Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA382884 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5448330_1.fastq.gz | Fastqsanger.gz | |||
| SRR5448330_2.fastq.gz | Fastqsanger.gz | |||
| SRR5448331_1.fastq.gz | Fastqsanger.gz | |||
| SRR5448331_2.fastq.gz | Fastqsanger.gz | |||
| SRR5448332_1.fastq.gz | Fastqsanger.gz |
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Project description:Insufficient activation of the TGF-b signaling pathway leads to abnormalities in embryonic lung development. Herein, we determined the effect of the epithelial over-activation of the TGF-b signaling pathway in the embryonic lung development by expressing the constitutive active form of the Tgf-b receptor 1. Ectopic activation of the TGF-b signaling pathway in the lung embryonic epithelium resulted in a complex and lethal phenotype in male mice, but not in female mice. Mutant male embryos died at birth due to their inability to breathe, and showed a bronchial-pulmonary-dysplasia-like phenotype which included reduced lung size, increased alveolar wall thickness, increased cellular density of the lung parenchyma and diminished population of club cells. While the NOTCH signaling, pathway was not affected, we found that protein expression of the endodermal stem cell marker Ssea1 was strongly reduced in proximal lung airways of male lungs. In the distal lung epithelium, ectopic activation of the TGF-b signaling pathway resulted in the increased number of Sox9+ alveolar progenitor cells. Moreover, deletion of one Sox9 allele reduced the severity of the phenotype in mutant males, suggesting that TGF-b mediated over-expression of Sox9 protein is critical for the development of the bronchial pulmonary dysplasia-like phenotype displayed by the mutant male animals. Gene expression profiling identified 993 differentially expressed genes in the mutant male lungs compared to the control male lung. Several of these genes, such as Cbr2 and Hp, are expressed by the club cell and were downregulated by the TGF-b signaling pathway in the mutant male lung. Others such as Spock2, Adamtsl2 and Adamts18 were previous found to be linked to fetal lung disease and indispensable for proper lung development. Finally, we showed that injection of b-estradiol in the pregnant female rescued the phenotype in the mutant male embryos which suggests a critical role of the sex hormones in the pathogenesis of the bronchial pulmonary dysplasia disease. In conclusion, we have established a novel sex-specific mouse model that may be helpful in elucidating specific pathways by which sex adversely affects the well-known but obscure more adverse outcome of male patients.
2019-04-11 | GSE97789 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis with poor prognosis. An aberrant recapitulation of lung developmental genes including transforming growth factor (TGF)-β and WNT has been widely implicated in the abnormal wound healing process following repetitive alveolar epithelial injury during IPF pathogenesis. Extracellular vesicles (EVs) including exosomes and microvesicles have been shown to carry various bioactive molecules and are involved in a variety of physiological and pathological processes. Here, we demonstrate that human bronchial epithelial cell-derived EVs (HBEC EVs) inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling. To ask how HBEC-EVs inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling, miRNA RNA-seq of HBEC-EVs was performed.
2021-08-18 | GSE156572 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis with poor prognosis. An aberrant recapitulation of lung developmental genes including transforming growth factor (TGF)-β and WNT has been widely implicated in the abnormal wound healing process following repetitive alveolar epithelial injury during IPF pathogenesis. Extracellular vesicles (EVs) including exosomes and microvesicles have been shown to carry various bioactive molecules and are involved in a variety of physiological and pathological processes. Here, we demonstrate that human bronchial epithelial cell-derived EVs (HBEC EVs) inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling. To ask how HBEC-EVs inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling, miRNA RNA-seq of HBEC-EVs was performed.
2021-08-18 | GSE158623 | GEO
Project description:Microarray analysis to examine glycan-related gene expression in idiopathic pulmonary fibrosis Heparan sulfate 6-O-endosulfatases (Sulf1 and Sulf2) remove 6-O sulfate groups from heparan sulfate intra-chain sites on the cell surface and in the extracellular matrix, and modulate the functions of many growth factors and morphogens including FGF, Wnt and TGF-beta. Works from our laboratory have shown that TGF-beta 1 induces Sulf1 and Sulf2 expression in a cell-type specific manner in the lung, specifically Sulf1 in lung fibroblasts and Sulf2 in type II alveolar epithelial cells. Interestingly TGF-beta 1-induced Sulf1 and Sulf2 in turn modulate TGF-beta 1 function in culture. The aim of this study is to examine the expression of Sulf1 and Sulf2 as well as other glycan-related genes (heparan biosynthetic enzymes, TGF-beta, FGF and Wnt signaling pathway components) in human idiopathic pulmonary fibrosis (IPF) lungs compared to normal lung samples. We will examine gene expression in triplicate samples from RNA of total lung homogenates from IPF and control (normal) lungs
2011-09-05 | E-GEOD-31934 | biostudies-arrayexpress
Project description:Transcriptome analysis to investigate the oncogenic TGF-β-Smad-Snail signaling pathway
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Project description:The hallmark of chronic thromboembolic pulmonary hypertension (CTEPH) is fibrotic transformation of pulmonary arterial thrombus, leading to mechanical obstruction of pulmonary arteries. We report the transcriptome profile of fibroblasts isolated from pairs of CTEPH thrombus and pulmonary artery adventitia of the same patient. Fibroblasts isolated from CTEPH thrombus demonstrated upregulation of genes associated with the TGF-β pathway indicating that TGF-β upregulation is associated with the intravascular remodeling process.
