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Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [AT2]

ABSTRACT: Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [AT2]

PROVIDER: PRJNA608191 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11149067.fastq.gz	Fastqsanger.gz
	SRR11149068.fastq.gz	Fastqsanger.gz
	SRR11149069.fastq.gz	Fastqsanger.gz
	SRR11149070.fastq.gz	Fastqsanger.gz
	SRR11149071.fastq.gz	Fastqsanger.gz

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Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis

Project description:Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis

| PRJNA606611 | ENA

Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [AT2]

Project description:Aging is among the most important risk factors for the development of pulmonary fibrosis. Inappropriate or prolonged activation of the integrated stress response has been implicated in the pathobiology of both aging and pulmonary fibrosis. We found that a small molecule that relieves translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity pulmonary fibrosis in young and old mice. We demonstrate that severe fibrosis in old mice was associated with increased number of pathogenic monocyte-derived alveolar macrophages. Using transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased recruitment of pathogenic monocyte-derived alveolar macrophages. Thus our data suggest that inhibition of the integrated stress response in the lung epithelium can ameliorate pulmonary fibrosis by preventing the recruitment of monocyte-derived alveolar macrophages.

2021-04-16 | GSE145771 | GEO

Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [dataset 2]

Project description:Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [dataset 2]

| PRJNA607692 | ENA

Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis

2021-04-16 | GSE145295 | GEO

Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [dataset 2]

2021-04-16 | GSE145590 | GEO

Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis.

Project description:Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.

| S-EPMC8157939 | biostudies-literature

Resetting Proteostasis of CIRBP with ISRIB Suppresses Neural Stem Cell Apoptosis under Hypoxic Exposure

Project description:Neurological disorders are often progressive and lead to disabilities with limited available therapies. Epidemiological evidence implicated that prolonged exposure to hypoxia leads to neurological damage and a plethora of complications. Neural stem cells (NSCs) are a promising tool for neurological damage therapy in terms of their unique properties. However, the literature on the outcome of NSCs exposed to severe hypoxia is scarce. In this study, we identified a responsive gene that reacts to multiple cellular stresses, marked cold-inducible RNA-binding protein (CIRBP), which could attenuate NSC apoptosis under hypoxic pressure. Interestingly, ISRIB, a small-molecule modulator of the PERK-ATF4 signaling pathway, could prevent the reduction and apoptosis of NSCs in two steps: enhancing the expression of CIRBP through the protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK) and activating transcription factor 4 (ATF4) axis. Taken together, CIRBP was found to be a critical factor that could protect NSCs against apoptosis induced by hypoxia, and ISRIB could be acted upstream of the axis and may be recruited as an open potential therapeutic strategy to prevent or treat hypoxia-induced brain hazards.

| S-EPMC9546721 | biostudies-literature

The Small Molecule ISRIB Reverses the Effects of eIF2α Phosphorylation on Translation and Stress Granule Assembly

Project description:We recently identified ISRIB as a potent inhibitor of the integrated stress response (ISR). ISRIB renders cells resistant to the effects of eIF2α phosphorylation and enhances long-term memory in rodents (10.7554/eLife.00498). Here we show by genome-wide in vivo ribosome profiling that translation of a restricted subset of mRNAs is induced upon ISR activation. ISRIB substantially reversed the translational effects elicited by phosphorylation of eIF2α and induced no major changes in translation or mRNA levels in unstressed cells. eIF2α phosphorylation-induced stress granule (SG) formation was blocked by ISRIB. Strikingly, ISRIB addition to stressed cells with pre-formed SGs induced their rapid disassembly, liberating mRNAs into the actively translating pool. Restoration of mRNA translation and modulation of SG dynamics may be an effective treatment of neurodegenerative diseases characterized by eIF2α phosphorylation, SG formation and cognitive loss. Ribosome profiling with paired RNA-seq

2015-02-27 | E-GEOD-65778 | biostudies-arrayexpress

Integrin beta-1 (Itgb1) in profibrotic myofibroblasts

Project description:Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes profibrotic features. This microarray study was performed to clarify the role of integrin beta-1 (Itgb1) in profibrotic myofibroblasts.

2016-08-18 | E-MTAB-4810 | biostudies-arrayexpress

The Small Molecule ISRIB Reverses the Effects of eIF2α Phosphorylation on Translation and Stress Granule Assembly

2015-02-27 | GSE65778 | GEO