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Project description:Resetting proteostasis with calumenin prevents the aggregation of misfolded vimentin during organ fibrosis
| PRJNA1093413 | ENA
Project description:Calumenin prevents fibroblasts senescence and lung aging by promoting vimentin proteostasis
| PRJNA1299348 | ENA
Project description:Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. Comprehensive transcriptome analysis was employed to validate the capacity of three prioritized compounds to remodel the ER proteostasis environment, and to assess the prefential activation of ATF6 transcriptional targets relative to targets of the IRE1/XBP1s and PERK arms of the UPR. HEK293T-Rex and HEK293-DAX cells were treated for 6 hr with vehicle (DMSO), 1 µM Tg, 10 mM TMP (in HEK293DAX), or 10 µM 132, 147 or 263 in biological triplicate at 37 ÌC
2016-07-21 | E-GEOD-84636 | biostudies-arrayexpress
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
Project description:Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. Comprehensive transcriptome analysis was employed to validate the capacity of three prioritized compounds to remodel the ER proteostasis environment, and to assess the prefential activation of ATF6 transcriptional targets relative to targets of the IRE1/XBP1s and PERK arms of the UPR.
2016-07-21 | GSE84636 | GEO
Project description:Progressive lung fibrosis is linked to aging-related dysfunction in fibroblasts, which remains poorly understood. We aimed to assess the impact of calumenin deficiency on fibroblast senescence and lung fibrosis.
2026-01-04 | GSE304185 | GEO
Project description:The intermediate filament vimentin is present in immune cells. It provides structural support to cells and functions in macrophages to coordinate inflammatory responses. Neutrophils are an abundance innate immune cell that function by distinct mechanisms from macrophages to mediate antimicrobial activities. The role of vimentin in neutrophils is not established. Here, we developed an immortalized neutrophil model to examine the requirement of vimentin. We demonstrate that vimentin restricts proinflammatory cytokine production and reactive oxygen species production, but enhances phagocytosis and swarming. We observe that vimentin is dispensable for neutrophil extracellular trap (NET) formation, degranulation, and for inflammasome activation. Moreover, gene expression analysis defined vimentin presence was associated with expression changes in multiple genes required for mitochondrial function and ROS overproduction in the absence of vimentin. By treatment of cells producing vimentin with rotenone, an inhibitor for complex I of the electron transport chain, or by treatment of cells lacking vimentin with mitoTEMPO, a SOD mimetic, we complement the changes in ROS levels through manipulation of mitochondrial function. Together, we suggest vimentin regulates neutrophil antimicrobial functions and alters ROS levels through regulation of mitochondrial activity.
2024-09-12 | GSE262717 | GEO
Project description:Purpose:The Vimentin gene plays a pivotal role in epithelial-to-mesenchymal transition (EMT) and is known to be over-expressed in the prognostically poor basal-like breast cancer subtype. Recent studies have reported Vimentin DNA methylation in association with poor clinical outcomes in other solid tumors, but not in breast cancer. We therefore quantified Vimentin DNA methylation in breast tumors and matched normal pairs in association with gene expression and survival in a cohort of 83 breast cancer patients. Materials and Methods:Vimentin methylation was quantified in 14 breast cell lines, 83 breast tumors, and 57 matched normal pairs using MALDI-TOF mass spectrometry. Gene expression data via qRT-PCR in cell lines, and oligo microarray data from breast tissues was correlated with percent methylation in the Vimentin promoter. A threshold of 20 percent average methylation was set for bivariate and multivariate tests of association between methylation and tumor subtype, tumor histopathology, and survival. Results:Vimentin was differentially methylated in luminal breast cancer cell lines, and in luminal A, luminal B and HER2+ breast tumor subtypes, but was rare in basal-like cell lines and tumors. Increased methylation was strongly correlated with decreased mRNA expression in cell lines, and had a moderate inverse correlation in breast tumors. Importantly, Vimentin methylation predicted poor overall survival independent of race, subtype, stage, nodal status or estrogen receptor positivity. Conclusion:Vimentin methylation predicts overall survival in breast cancer patients and holds promise as a prognostic biomarker for guiding treatment and prophylaxis. reference x sample
2013-02-19 | E-GEOD-35629 | biostudies-arrayexpress
Project description:To study the biological and functional role of vimentin in maintenance of the mesenchymal phenotype of mammary epithelial cells, vimentin was silenced in the non-transformed MCF10A cells and vimentin-dependent changes in gene expression were analyzed. Scrambled is the siScr-transfected control with two replicates; KD the sample with vimentin knockdown, also two replicates.
2010-11-18 | E-GEOD-17802 | biostudies-arrayexpress
Project description:To study the biological and functional role of vimentin in maintenance of the mesenchymal phenotype of mammary epithelial cells, vimentin was silenced in the non-transformed MCF10A cells and vimentin-dependent changes in gene expression were analyzed.
2010-11-18 | GSE17802 | GEO