Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Spatial transcriptome profiling identifies CREB1 as a regulator of core transcriptional programs in idiopathic pulmonary fibrosis

ABSTRACT: A defining feature of idiopathic pulmonary fibrosis is the regional heterogeneity of the lung pathology. Here we established methodology to study the transcriptome of spatially discrete morphological areas in IPF lung tissue through the integration of laser capture microdissection of formalin fixed paraffin embedded lung tissue with low input RNA-Seq. We applied this methodology to obtain an in situ transcriptome for fibroblast foci and alveolar septae from IPF tissue as well as alveolar septae from age sex-matched control lung tissue. Differential gene expression analysis was performed between IPF alveolar septae vs control alveolar septae and between IPF fibroblast foci vs alveolar epithelium. Metacore TM was used for gene enrichment analysis of significantly differentially expressed genes, for transcription factor (TF) network analysis to identify predicted TF from human TF-target gene interaction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169500 | GEO | 2022/03/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Bi-directional epithelial-mesenchymal crosstalk provides self-sustaining pro-fibrotic signals in pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2-4 years. Injury to and/or dysfunction of alveolar epithelium are strongly implicated in IPF disease initiation, but what factors determine why fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that ZEB1-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments TGF-β-induced profibrogenic responses in underlying lung fibroblasts by paracrine signalling. Here we investigated bi-directional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA sequencing (RNA-seq) of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced EMT identified many differentially expressed genes including those involved in cell migration and extracellular matrix (ECM) regulation. We confirmed that paracrine signalling between AS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a ZEB1-tissue plasminogen activator (tPA) axis. In a reciprocal fashion, paracrine signalling from TGF-β-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially via the secreted protein, SPARC. Together these data identify that aberrant bi-directional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining pro-fibrotic signals.

2021-08-19 | PXD025821 | Pride

DIA proteomics of OGG1 inhibition in murine model of fibrosis

Project description:Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation, with both increased in fibrotic murine and IPF patient lung tissue. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF. This DIA-MS dataset entails the raw data and peptide-centric DIA-NN search results of both, lung tissue and bronchoalveolar lavage fluid of n=5 mice profiled across the treatment groups bleomycin combined with TH (BTH), dexamethasone (DEX), TH alone (TH) and vehicle control (V) relative to bleomycin alone (B) as control. Different animals within protein groups were considered biological replicates of the respective treatment condition.

2023-02-06 | PXD029625 | Pride

Alteration in the transcriptome of lung resident fibroblast isolated from fibrotic lungs of IPF upon genetic knockdown of SOX9

Project description:Pulmonary fibrosis (PF) is associated with many chronic lung diseases including Systemic sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF) and Cystic Fibrosis (CF) which are characterized by the progressive accumulation of mesenchymal cells and formation of scar tissue. Pulmonary fibrosis is a dysregulated response to alveolar injury which causes a progressive decline in lung function and refractory to current pharmacological therapies. Airway and alveolar epithelial cells and mesenchymal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Our new findings have identified the aberrant activation of Sox9 in lung resident fibroblasts and myofibroblasts in IPF lung biopsies and the mouse model of transforming growth factor-α (TGFα) and bleomycin-induced pulmonary fibrosis. In this study, we sought to determine Sox9-driven gene networks in lung resident fibroblast during pulmonary fibrosis. Our results showed that Sox9 regulates the transcriptional changes that are required for the fibroblast activation including migration, myofibroblast transformation, survival and extracellular matrix deposition during pulmonary fibrosis. In summary, this new study demonstrates that Sox9 is a critical regulator of fibroblast activation in IPF and hence serve as a target for therapeutic intervention.

2021-12-31 | GSE171532 | GEO

Alteration in the transcriptome of lung resident fibroblast upon genetic knockdown of Wilms' tumor1 transcription factor

Project description:Pulmonary fibrosis (PF) is associated with many chronic lung diseases including Systemic sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF) and Cystic Fibrosis (CF) which are characterized by the progressive accumulation of stromal cells and formation of scar tissue. Pulmonary fibrosis is a dysregulated response to alveolar injury which causes a progressive decline in lung function and refractory to current pharmacological therapies. Airway and alveolar epithelial cells and stromal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Recent published reports from our lab demonstrated the aberrant activation of Wilms' tumor1 (WT1) transcription factor in lung resident fibroblast and myofibroblast in IPF lung biopsies and the mouse model of transforming growth factor-α (TGFα) and bleomycin induced fibrosis. In this study, we sought to determine the role of WT1 in transcriptome changes in lung resident fibroblast during pulmonary fibrosis. Our results showed that WT1 regulates the transcriptional changes that are required for the fibroblast activation processes such fibroproliferation, myofibroblast transformation and extracellular matrix deposition during pulmonary fibrosis. Finally, this study demonstrates that WT1 is a critical regulator of fibroblast activation in IPF and hence serve as a target for therapeutic intervention.

