RGS4 controls airway hyperresponsiveness through GAP-independent mechanisms
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ABSTRACT:
PROVIDER: PRJNA1013911 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25939232_1.fastq.gz | Fastqsanger.gz | |||
| SRR25939232_2.fastq.gz | Fastqsanger.gz | |||
| SRR25939233_1.fastq.gz | Fastqsanger.gz | |||
| SRR25939233_2.fastq.gz | Fastqsanger.gz | |||
| SRR25939234_1.fastq.gz | Fastqsanger.gz |
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Project description:Regulators of G protein signaling (RGS proteins) constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not exclusively, through their GTPase activating (GAP) activity. Asthma is a highly prevalent condition characterized by airway hyper-responsiveness (AHR) to environmental stimuli resulting in part from amplified GPCR-mediated airway smooth muscle (ASM) contractility. Rgs2 or Rgs5 gene deletion in mice enhances AHR and ASM contraction whereas RGS4 knockout (KO) mice unexpectedly have decreased AHR due to increased production of the bronchodilator prostaglandin E2 (PGE2) by lung epithelial cells. Here we found that knockin mice harboring Rgs4 alleles encoding a point mutation (N128A) that sharply curtails RGS4 GAP activity had increased AHR, reduced airway PGE2 levels, and augmented GPCR-induced bronchial contraction compared to either RGS4 KO mice or WT controls. RGS4 interacted with the p85a subunit of PI3 kinase (PI3K) and inhibited PI3K-dependent PGE2 secretion elicited by TGFb in airway epithelial cells. Together these findings suggest that RGS4 affects asthma severity in part by regulating the airway inflammatory milieu in a G protein-independent manner.
2024-05-08 | GSE242546 | GEO
Project description:Airway hyperresponsiveness is found to be a heritable trait and the parents of respiratory patients often have this trait. To understand if airway constriction affects the lung and contributes to lung disease, we investigated the lungs that often occur airway constriction and compared those lungs with healthy lung and the lung with inflammation.
2022-11-18 | GSE212406 | GEO
Project description:Asthma is a heterogeneous disease largely defined by chronic airway inflammation with similar symptomatology in patients that includes wheezing, shortness of breath, chest tightness and cough. However, underlying these common symptoms are varying endotypes with distinct pathophysiological processes. Metabolomic studies in patients with asthma are emerging and suggest that metabolomics can characterize distinct asthma phenotypes. In a completed study, we identified a population of patients with asthma who have increased airway hyperresponsiveness (airway hyperresponsiveness is a marker for asthma disease severity) who are characterized by race (African American) and genotype (ADRB2 Arg16/Arg) compared with patients who have less airway hyperresponsiveness (African Americans and whites with differing ADRB2 genotypes). This group may represent a distinct endotype of asthma with unique metabolomic and lipidomic characteristics. The aims of this project are to (1) use metabolomic and lipidomic analysis to identify metabolites present in plasma in this population of patients with asthma who have increased airway hyperresponsiveness (African Americans who carry the ADRB2 Arg16/Arg genotype) and patients with asthma who have less airway hyperresponsiveness (African Americans and whites with differing ADRB2 genotypes); and (2) identify pathways that will improve the understanding of increased airway hyperresponsiveness in this population. We hypothesize that there will be unique metabolic pathways in the population with increased airway hyperresponsiveness that will be distinct from pathways in patients with lower airway hyperresponsiveness. In this project will use data and samples that were previously collected as part of the NIH funded project “Pharmacogenetics of β2-Agonists in Asthma” (Blake, PI K23 HL081245). Blood was collected in 55 African Americans and whites after receiving 2-weeks treatment with inhaled fluticasone. Samples were stored on ice until processed and plasma frozen at -80°C. If our findings indicate distinct metabolic pathways are present using global metabolomic and lipodomic analysis, we will seek to replicate our findings using samples and data from phenotypically well characterized participants who participated in trials conducted through the American Lung Association Airways Clinical Research Centers network, of which Nemours has been a highly productive site since 1999. Future controlled trials would be conducted to evaluate treatments based upon molecular pathways identified through metabolomic and lipidomic analysis.
