Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA319995 | ENA |
REPOSITORIES: ENA
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Project description:Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the most frequent of which is F508del-CFTR. CF is characterized by excessive secretion of pro-inflammatory chemokines into the airway lumen, inducing a highly inflammatory cellular phenotype. This process triggers fibrosis, causing airway destruction and leading to high morbidity and mortality. We previously reported that miR-155 is up-regulated in CF lung epithelial cells, but the molecular mechanisms by which miR-155 affects the disease phenotype is not understood. Here we report that the protein RPTOR (regulatory associated protein of mTOR, complex 1) is a novel target of miR-155 in CF lung epithelial cells. The suppression of RPTOR expression and subsequent activation of TGF-β signaling resulted in the induction of fibrosis by up-regulation of connective tissue growth factor (CTGF) in CF lung epithelial cells. Thus, we propose that miR-155 can regulate fibrosis of CF lungs through the RPTOR-TGF-β-CTGF axis, highlighting its potential value in CF therapy.
2024-07-16 | GSE80798 | GEO
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 animals models generated in our lab demonstrate clinical phenotypes seen in human fibrotic disease. The mouse model of transforming growth factor-? (TGF?)-induced fibrosis include conditionally expressing TGF? in the lung epithelium under control of the CCSP promoter driving rtTA expression (CCSP/TGF?). This allow the TGF? is only expressed in airway and alveolar epithelial cells and only when mice fed doxycycline (Dox). Similar to PF in humans, TGF? mice on Dox developed a progressive and extensive adventitial, interstitial and pleural fibrosis with a decline in lung mechanics. Thus, the TGF? transgenic mouse is a powerful model to determine lung cell-specific molecular signatures involved in pulmonary fibrosis. In this study, we sought to determine changes in the transcriptome during TGF?-induced pulmonary fibrosis. Our results showed that several pro-fibrotic genes increased in the lungs of TGF? mice. This study demonstrates that WT1 network gene changes associated with fibrosis and myfibroblast accumulation and thus may serve as a critical regulator fibrotic lung disease. mRNA profiles of CCSP/- and CCSP/TGFalpha mice treated with Dox
2015-03-07 | E-GEOD-66634 | biostudies-arrayexpress
Project description:In this study, we evaluated genetic mouse models of inducible renal epithelia-specific miR-17~92 loss-of-function and gain-of-function using unilateral ureteral obstruction. We utilized PAR-CLIP in HK2 cells to identify miR-17/-20a targets, which we subsequently validated in vitro. We examined expression of a novel miR-17/-20a target in human nephrectomy samples with varying degrees of fibrosis. We identify an activator of Hippo signaling, FERM domain-containing protein 6 (FRMD6, also known as Willin), as a novel miR-17/20a target. Frmd6 is upregulated in tubular epithelium of obstructed kidneys that lack miR-17~92, along with increased phosphorylation of Smad3 and STAT3, two known miR-17~92 profibrotic targets. Frmd6 overexpression is sufficient to result in elevated secretion of the extracellular matrix component collagen III in vitro. Finally, we demonstrate that FRMD6 expression is associated with collagen III expression in human nephrectomy samples.Our findings demonstrate that the miR-17~92 cluster in renal epithelia functions in an anti-fibrotic manner by regulating multiple pro-fibrotic pathways. We also identify Frmd6 as a novel miR-17/20a target in renal epithelia, which may drive renal fibrosis.
2025-01-30 | GSE254784 | GEO
Project description:In this study, we evaluated genetic mouse models of inducible renal epithelia-specific miR-17~92 loss-of-function and gain-of-function using unilateral ureteral obstruction. We utilized PAR-CLIP in HK2 cells to identify miR-17/-20a targets, which we subsequently validated in vitro. We examined expression of a novel miR-17/-20a target in human nephrectomy samples with varying degrees of fibrosis. We identify an activator of Hippo signaling, FERM domain-containing protein 6 (FRMD6, also known as Willin), as a novel miR-17/20a target. Frmd6 is upregulated in tubular epithelium of obstructed kidneys that lack miR-17~92, along with increased phosphorylation of Smad3 and STAT3, two known miR-17~92 profibrotic targets. Frmd6 overexpression is sufficient to result in elevated secretion of the extracellular matrix component collagen III in vitro. Finally, we demonstrate that FRMD6 expression is associated with collagen III expression in human nephrectomy samples.Our findings demonstrate that the miR-17~92 cluster in renal epithelia functions in an anti-fibrotic manner by regulating multiple pro-fibrotic pathways. We also identify Frmd6 as a novel miR-17/20a target in renal epithelia, which may drive renal fibrosis.
2025-01-30 | GSE254782 | GEO
Project description:In this study, we evaluated genetic mouse models of inducible renal epithelia-specific miR-17~92 loss-of-function and gain-of-function using unilateral ureteral obstruction. We utilized PAR-CLIP in HK2 cells to identify miR-17/-20a targets, which we subsequently validated in vitro. We examined expression of a novel miR-17/-20a target in human nephrectomy samples with varying degrees of fibrosis. We identify an activator of Hippo signaling, FERM domain-containing protein 6 (FRMD6, also known as Willin), as a novel miR-17/20a target. Frmd6 is upregulated in tubular epithelium of obstructed kidneys that lack miR-17~92, along with increased phosphorylation of Smad3 and STAT3, two known miR-17~92 profibrotic targets. Frmd6 overexpression is sufficient to result in elevated secretion of the extracellular matrix component collagen III in vitro. Finally, we demonstrate that FRMD6 expression is associated with collagen III expression in human nephrectomy samples.Our findings demonstrate that the miR-17~92 cluster in renal epithelia functions in an anti-fibrotic manner by regulating multiple pro-fibrotic pathways. We also identify Frmd6 as a novel miR-17/20a target in renal epithelia, which may drive renal fibrosis.
