Idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) is a devastating interstitial lung disease of unknown etiology, characterized by (myo)fibroblast activation/proliferation, extracellular matrix (ECM) deposition and progressive lung destruction. A central role for alveolar epithelium in IPF/UIP pathogenesis has recently been postulated. In this paradigm, injured alveolar epithelial cells (AEC) actively participate in fibrogenesis by releasing fibroproliferative mediators that promote proliferation an differentiation of fibroblasts that in turn induce AEC apoptosis and/or giving rise directly to fibroblasts through epithelial-mesenchymal transition (EMT). However, mechanisms underlying AEC injury/activation and downstream molecular pathways linking epithelial abnormalities to fibrosis remain unclear. Association between endoplasmic reticulum (ER) stress and both sporadic and familial pulmonary fibrosis associated with surfactant protein (SP) mutations has been reported. We recently found that ER stress triggers protective signaling known as the unfolded protein response (UPR) and induces both apoptosis and EMT in AEC in vitro via activation of the non-receptor membrane-associated tyrosine kinase Src, supporting a causal role for ER stress in the dysfunctional AEC phenotype in pulmonary fibrosis. Preliminary data suggest that reactive oxygen species (ROS) and -catenin activation/interaction with the co-activator CBP are involved in Src-dependent signaling. The ER chaperone glucose-regulated protein 78 (GRP78) is a master regulator of ER homeostasis and thus represents an ideal target with which to modulate ER stress responses in alveolar epithelium. The overall goals of this proposal are to investigate mechanisms underlying ER stress-induced epithelial abnormalities implicated in the pathogenesis of fibrosis by modulating GRP78 utilizing mice with lung epithelial cell-specific deletion of Grp78. We hypothesize that (1) loss of Grp78 induces and/or exacerbates experimental fibrosis in vivo; (2) GRP78 insufficiency-induced epithelial injury contributes to fibrosis via direct effects on the epithelium (e.g., apoptosis/EMT) and/or abnormal epithelial-fibroblast crosstalk; and, (3) effects of GRP78 insufficiency on EMT/fibrosis are mediated via Src and/or ROS-dependent -catenin/CBP signaling. We will use AEC-specific Grp78 knockout mice, in conjunction with clinically relevant mutant SP-C?exon4, our well- established primary AEC in vitro monolayer model, and ICG-001, a novel inhibitor of -catenin/CBP interaction, to address the following Specific Aims: 1. Evaluate effects of ER stress mediated by loss of Grp78 on pulmonary fibrosis in inducible AEC-specific Grp78 knockout mice; 2. Investigate the role of ER stress in AEC abnormalities (apoptosis vs EMT vs aberrant epithelial-fibroblast crosstalk) implicated in fibrosis in inducible AEC-specific Grp78 knockout mice; and 3. Determine mechanisms underlying ER stress-induced AEC injury/fibrosis. These studies will provide insights into mechanisms underlying the pathogenesis of IPF and facilitate identification of novel therapeutic targets for this incurable disease.

Public Health Relevance

It is becoming apparent that injury to cells lining the airspaces of the lung (called epithelial cells) is a major causative factor in formation of scar tissue (fibrsis) in the lung in a disease called idiopathic pulmonary fibrosis (IPF). Recently it has been shown that activation of a part of the cell known as the endoplasmic reticulum (ER) may injure epithelial cells by inducing a condition known as ER stress. Our overall objective is to understand how ER stress in epithelial cells leads to formation of scar-forming cells in order to understand its rolein fibrosis and elucidate new treatment strategies for this otherwise fatal disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Craig, Matt
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University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
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Zhou, Beiyun; Flodby, Per; Luo, Jiao et al. (2018) Claudin-18-mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis. J Clin Invest 128:970-984
Luo, Jiao; Chimge, Nyam-Osor; Zhou, Beiyun et al. (2018) CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro. Int J Cancer 143:3169-3180
Flodby, Per; Liebler, Janice M; Sunohara, Mitsuhiro et al. (2017) Region-specific role for Pten in maintenance of epithelial phenotype and integrity. Am J Physiol Lung Cell Mol Physiol 312:L131-L142
Flodby, Per; Li, Changgong; Liu, Yixin et al. (2017) Cell-specific expression of aquaporin-5 (Aqp5) in alveolar epithelium is directed by GATA6/Sp1 via histone acetylation. Sci Rep 7:3473
Marconett, Crystal N; Zhou, Beiyun; Sunohara, Mitsuhiro et al. (2017) Cross-Species Transcriptome Profiling Identifies New Alveolar Epithelial Type I Cell-Specific Genes. Am J Respir Cell Mol Biol 56:310-321
Zuber, Verena; Marconett, Crystal N; Shi, Jianxin et al. (2016) Pleiotropic Analysis of Lung Cancer and Blood Triglycerides. J Natl Cancer Inst 108:
Stueve, Theresa Ryan; Marconett, Crystal N; Zhou, Beiyun et al. (2016) The importance of detailed epigenomic profiling of different cell types within organs. Epigenomics 8:817-29
Liebler, Janice M; Marconett, Crystal N; Juul, Nicholas et al. (2016) Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung. Am J Physiol Lung Cell Mol Physiol 310:L114-20
Rieger, Megan E; Zhou, Beiyun; Solomon, Nicola et al. (2016) p300/?-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC). J Biol Chem 291:6569-82
Flodby, Per; Li, Changgong; Liu, Yixin et al. (2016) The 78-kD Glucose-Regulated Protein Regulates Endoplasmic Reticulum Homeostasis and Distal Epithelial Cell Survival during Lung Development. Am J Respir Cell Mol Biol 55:135-49

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