# Surfactant Protein C Mutations and Interstitial Lung Disease > **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2020 · — ## Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive scarring interstitial lung disease (ILD) that affects mainly older adults. Recently, a paradigm shift has occurred wherein the concepts of epithelial cell dysfunction and abnormal wound healing have been placed at center stage as mechanisms driving fibrotic lung remodeling offering new opportunities for therapeutic discovery for IPF. Surfactant protein C (SP-C), an alveolar type 2 (AT2) cell-specific hydrophobic protein that enhances the biophysical activity of surfactant phospholipid, has provided an important clue for understanding epithelial cell dysfunction in IPF pathogenesis as the heterozygous expression of over 50 mutations in the SFTPC gene in humans is associated with chronic ILD. During the current funding period we have shown that sequence alterations in the SP-C primary translation product (proSP-C) associated with clinical ILD phenotypes result in either of 2 distinct aberrant cellular expression patterns, each capable of triggering a series of aberrant cellular responses. ILD-associated, aggregation-prone SP- C isoforms resulting from mutations within the distal COOH domain of the SP-C proprotein (termed “BRICHOS”) produce vigorous induction of an unfolded protein response (UPR), ER stress, and apoptosis. We have also made the seminal observation that SFTPC mutations found in the more proximal proSP-C COOH linker domain (“Non-BRICHOS”) are mistrafficked to the plasma membrane with a secondary disruption of endosomal / lysosomal function. The induced cellular phenotype includes a late block in macroautophagy, impaired mitophagy, and alterations in general proteostasis repertoires. Building on this, the overall goal of this Merit Review renewal is to now use SFTPC mutants as substrates in vivo to identify and translate molecular mechanisms underlying the disrupted cellular quality control and epithelial dysfunction to the pathophysiology of IPF/ILDs. This proposal will leverage a novel mouse model also generated in the current cycle which expresses the disease-causing clinical non-BRICHOS SFTPC mutant, SP-CI73T, exclusively in AT2 cells. Our Preliminary Data reveals that SP-CI73T mice exhibit alterations in normal proSP-C biosynthetic routing, acquire disruptions in AT2 cell autophagy, and develop diffuse parenchymal lung remodeling. Our experimental approach will be to exploit the unique features of this genetic model combined with tools and reagents available in our program designed to interogate cell quality control and integrated stress responses to first define the ontogeny of and cellular mechanisms mediating the aberrant lung injury, repair, and remodeling responses induced by non-BRICHOS SP-C mutations in vivo [Specific Aim 1]. This will be combined with reductionist studies using primary AT2 cell culures isolated from SP-CI73T mice at key time points in the development of the lung phenotype to characterize the biosynthesis and specific AT2 cellular responses to mutant SP-C... ## Key facts - **NIH application ID:** 9814678 - **Project number:** 5I01BX001176-08 - **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER - **Principal Investigator:** MICHAEL FRANCIS BEERS - **Activity code:** I01 (R01, R21, SBIR, etc.) - **Funding institute:** VA - **Fiscal year:** 2020 - **Award amount:** — - **Award type:** 5 - **Project period:** 2012-07-01 → 2021-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9814678 ## Citation > US National Institutes of Health, RePORTER application 9814678, Surfactant Protein C Mutations and Interstitial Lung Disease (5I01BX001176-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9814678. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*