Function-selective targeting of the extracellular signal-regulated kinase (ERK1/2) mitigates multiple pathophysiological features of allergen-induced asthma in mice
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PROVIDER: PRJNA814688 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: To test the in vivo effectiveness of a novel function-selective inhibitor of ERK1/2 in a murine model of house dust mite (HDM)-induced allergic asthma. Methods: Mice challenged with HDM for 3 weeks were treated with SF-3-030 or vehicle and asthma phenotype was assessed by histology and lung function measurements. Total RNA from lung samples were subjected to RNAseq analysis to determine the molecular signature perturbed by SF-3-030 treatment in mice. Results: RNA-seq analysis revealed modulation (up- or down-regulation) of expression of a number of genes by HDM challenge. SF-3-030 treatment significantly modulated the expression of genes involved in HDM-induced airway inflammation, cell proliferation, and extracellular matrix production. Conclusion: Function-selective inhibitor of ERK1/2 SF-3-030 mitigates multiple features of asthma in a murine model by modulating expression of genes involved in the regulation of key pathological functions in airway cells.
2022-09-01 | GSE198355 | GEO
Project description:Asthma is a complex syndrome associated with episodic decompensations provoked by aeroaller-gen exposures. The underlying pathophysiological states driving exacerbations are latent in the resting state and do not adequately inform biomarker-driven therapy. A better understanding of the pathophysiological pathways driving allergic exacerbations is needed. We hypothesized that disease-associated pathways could be identified in humans by unbiased metabolomics of bron-choalveolar fluid (BALF) during the peak inflammatory response provoked by a bronchial aller-gen challenge. We analyzed BALF metabolites in samples from 12 volunteers who underwent segmental bronchial antigen provocation (SBP-Ag). Metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC–MS/MS) followed by pathway analysis and cor-relation with airway inflammation. SBP-Ag induced statistically significant changes in 549 fea-tures that mapped to 72 uniquely identified metabolites. From these features, two distinct induci-ble metabolic phenotypes were identified by the principal component analysis, partitioning around medoids (PAM) and k-means clustering. Ten index metabolites were identified that in-formed the presence of asthma-relevant pathways, including unsaturated fatty acid produc-tion/metabolism, mitochondrial beta oxidation of unsaturated fatty acid, and bile acid metabolism. Pathways were validated using proteomics in eosinophils. A segmental bronchial allergen chal-lenge induces distinct metabolic responses in humans, providing insight into pathogenic and pro-tective endotypes in allergic asthma.
2022-06-09 | PXD033172 | Pride
Project description:This protocol outlines a single-site mechanistic study aiming to investigate long RNAs differentially expressed in the airway epithelium of asthma patients both at baseline and in response to segmental airway allergen challenges. Over approximately 14 days, the study spanned three visits: Visit 1: Comprehensive characterization of participants, encompassing lung function testing, methacholine challenge testing, and allergen skin prick testing. Visit 2: Participants underwent bronchoscopy wherein three procedures were performed a. Epithelial brushings were performed in a segmental airway (baseline sample) b. Diluent (inactive control) was instilled into another segmental airway c. A small dose of allergen was administered into a third segmental airway using standardized cat or dust mite allergen extracts. Visit 3 (24 hours or 7 days post Visit 2): Another bronchoscopy was carried out to collect epithelial brushings in the diluent challenged and allergen challenged segments The collected epithelial brush samples underwent analysis for mRNA expression in the epithelial brushings. The study successfully incorporated a total of 23 subjects, which included 18 asthmatics (with stable or well-controlled conditions), 2 allergic non-asthmatics, and 3 non-allergic non-asthmatics.
2024-03-08 | GSE250241 | GEO
Project description:CD4+ helper T cells (TH) and regulatory T cells (Treg) that respond to common allergens play an important role in driving and dampening airway inflammation in patients with asthma. Until recently, direct, unbiased molecular analysis of allergen-reactive TH and Treg cells has not been possible. To better understand the diversity of these T cell subsets in allergy and asthma, we analyzed the single-cell transcriptome of ~50,000 house dust mite (HDM) allergen-reactive TH cells and Treg cells from asthmatics with HDM allergy and from three control groups: asthmatics without HDM allergy and non-asthmatics with and without HDM allergy. Our analyses show that HDM allergen-reactive TH and Treg cells are highly heterogeneous, and certain subsets are quantitatively and qualitatively different in subjects with HDM-reactive asthma. The number of interleukin (IL)-9 expressing HDM-reactive TH cells is greater in asthmatics compared with non-asthmatics with HDM allergy, and display enhanced pathogenic properties. More HDM-reactive Th and Treg cells expressing the interferon-response signature (THIFNR and TregIFNR) are present in asthmatics without HDM allergy compared with those with HDM allergy. In cells from these subsets (THIFNR and TregIFNR), expression of TNFSF10 was enriched; its product, TRAIL, dampens activation of TH cells. These findings suggest that the THIFNR and TregIFNR subsets may dampen allergic responses, which may help explain why only some people develop TH2 responses to nearly ubiquitous allergens.
