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RGS4 controls airway hyperresponsiveness through GAP-independent mechanisms

ABSTRACT: RGS4 controls airway hyperresponsiveness through GAP-independent mechanisms

PROVIDER: PRJNA1013911 | ENA |

REPOSITORIES: ENA

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			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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RGS4 controls airway hyperresponsiveness through GAP-independent mechanisms

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

Mapping of a QTL for airway hyperresponsiveness on mouse chromosome 12

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

Distinct Epithelial-Innate Immune Cell Transcriptional Circuits Underlie Airway Hyperresponsiveness in Asthma

Project description:Indirect airway hyperresponsiveness (AHR) is a highly specific feature of asthma but the underlying mechanisms responsible for driving indirect AHR remain incompletely understood. We aimed to identify differences in gene expression in epithelial brushings obtained from individuals with asthma who were characterized for indirect AHR in the form of exercise-induced bronchoconstriction (EIB). RNA-sequencing (RNA-seq) analysis was performed on epithelial brushings obtained from individuals with asthma with (n=11) and without EIB (n = 9).

2023-08-16 | GSE241016 | GEO

Sex-dependent Influence of LMAN1 on Allergen-induced Airway Hyperresponsiveness

Project description:Sex-dependent Influence of LMAN1 on Allergen-induced Airway Hyperresponsiveness

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Urokinase plasminogen activator receptor (uPAR) attenuates allergen-induced eosinophil migration and airway hyperresponsiveness through distinct mechanisms

Project description:Urokinase plasminogen activator receptor (uPAR) attenuates allergen-induced eosinophil migration and airway hyperresponsiveness through distinct mechanisms

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Urokinase plasminogen activator receptor (uPAR) attenuates allergen-induced eosinophil migration and airway hyperresponsiveness through distinct mechanisms [CD45+]

Project description:Urokinase plasminogen activator receptor (uPAR) attenuates allergen-induced eosinophil migration and airway hyperresponsiveness through distinct mechanisms [CD45+]

| PRJNA1263210 | ENA

Genetic background and transient prenatal disruption of vitamin A signaling determine susceptibility to airway hyperresponsiveness in mice [scMultiome]

Project description:Airway structural changes and hyperresponsiveness (AHR), hallmarks of asthma, are crucially influenced by genetic variations and adverse exposures. While intrauterine environmental perturbations leading to dysfunctional lung development have been linked to adult pulmonary disease, still little is known about the developmental events leading to these postnatal abnormalities. Here, we provide evidence of genetic background playing a key role in this process. Using A/J and C57BL/6J mice known for their distinct susceptibility to AHR, we show that A/J but not C57BL/6J develop an aberrant airway smooth muscle (SM) program and AHR in adulthood when exposed transiently to a vitamin A/retinoic acid (RA)-disrupted intrauterine environment in vivo by a maternal BMS493 administration. Single nuclei multiomics analysis identified a subpopulation of mesenchymal cells that overactivated TGFβ targets in response to BMS selectively in A/J, but not C57BL/6J, embryonic lungs. These cells, localized to sites of airway SM initiation, exhibited robust BMS-mediated upregulation of SMAD2/3 targets, including regulators of SM program Pdgfra and Tnc, and showed stable cell proportions despite the marked transcriptional rewiring following RA disruption. These findings identify TGFβ-activating mesenchymal cells as a critical niche responsive to RA signaling and reveal how genetic background determines developmental susceptibility to micronutrient perturbations with long-term impact on airway function.

2026-01-28 | GSE307731 | GEO

Genetic background and transient prenatal disruption of vitamin A signaling determine susceptibility to airway hyperresponsiveness in mice [RNA-Seq]

2026-01-28 | GSE307576 | GEO

Urokinase plasminogen activator receptor (uPAR) attenuates allergen-induced eosinophil migration and airway hyperresponsiveness through distinct mechanisms

Project description:Allergic asthma is a widespread disease of the airway stemming from the actions of multiple cell types, including eosinophils and epithelial cells. The urokinase plasminogen activator receptor (uPAR) is a membrane bound protein that can contribute to the activation and mobilization of leukocytes and is present at increased levels in asthmatics. However, its role in allergic asthma remains poorly understood. Here, we have used multiple mouse strains and different models of allergic asthma to study the function of uPAR in allergic airway inflammation (AHR). Plaur, the gene encoding uPAR, was rapidly induced following allergic sensitization through the airway, and again following subsequent allergen challenge. Plaur-deficient mice displayed both increased numbers of eosinophils and heightened AHR in multiple models of allergic asthma. Mice selectively lacking Plaur in eosinophils also had more robust eosinophilia than did WT mice, and eosinophils lacking Plaur displayed increased activity in an ex-vivo assay of chemokine-dependent migration. However, those mice did not have increased AHR compared with WT mice. Conversely, although mice selectively lacking Plaur in lung epithelial cells did not have increased inflammation compared with WT mice, they displayed heightened AHR. These findings suggest that uPAR controls both airway inflammation and AHR, but through distinct mechanisms. Targeting uPAR might have therapeutic potential for treating inflammation and AHR in asthma.

2026-01-12 | GSE297229 | GEO

Sex-dependent Influence of LMAN1 on Allergen-induced Airway Hyperresponsiveness

Project description:Allergic asthma is a chronic inflammatory disease of the airways characterized by a type 2-high adaptive immune response towards common aeroantigens such as dust mite, pollen and animal dander. Despite the advances made towards translation of various biologics into the clinic, the limited efficacy of these therapies in certain populations, combined with the ineligibility of some patients for treatment (clinically or economically), have led to the continued need for the development of more widely effective allergic asthma therapies. Our lab previously identified lectin mannose-binding 1 (LMAN1) as a novel receptor for house dust mite (HDM) and showed that in vitro, LMAN1 downregulated inflammatory NF-κB signaling in DCs in response to HDM. In this follow-up work, we investigated the in vivo relevance of LMAN1 by subjecting LMAN1 knockout (KO) mice and wild type (WT) littermate controls to a model of HDM-induced allergic asthma. Surprisingly, we discovered that loss of LMAN1 led to opposing effects on airway hyperresponsiveness (AHR) which were dependent on the sex of the mice. HDM-treated female LMAN1 KO mice showed increased AHR, while HDM-treated male KO mice showed decreased AHR, compared with their WT counterparts. We further identified the features of HDM-induced asthma which may account for the gender-biased effects of LMAN1 on lung function. This work not only highlights the complexity of the loss of LMAN1 in vivo but also suggests that such sex-dependent responses should be taken into consideration when pursuing LMAN1 as a therapeutic target for treatment of allergic asthma.

2025-05-12 | GSE294581 | GEO

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