# Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets > **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $551,525 ## Abstract ABSTRACT Fibrotic lung remodeling represents the final common pathway to respiratory failure for a variety of Interstitial Lung Diseases (ILD) in children and adults. Based on a recent paradigm shift wherein the concepts of epithelial cell dysfunction and abnormal wound healing are postulated as “drivers” of pulmonary fibrosis, new opportunities are emerging for therapeutic discovery for ILD. Mutations in the Surfactant Protein C [SP-C] gene [SFTPC], an alveolar type 2 cell (AT2) restricted protein, have been found in sporadic and familial ILD and can provide important clues for understanding the role of epithelial cell dysfunction in ILD pathogenesis. Prior in vitro studies from our lab have shown that SFTPC mutations described in both adults and children with ILD result in production of aberrant SP-C proprotein isoforms that adopt non-native conformations resulting in at least 2 outcomes: ER stress and intracellular aggregation (BRICHOS) or mistrafficking to non-native organelles and inhibition of macroautophagy (Non-BRICHOS). This application proposes to leverage two novel knock-in mouse models of spontaneous lung fibrosis already in hand which express Non-BRICHOS or BRICHOS clinical SFTPC mutants in AT2 cells in an allelic and inducible fashion. Our Published and Preliminary Data reveal that expression of either a non-BRICHOS mutant (SP-CI73T) or BRICHOS mutant (SP- CC121G) is extremely toxic to the lung in vivo with each resulting in time-dependent spontaneous lung fibrosis marked by 3 phases: ii) early AT2 cytokine elaboration and monocyte recruitment,; (ii) a polycellular alveolitis and lung injury; (iii) physiologically restrictive peripheral fibrotic remodeling. These models also elaborate translationally relevant biomarkers reported in human ILD. In order to define both consensus and divergent molecular mechanisms linking these two AT2 cell phenotypes with the downstream lung injury and fibrotic lung remodeling, our experimental approach will be to exploit the unique features of these genetic models combined with tools, reagents, and expertise available in our program. In 3 specific aims, we propose to comprehensively characterize the transcriptomic and functional AT2 cell phenotypes evoked by expression of non-BRICHOS (SP-CI73T) and BRICHOS (SP-CC121G) Sftpc mutants [Specific Aim 1], to define the role of a key proinflammatory/profibrotic monocyte population recruited by AT2 mutant Sftpc expression in the development of fibrosis [Specific Aim 2], and to examine changes in epithelial-mesenchymal crosstalk that disrupt alveolar niche homeostasis and promote fibrotic remodeling [Specific Aim 3]. As epithelial dysfunction has not been studied extensively in vivo in the context of relevant preclinical models of fibrotic lung disease, this approach offers the unique opportunity to provide proof of concept both for the causal effect of mutant SFTPC in familial ILD and for the role of AT2 dysfunction as a key upstream driver of inflammatory ce... ## Key facts - **NIH application ID:** 10407546 - **Project number:** 5R01HL145408-04 - **Recipient organization:** UNIVERSITY OF PENNSYLVANIA - **Principal Investigator:** MICHAEL FRANCIS BEERS - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $551,525 - **Award type:** 5 - **Project period:** 2019-06-01 → 2024-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10407546 ## Citation > US National Institutes of Health, RePORTER application 10407546, Alveolar Epithelial Cell Dysfunction in Pulmonary Fibrosis: Leveraging SFTPC Mutations for Discovery of Molecular and Cellular Targets (5R01HL145408-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10407546. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*