ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a progressive scarring interstitial lung disease (ILD) that affects mainly older adults for which there remains a significant unmet therapeutic need. While the pathophysiologic underpinnings of IPF remain incompletely understood, an additional critical 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. Over 60 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 veterans with IPF, this proposal builds upon on a strong foundation of our prior work funded by this Merit Review program 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 cell stress phenotypes: ER stress induced by intracellular SP-C misfolding (“BRICHOS”) or impaired autophagy/mitophagy secondary to 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. Building on this, our Merit Review renewal will now leverage these Sftpc mutant mice to map distal lung cell populations in IPF while also identifying and translating molecular mechanisms linking the disrupted cellular quality control, epithelial dysfunction, and pathophysiology of IPF/ILDs. In 3 specific aims, our experimental approach will be to exploit the unique features of these genetic models combined with tools and reagents available in our program designed to interogate cell quality control and integrated stress responses to first define key alveolar niche cell populations emerging during initiation, injury amplification, and fibrosis stages induced by SP-C mutations in vivo [Specific Aim 1]. Then armed with this functional map we will couple Sftpc mice with reductionist models such as AT2 organoids to define the role of endogenous endoplasmic reticulum (ER) stress in AT2 dysfunction and the aberrant injury/repair pathways found in IPF [Specific Aim 2]. Fin...