2018-04-13 | ST000954 | MetabolomicsWorkbench
Project description:The BcA86 strain is a unique recombinant congenic strain created from parental strains A/J and C57BL/6J. Naive mice from the BcA86 strain have a lung responsiveness phenotype resembling mice from airway hyperresponsive strain A/J. However, majority of the BcA86 genome is from the hyporesponsive strain C57BL/6J. Our goal was to identify the genomic regions that are associated with this BcA86 phenotype. Using F2 mice generated from BcA86 backcrossed to C57BL/6J, we identified a QTL for airway hyperresponsiveness on mouse chromosome 12. We validated the importance of mouse chromosome 12 in airway responsiveness using a chromosome 12 substitution strain (CSS12) which contains A/J chromosome 12 on a C57BL/6J background. The CSS12 strain also had a lung responsiveness phenotype similar to A/J. We selected genes within our QTL as candidates for airway hyperresponsiveness if they contained a deleterious coding variant (based on PROVEAN analysis) or if they were differently expressed between hyperresponsive (A/J, BcA86, CSS12) and hyporesponsive (C57BL/6J) strains.
2014-11-11 | GSE52356 | GEO
Project description:An important feature of human asthma and animal models of asthma is airway hyperresponsiveness. The symptoms of asthma are a narrowing of the airways caused by edema and the influx of inflammatory cells. The aim of this project is to determine the temporal relationship between gene expression and airway allergen challenge. 4 weeks old BALB/CJ mice were challenged on days 0,3,10 and 17 with PBS and ragweed pollen protein plus Alum.
2007-12-13 | E-GEOD-483 | biostudies-arrayexpress
Project description:Rationale: Asthma and atopy shares common features including Th2-inflammation. However, impairment of airway function seems to be absent in atopy. Increased understanding of the complex cellular and molecular pathways defining the similarities and differences between asthma and atopy may be achieved by transcriptomic analysis (RNA-Seq). Hypothesis and Aims: As the airway smooth muscle (ASM) layer plays an important role in airway function, we hypothesized that the transcriptomic profile of the ASM layer in endobronchial biopsies is different between atopic asthma patients and atopic healthy controls. First, we examined the differences in transcriptomic profiles of the ASM layer in endobronchial biopsies between atopic mild, steroid-free asthma patients, and atopic and non-atopic healthy controls. Second, we investigated the association between the transcriptomic profiles of the ASM layer and airway function. Methods: This cross-sectional study included 12 steroid-free atopic asthma patients, 6 atopic, and 6 non-atopic healthy controls. RNA of ASM from 4 endobronchial biopsies per subject was isolated and sequenced (GS FLX+, 454/Roche). Ingenuity Pathway Analysis was used to identify gene networks. Comparison of the numbers of reads per gene in asthma and controls was based on the negative binomial distribution. At the current sample size the estimated false discovery rate was approximately 1%. Results: Yield of isolated RNA was 30-821ng. We identified 174 differentially expressed genes between asthma and atopic controls, 108 between asthma and non-atopic controls, and 135 between atopic and non-atopic controls. A set of 8 genes was identified, which seems to define asthma patients from non-asthmatic controls regardless of atopy. Four of these genes were significantly associated with airway hyperresponsiveness. Conclusion: A difference in transcriptomic profile of the airway smooth muscle layer in asthma patients compared to atopic and non-atopic healthy controls may lead to a different regulation of inflammatory pathways and of airway smooth muscle function and development resulting in impaired airway function. This cross-sectional transcriptomics study consisted of 2 visits. At visit 1, asthma patients (n=12), and healthy atopic (n=6) and non-atopic (n=6) controls were screened for eligibility to participate according to the in- and exclusion criteria. Spirometry and a methacholine bronchoprovocation test were performed. At visit 2, FEV1 reversibility was measured and 4 endobronchial biopsies per subject were collected during a bronchoscopy. Airway smooth muscle was collected from the biopsies by laser capture microdissection and total RNA isolated. cDNA was prepared using the Ovation RNA-Seq System (NuGEN). RNA-Seq was performed using the GS FLX+ instrument (454/Roche). Sequence reads were mapped against the human genome (hg19; UCSC). Comparison of the numbers of reads per gene between asthma and healthy controls was based on the negative binomial distribution and carried out with the R package DESeq including correction for multiple testing.
2014-08-15 | E-GEOD-38003 | biostudies-arrayexpress