2025-01-30 | GSE254785 | GEO
Project description:MYC regulates the expression of multiple microRNA (miRNA) genes and defines the Burkitt lymphoma (BL) miRNA signature. Here, we investigate the role of the MYC-regulated miRNAs by gain- and loss-of-function analysis. Overexpression of 5 miRNAs that were significantly downregulated by MYC resulted in strong (miR-150, miR-26a, miR-26b) and mild (miR-29a, let-7a) impaired cell growth. Overexpression of miR-155 increased proliferation of BL cells. By RNA immunoprecipitation of Argonaute 2 in BL cells with and without miR-155 we identified 54 miR-155 target genes. Using an shRNA approach we identified TBRG1 (NIAM1) as a miR-155 target gene that copied the miR-155-induced phenotype upon its inhibition. Analysis of TBRG1 protein expression and miR-155 levels in primary cases of B-cell lymphoma revealed that miR-155 levels are significantly lower in TBRG1 positive cases suggesting that TBRG1 is also regulated by miR-155 in primary B-cell lymphoma. Our data demonstrate that overexpression of individual MYC-repressed miRNAs has a strong suppressive effect on BL cell growth, whereas overexpression of miR-155 enhances B-cell lymphoma growth by targeting the tumor suppressor gene TBRG1. Gene expression profile was performed in ST486 Burkitt lymphoma cell line in 4 samples: ST486 EV (empty MXW-PGK-IRES-GFP vector) total cell lysate, ST486 EV Ago2-IP, ST486 miR-155 (ST486 with ectopic miR-155) total cell lysate, ST486 miR-155 Ago2-IP.
2015-02-20 | E-GEOD-64484 | biostudies-arrayexpress
Project description:Objective: MicroRNAs (miRNAs) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from SSc-ILD patients. A chronic lung fibrotic murine model was used. Methods: RNA was isolated from lung tissue of 12 SSc-ILD patients and 5 control lungs. High-resolution computed tomography (HRCT) was performed at baseline and 2-3 years after treatment. Lung fibroblasts and PBMCs were isolated from healthy controls and SSc-ILD patients. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DIANA-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin. Results: Lung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q<0.25). DIANA-miRPath revealed 57 KEGGs pathways related to the most dysregulated miRNAs. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts showed only mild expression of miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and showed a weaker lung induction of several genes after bleomycin exposure compared to wild-type mice. Conclusions: miRNAs are dysregulated in lungs and PBMCs of SSc-ILD patients. Based on mRNA-miRNA interaction analysis and pathway tools, miRNAs may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD. Lung biopsies taken from open lung biopsy from SSc-ILD patients (n=15 samples) and from cancer free control patients (n=5) during ressection of the lung tumor.
2016-08-01 | E-GEOD-81292 | biostudies-arrayexpress
Project description:Objective: MicroRNAs (miRNAs) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from SSc-ILD patients. A chronic lung fibrotic murine model was used. Methods: RNA was isolated from lung tissue of 12 SSc-ILD patients and 5 control lungs. High-resolution computed tomography (HRCT) was performed at baseline and 2-3 years after treatment. Lung fibroblasts and PBMCs were isolated from healthy controls and SSc-ILD patients. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DIANA-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin. Results: Lung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q<0.25). DIANA-miRPath revealed 57 KEGGs pathways related to the most dysregulated miRNAs. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts showed only mild expression of miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and showed a weaker lung induction of several genes after bleomycin exposure compared to wild-type mice. Conclusions: miRNAs are dysregulated in lungs and PBMCs of SSc-ILD patients. Based on mRNA-miRNA interaction analysis and pathway tools, miRNAs may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD. Lung biopsies taken from open lung biopsy from SSc-ILD patients (n=15 samples) and from cancer free control patients (n=5) during ressection of the lung tumor.
2016-08-01 | E-GEOD-81293 | biostudies-arrayexpress
Project description:MicroRNA (miRNA)-mediated mRNA regulation directs many homeostatic and pathological processes, but how miRNAs coordinate aberrant esophageal inflammation during eosinophilic esophagitis (EoE) is poorly understood. Here, we report a deregulatory axis where microRNA-155 (miR-155) regulates epithelial barrier dysfunction by selectively constraining tight junction CLDN7 (claudin-7). MiR-155 is elevated in the esophageal epithelium of biopsies from patients with active EoE and in cell culture models. miR-155 localisation using in situ hybridisation (ISH) in patient biopsies, and intra-epithelial compartmentalisation of miR-155 shows expression predominantly within the basal epithelia. Epithelial miR-155 activity was evident through diminished target gene expression in 3D organotypic cultures, particularly in relatively undifferentiated basal cell states. Mechanistically, generation of a novel cell line with enhanced epithelial miR-155 stable overexpression induced a functionally deficient epithelial barrier in 3D air-liquid interface epithelial cultures measured by transepithelial electrical resistance (TEER). Histological assessment of 3D esophageal organoid cultures overexpressing miR-155 showed notable dilated intra-epithelial spaces. Unbiased RNA-sequencing analysis and immunofluorescence determined a defect in epithelial barrier tight junctions and revealed a selective reduction in the expression of critical esophageal tight junction molecule, claudin-7. Together, our data reveal a previously unappreciated role for miR-155 in mediating epithelial barrier dysfunction in esophageal inflammation.
2023-12-12 | GSE244629 | GEO
Project description:Experiment 1 - miR-155 and miR-199 Phenotype miR-155 and miR-199 as 23mer miRNA mimics induced a double-stranded RNA response
2015-12-09 | GSE75800 | GEO