **NIH application ID:** 10025851
- **Project number:** 1U01HL152970-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MICHAEL FRANCIS BEERS
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $616,340
- **Award type:** 1
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025851

## Citation

> US National Institutes of Health, RePORTER application 10025851, Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis (1U01HL152970-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10025851. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*