2020-12-31 | GSE149413 | GEO
Project description:Smad2 and Smad3 (Smad2/3) primarily mediates the transforming growth factor-β (TGF-β) signaling that drives cell proliferation, differentiation, and migration. The dynamics of the Smad2/3 phosphorylation provides the key mechanism for regulating the TGF-β signaling pathway. Here we identified NLK as a novel regulator of TGF-β signaling pathway via modulating the phosphorylation of Smad2/3 in the linker region.
2021-09-10 | PXD023957 | Pride
Project description:Pedro Vizán, Daniel S. J. Miller, Ilaria Gori, Debipriya Das, Bernhard Schmierer & Caroline S. Hill. Controlling long-term signaling: receptor dynamics determine attenuation and refractory behavior of the TGF-β pathway. Science Signaling 6, 305 (2013).
Understanding the complex dynamics of growth factor signaling requires both mechanistic and kinetic information. Although signaling dynamics have been studied for pathways downstream of receptor tyrosine kinases and G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors, they have not been investigated for the transforming growth factor-β (TGF-β) superfamily pathways. Using an integrative experimental and mathematical modeling approach, we dissected the dynamic behavior of the TGF-β to Smad pathway, which is mediated by type I and type II receptor serine/threonine kinases, in response to acute, chronic, and repeated ligand stimulations. TGF-β exposure produced a transient response that attenuated over time, resulting in desensitized cells that were refractory to further acute stimulation. This loss of signaling competence depended on ligand binding, but not on receptor activity, and was restored only after the ligand had been depleted. Furthermore, TGF-β binding triggered the rapid depletion of signaling-competent receptors from the cell surface, with the type I and type II receptors exhibiting different degradation and trafficking kinetics. A computational model of TGF-β signal transduction from the membrane to the nucleus that incorporates our experimental findings predicts that autocrine signaling, such as that associated with tumorigenesis, severely compromises the TGF-β response, which we confirmed experimentally. Thus, we have shown that the long-term signaling behavior of the TGF-β pathway is determined by receptor dynamics, does not require TGF-β-induced gene expression, and influences context-dependent responses in vivo.
2024-09-02 | BIOMD0000000499 | BioModels
Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while gene expression was profiled in the adjacent sample from the same region using the Affymetrix Human Exon 1.0 ST GeneChip. Human fibroblast cell lines (HLF-1) were treated with GHK or TGF-Beta1 for 48 hours and profiled using the Affymetrix Human Gene 1.0 ST GeneChip.
2012-09-11 | E-GEOD-27597 | biostudies-arrayexpress
Project description:RATIONALE: Given the paucity of effective treatments for Idiopathic Pulmonary Fibrosis (IPF), new insights into the deleterious mechanisms controlling lung fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. Transforming growth factor β (TGF-β) is the main pro-fibrotic factor, but its inhibition is associated with severe side effects due to its pleiotropic role. OBJECTIVES: We hypothesized that downstream non-coding effectors of TGF-β in fibroblasts may represent new effective therapeutic targets whose modulation may be well-tolerated. METHODS: We investigated the whole non-coding fraction of TGF-β-stimulated lung fibroblast transcriptome to identify new genomic determinants of lung fibroblast differentiation into myofibroblast. Differential expression of the long non-coding RNA DNM3OS and its associated miRNAs was validated in a murine model of pulmonary fibrosis and in IPF tissue samples. Distinct and complementary antisense oligonucleotide-based strategies aiming at interfering with DNM3OS were used to elucidate the role of DNM3OS and its associated miRNAs in IPF pathogenesis. MEASUREMENTS AND MAIN RESULTS: We identified DNM3OS as a fibroblast-specific critical downstream effector of TGF-β-induced lung myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to three distinct profibrotic mature miRNAs (i.e. miR-199a-5p/3p and miR-214-3p), which influence both SMAD and non-SMAD components of TGF-β signaling in a multifaceted way. In vivo, we showed that interfering with DNM3OS function not only prevents lung fibrosis but also improves established pulmonary fibrosis. CONCLUSION: Pharmacological approaches aiming at interfering with DNM3OS may represent new effective therapeutic strategies in IPF. This SuperSeries is composed of the SubSeries listed below.
2019-04-10 | GSE97834 | GEO