Role of the ER stress transcription factor XBP1S in the development of idiopathic pulmonary fibrosis

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Principal Investigator: Gang  Chen
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $408,889
Funding agency: National Heart Lung and Blood Institute

Idiopathic pulmonary fibrosis (IPF) is a progressive and end-stage lung disease of unknown etiology and
no cure. It is likely that genetic changes increase a person's risk of developing IPF, and then exposure to certain
environmental factors and/or aging trigger the onset of the disease. The MUC5B promoter variant rs35705950
is present in ∼50% of individuals with IPF and is recognized as the strongest known risk factor (genetic and
otherwise) for the development of IPF. This variant leads to overexpression of MUC5B mRNA and protein in
both distal airway epithelia and honeycomb cysts in the peripheral lung. These observations raise the question
of why excessive MUC5B expression in distal airways is associated with IPF? Recently, our laboratory identified
for the first time that the ER stress transcription factor XBP1S is highly expressed in the epithelium lining the
distal airways and honeycomb cysts of IPF lung, activates MUC5B gene expression by direct binding to its
promoter. Further, XBP1S differentially regulating the MUC5B promoter variant. These data connected activation
of ER stress with excessive MUC5B expression in a promoter variant-dependent model likely impairs mucociliary
clearance and function of distal airway stem cells that increase susceptibility of development of pulmonary
fibrosis. We hypothesize that activation of XBP1S induces MUC5B expression in the distal airways that
promotes pulmonary fibrosis. To test this central hypothesis, we propose the following aims: 1) XBP1S-
mediated MUC5B secretion in distal airway epithelium enhances susceptibility to development of
pulmonary fibrosis in vivo. We will assess the role of XBP1S by exposing Xbp1 airway epithelium-specific
overexpression or deletion mice to bleomycin induced respiratory epithelial injury. 2) XBP1S-mediated MUC5B
secretion impairs distal airway stem cell function to repair peripheral lung epithelia after injury. We will
utilize mouse airway epithelium-lineage tracing system and in vitro 2-D and 3-D differentiation assays to evaluate
the role of XBP1S and mucin in maintenance of the airway stem cell homeostasis in response to injury. 3)
Activation of XBP1S and presence of MUC5B promoter variant cause abnormal mucus secretion,
impaired mucociliary clearance and activation of myofibroblast differentiation. We will analyze the
biochemical and biophysical properties of the secreted mucus and electrophysiology of the DAE carrying the
MUC5B promoter variant rs35705950 at baseline and after activation of ER stress. We will also test whether
XBP1S-expressing DAE carrying the MUC5B promoter variant and/or hypoxia-induced epithelial injury directly
promotes myofibroblast differentiation. Completing the aims proposed in this application will provide novel
mechanisms underlying ER stress-mediated excessive mucin secretion by DAE promotes pulmonary fibrosis.
These mechanistic studies will likely identify novel biomarkers for early diagnosis as well as therapeutic targets
(e.g., suppression of XBP1S activation as a promising approach to resolve MUC5B hypersecretion, even for
those carrying the MUC5B promoter variant) in the distal lung to prevent or reverse fibrotic disease progression.

Terms: <3-D><3-Dimensional><3D><Affect><Aging><Alleles><Allelomorphs><Alveolus><Apoptosis><Apoptosis Pathway><Assay><Autoprothrombin III><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Proteins><Bioassay><Biochemical><Biological Assay><Bleo><Bleomycin><Blood Coagulation Factor X><Bronchial Alveolus><Causality><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Stress><Cellular Stress Response><Coagulation Factor X><Cyst><Data><Defect><Development><Disease Progression><Distal><Dysfunction><ER stress><Early Diagnosis><Electrophysiology><Electrophysiology (science)><Environmental Factor><Environmental Risk Factor><Epithelial Cells><Epithelium><Etiology><Exposure to><Factor X><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Functional disorder><Gene Expression><Gene variant><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genotype><Grippe><H1N1><H1N1 Virus><Host Defense><Hypoxia><Hypoxic><Impairment><In Vitro><Individual><Infection><Inflammation><Influenza><Influenza A Virus, H1N1 Subtype><Injury><Intracellular Communication and Signaling><Laboratories><Lead><Ligand Binding Protein><Ligand Binding Protein Gene><Lung><Lung Alveolar Epithelia><Lung Diseases><Lung Respiratory System><Lung Tissue Fibrosis><MG1><MUC5B><MUC5B gene><Maintenance><Mediating><Messenger RNA><Mice><Mice Mammals><Minor><Modeling><Molecular Interaction><Mucins><Mucociliary Clearance><Mucociliary Transport><Mucous body substance><Mucus><Mucus Glycoprotein><Murine><Mus><Mutation><Myofibroblast><Natural regeneration><Neurophysiology / Electrophysiology><Onset of illness><Oxygen Deficiency><Pb element><Peripheral><Persons><Phenotype><Physiopathology><Predisposition><Probability><Production><Progenitor Cells><Programmed Cell Death><Protein Binding><Proteins><Prower factor><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><RNA Splicing><Regeneration><Respiratory Epithelium><Risk><Risk Factors><Role><Signal Transduction><Signal Transduction Systems><Signaling><Splicing><Structure of respiratory epithelium><Stuart Factor><Stuart-Prower Factor><Subcellular Process><Susceptibility><System><Telomerase><Testing><Time><Transcription Factor Proto-Oncogene><Transcription factor genes><Type II Pneumocyte><Variant><Variation><XBP1><XBP1 gene><airway epithelium><airway remodeling><allele variant><allelic variant><alveolar epithelium><alveolar type II cell><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><bound protein><causation><cell stress><developmental><diffuse interstitial pulmonary fibrosis><disease causation><disease of the lung><disease onset><disorder of the lung><disorder onset><early detection><effective therapy><effective treatment><electrophysiological><endoplasmic reticulum stress><environmental risk><epithelial injury><fibrosis in the lung><genetic variant><genome mutation><genomic variant><heavy metal Pb><heavy metal lead><human model><idiopathic pulmonary fibrosis><in vitro Assay><in vivo><injuries><injury and repair><injury response><lung disorder><lung fibrosis><lung repair><lung tissue repair><mRNA><model of human><mouse genetics><mouse model><mucous><murine model><new marker><notch><notch protein><notch receptors><novel><novel biomarker><novel marker><overexpress><overexpression><pathophysiology><prevent><preventing><progenitor><progenitor cell function><progenitor cell homeostasis><progenitor function><promoter><promotor><pulmonary><pulmonary repair><regenerate><repair><repaired><respiratory tract epithelium><response><response to injury><social role><stem and progenitor cell function><stem and progenitor function><stem cell function><stem cell homeostasis><stem cells><surfactant><therapeutic target><three dimensional><transcription factor>