2020-06-10 | GSE146170 | GEO
Project description:CD4+ helper T cells (TH) and regulatory T cells (Treg) that respond to common allergens play an important role in driving and dampening airway inflammation in patients with asthma. Until recently, direct, unbiased molecular analysis of allergen-reactive TH and Treg cells has not been possible. To better understand the diversity of these T cell subsets in allergy and asthma, we analyzed the single-cell transcriptome of ~50,000 house dust mite (HDM) allergen-reactive TH cells and Treg cells from asthmatics with HDM allergy and from three control groups: asthmatics without HDM allergy and non-asthmatics with and without HDM allergy. Our analyses show that HDM allergen-reactive TH and Treg cells are highly heterogeneous, and certain subsets are quantitatively and qualitatively different in subjects with HDM-reactive asthma. The number of interleukin (IL)-9 expressing HDM-reactive TH cells is greater in asthmatics compared with non-asthmatics with HDM allergy, and display enhanced pathogenic properties. More HDM-reactive Th and Treg cells expressing the interferon-response signature (THIFNR and TregIFNR) are present in asthmatics without HDM allergy compared with those with HDM allergy. In cells from these subsets (THIFNR and TregIFNR), expression of TNFSF10 was enriched; its product, TRAIL, dampens activation of TH cells. These findings suggest that the THIFNR and TregIFNR subsets may dampen allergic responses, which may help explain why only some people develop TH2 responses to nearly ubiquitous allergens.
2020-06-10 | GSE146046 | GEO
Project description:The analysis examined the effects of a global ERK1 and/or tamoxifen-inducible, hepatocyte-specific ERK2 knockout on the liver transcriptome. Transcriptomes from the livers with a ERK1/2 double knockout were compared to the livers of mice with an ERK1 or ERK2 knockout.
2021-08-13 | GSE181803 | GEO
Project description:Angiogenesis is a complex process orchestrated by both growth factors and cell adhesion to the extracellular matrix and is initiated by focal degradation of the vascular basement membrane with subsequent migration and proliferation of endothelial cells (EC). The Ras/Raf/MEK/ERK pathway is critical for EC function during angiogensis. Although in vitro studies implicate ERK1 and ERK2 in EC survival, their precise role in EC function in vivo remains poorly defined. Cre/loxP technology was used to inactivate Erk1 and Erk2 in EC during murine development, resulting in embryonic lethality due to a drastic reduction in angiogenesis. The angiogenic defect was linked to diminished EC proliferation and migration, but not to increased cell apoptosis. Expression of key cell cycle regulators was diminished in the double knockout cells. In addition, both Paxillin and Focal Adhesion Kinase were expressed at lower levels and failed to correctly localize to the cell membrane in EC lacking Erk1 and Erk2, leading to defects in the organization of the cytoskeleton and in cell motility. The results demonstrate that ERK1 and ERK2 coordinate cell proliferation and migration during angiogenesis. Lentivirus infected cells to generate ERK1/2 WT and ERK1/2 DKO endothelial cells were cultured, RNA was extracted and Affymetrix gene expression arrays were performed.
2010-07-30 | E-GEOD-16967 | biostudies-arrayexpress
Project description:Allergen Challenge for Evoked Phenotypes in Asthma (the ACE Study)
| PRJNA1052718 | ENA
Project description:Changes occur in the lung epithelium after allergen challenge that may give insight into asthma pathogenesis and we sought to identify novelepithelial genes induced by allergen exposure. We used microarrays to identify up-regulated genes induced by allergen challenge in lung epithelium.
2011-12-30 | GSE34764 | GEO
Project description:Changes occur in the lung epithelium after allergen challenge that may give insight into asthma pathogenesis and we sought to identify novelepithelial genes induced by allergen exposure. We used microarrays to identify up-regulated genes induced by allergen challenge in lung epithelium. Epithelal brushing of the large airways in mouse lungs was performed 24 hours after Alternaria allergen or PBS control challenge 24. Collected epithelial cells underwent RNA extraction and hybridization on Affymetrix microarrays. There are a total of 6 samples, 3 allergen and 3 control samples.
2011-12-30 | E-GEOD-34764 | biostudies-arrayexpress