2018-08-01 | GSE110177 | GEO

Gene expression signatures for Normal-looking, fibrotic foci and hyperplastic (adjacent to fibrotic foci) area in IPF lungs

Project description:To further understand the pathologic microenvironment in IPF, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish normal and IPF lung in normal-looking, fibrotic foci and hyperplastic areas of IPF lung. Four IPF lungs were dissected into normal-looking, fibrotic foci and hyperplastic areas by Laser-Capture-Microdissection. Gene expression analysis showed that 638 significantly different genes were identified that clearly distinguished the different IPF microenvironments . Among them, MMP19 was revealed as one of the most significantly up-regulated genes that distinguished normal looking epithelial cells (N) to hyperplastic epithelial cells, MMP19 up-regulation in IPF lungs was verified by immunohistochemical (IHC), qRT-PCR and Western-blot. IPF lungs are heterogeneity complex, which comprise normal looking area, fibrotic foci and hyperplastic area. In this study we separated the normal, fibrotic foci and hyperplastic area by LCM and employed Agilent whole genome gene expression microarray profiling to identify genes with the potential to distinguish the unique microenironment of IPF

2013-01-11 | E-GEOD-35309 | biostudies-arrayexpress

microRNA expression profiles in Idiopathic Pulmonary Fibrosis (IPF)

Project description:Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease characterized by enhanced fibroblast proliferation, collagen synthesis, extracellular matrix deposition. We obtained 28 IPF patient lung tissue samples from the Lung Tissue Research Consortium (LTRC). Here we determined the miRNA expression profiles in these IPF lung samples.

2019-04-02 | GSE129126 | GEO

LKB1 inhibition in alveolar epithelial cells induces fibroblast activation in pulmonary fibrosis [RNA-seq in 2D-cultured ATII]

Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and lethal lung disease. The initiation of IPF involves microinjuries to and/or dysfunction of the alveolar epithelium, but factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signalling. Here, we report that liver kinase B1 (LKB1) inactivation in ATII cells induces autophagy inhibition and EMT as a consequence. In IPF lungs, this is caused by a downregulation of CAB39L, a key subunit within the LKB1 complex. 3D co-cultures of ATII cells and lung fibroblast MRC5 coupled with RNA sequencing (RNA-seq) confirmed that paracrine signalling between LKB1-depleted ATII cells and fibroblasts augmented myofibroblast differentiation. Together these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATII cells and contribute to fibrosis via aberrant epithelial–fibroblast crosstalk.

2023-08-09 | GSE205969 | GEO

LKB1 inhibition in alveolar epithelial cells induces fibroblast activation in pulmonary fibrosis [RNA-seq in 3D co-cultured ATII+MRC5]

2023-08-09 | GSE205965 | GEO

Alteration in the transcriptome of lung resident fibroblast isolated from fibrotic lungs of TGFalpha mice upon genetic knockdown of Aurora Kinase B

Project description:Pulmonary fibrosis (PF) is associated with many chronic lung diseases including Systemic sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF) and Cystic Fibrosis (CF) which are characterized by the progressive accumulation of mesenchymal cells and formation of scar tissue. Pulmonary fibrosis is a dysregulated response to alveolar injury which causes a progressive decline in lung function and refractory to current pharmacological therapies. Airway and alveolar epithelial cells and mesenchymal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Our new findings have identified the abberent activation of Aurora Kinase B (AURKB) in lung resident fibroblast and myofibroblast in IPF lung biopsies and the mouse model of transforming growth factor-α (TGFα) and bleomycin induced fibrosis. In this study, we sought to determine the role of AURKB in transcriptome changes in lung resident fibroblast during pulmonary fibrosis. Our results showed that AURKB regulates the transcriptional changes that are required for the fibroblast activation processes such fibroproliferation, myofibroblast survival and extracellular matrix deposition during pulmonary fibrosis. Finally, this study demonstrates that AURKB is a critcal regulator of fibroblast activation in IPF and hence serve as a target for therapeutic intervention. Grantee: Satish K Madala Grantor: US Department of Defense funds Grant ID: W81XWH-17-1-0666 Grant Title: Therapeutic Benefit of Hsp90 Inhibition in Pulmonary Fibrosis

2020-07-08 | GSE153898 | GEO

microRNA expression in fibroblastic foci within idiopathic pulmonary fibrosis lungs reveals novel disease relevant pathways.

Project description:MicroRNAs (miRs) are a class of non-coding RNAs of ~22nt long that play an important role in regulating gene expression at a post-transcriptional level. Aberrant levels of miRs have been associated with profibrotic processes in idiopathic pulmonary fibrosis (IPF). However, the majority of these studies used whole IPF tissue or in vitro monocultures in which fibrosis has been artificially induced. In this study, we used laser microdissection to collect fibroblastic foci (FF), the key pathological lesion in IPF, then isolate miRs and compare their expression levels to those found in whole IPF lung tissue and/or in vitro cultured fibroblast from IPF or normal lungs. Methods – LCM was utilised on formalin embedded IPF tissue to isolate multiple FF and isolate miRs. Libraries were generated and sequenced; data were bioinformatically analysed and Ingenuity Pathway Analysis (IPA) used for integration. Results - Our analysis revealed a total of 49 miRs differentially expressed in FF, of which only 7 were also differentially expressed in in vitro cultured fibroblast. This approach uncovered novel miRs that could be related to IPF. Conclusion - miR expression analyses in LCM isolated FF were able to identify up to 40 miRs not previously described in IPF. Differential expression of these miRs could potentially contribute to IPF development and progression.

2023-01-09 | GSE220107 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data