Document text
Principal Investigator: Darrell N. Kotton
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $638,086
Funding agency: National Heart Lung and Blood Institute
Project Summary/Abstract
Idiopathic pulmonary fibrosis (IPF) remains a deadly interstitial lung disease (ILD) with treatment
options limited by an incomplete understanding of the mechanisms that initiate and perpetuate
disease. A growing literature now implicates lung epithelial dysfunction as playing a role in the events
that lead to downstream fibroblast activation, culminating in relentless fibrosis. These studies,
together with the observation that lung epithelial cells in all forms of IPF display shortened telomeres,
suggests that lung epithelial dysfunction may initiate IPF, and accelerated aging phenotypes or
telomerase pathway abnormalities likely contribute to this pathogenesis. However, without access to
patient-specific human epithelial-mesenchymal model systems, there are limited options for testing
hypotheses of how epithelial changes induced by gene polymorphisms or telomerase perturbations
might mechanistically contribute to IPF. Here we propose to develop a human organoid-based in vitro
model system for the study of IPF. We have established a biorepository of induced pluripotent stem
cells (iPSCs) generated from individuals with sporadic or familial pulmonary fibrosis. In aim 1 we
apply this repository by directing the in vitro differentiation of banked IPF iPSCs carrying telomerase
mutations (vs normal iPSCs) into various airway and alveolar lung epithelial cells for the purpose of
generating a reductionist, epithelial-only 3D culture model of the intrinsic epithelial dysfunction that
we posit may initiate pulmonary fibrosis. In aim 2 we augment the complexity of this model by
introducing human organoids composed of iPSC-derived lung epithelia juxtaposed with human
mesenchymal lineages in order to model the epithelial-mesenchymal interactions hypothesized to
perpetuate IPF. Finally, in aim 3 we test the hypothesis that different telomerase pathway mutations
result in shared lung epithelial perturbations, including short telomeres and p53 activation, that then
leads to downstream mesenchymal activation.
Terms: <3D cell culture><3D culture><ABC3><ABCA3><ABCA3 gene><ATP Binding Cassette A3><ATP binding cassette A member-3><Antioncogene Protein p53><Assay><Basal Cell><Bioassay><Biologic Models><Biological Assay><Biological Models><Body Tissues><Cell Body><Cells><Cellular Tumor Antigen P53><Collaborations><DNA Recombination><Data><Development><Differentiation in cell culture><Disease><Disorder><Drug Therapy><Dysfunction><Engineering><Epithelial Cells><Epithelium><Event><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Functional disorder><GWA study><GWAS><Gene variant><Genes><Genetic Alteration><Genetic Change><Genetic Polymorphism><Genetic Recombination><Genetic defect><Goals><Human><Hybrid Cells><In Vitro><In vitro cell differentiation><Individual><Interstitial Lung Diseases><Interstitial Lung Inflammation><Interstitial Pneumonia><Interstitial Pneumonitis><Interstitial Pulmonary Inflammation><Literature><Lung><Lung Alveolar Epithelia><Lung Respiratory System><Lung Tissue Fibrosis><MG1><MUC5B><MUC5B gene><Mesenchymal><Mesenchymas><Mesenchyme><Model System><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mutation><Myofibroblast><Oncoprotein p53><Organoids><P53><Pathogenesis><Pathway interactions><Patients><Pharmacotherapy><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Physiopathology><Protein TP53><Publishing><Pulmonary Fibrosis><Recombinants><Recombination><Reporter><Sampling><Secretory Cell><Somatic Cell Hybrids><Source><System><TP53><TP53 gene><TRP53><Telomerase><Telomere Shortening><Testing><Tissues><Tumor Protein p53><Tumor Protein p53 Gene><accelerated aging><accelerated biological age><accelerated biological aging><age acceleration><allele variant><allelic variant><alveolar epithelium><biobank><biorepository><cell repository><cellular repository><depository><developmental><differentiation in culture><differentiation in vitro><diffuse interstitial pulmonary fibrosis><disease risk><disorder risk><drug treatment><fibrogenesis><fibrosis in the lung><genetic variant><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><hiPSC><high-throughput drug screening><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPSC><iPSCs><idiopathic pulmonary fibrosis><in vitro Model><in vitro cellular differentiation><in vivo><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><knock-down><knockdown><lung basal segment><lung base><lung fibrosis><mitochondrial dysfunction><mortality><mutant><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><open source><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathophysiology><pathway><polymorphism><protein p53><pulmonary><repository><response><scRNA-seq><scale up><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><telomere><telomere attrition><three dimensional cell culture><whole genome association analysis><whole genome association studies><whole genome association study>