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

University Of Pennsylvania, Philadelphia PA

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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. Key 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 in vivo 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 lung phenotype with recapitulation of many consensus IPF defining elements. Further, we also published that SftpcC121G mice develop marked activation of the AT2 UPR with emergence of a reprogrammed transition state. Our Preliminary Data will show that mutant Sftpc expression in mice can also cause AT2 glycolytic reprogramming and altered mitochondrial dynamics (biogenesis, fission, and respiration) along with emergence of the aberrant alveolar epithelial cell transition state. Thus, this renewal application now seeks to mechanistically understand how altered UPR signaling and metabolism each contribute to AT2 reprogramming and promotion of a fibrotic niche. Leveraging our two 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 IRE1 and ATF6 to define its impact on AT2 proteostasis, cell states, and progenitor function [Specific Aim 1]. Then using SftpcI73T mice we will assess 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]. When completed deliverables produced from these studies will enhance our understanding of the role of two understudied pathways on IPF pathogenesis and provide equipoise and experimental platforms to catalyze discovery and testing of new IPF therapies.