Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA375074 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5262350.fastq.gz | Fastqsanger.gz | |||
| SRR5262351.fastq.gz | Fastqsanger.gz | |||
| SRR5262343.fastq.gz | Fastqsanger.gz | |||
| SRR5262344.fastq.gz | Fastqsanger.gz | |||
| SRR5262345.fastq.gz | Fastqsanger.gz |
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Project description:IDH1-R132H is expressed in Low Grade Glioma (LGG) in combination with mutation in ATRX and TP53 genes. IDH1-R132H results in gain of function with production of 2-hydroxygluatrate, that in turn generates a hypermethylatyed phenotype in DNA and histone with consequences in epigenetic regulation of gene expression. Here we will compare the gene expression profile between IDH1-R132H and IDH1 Wt tumor neurospheres.
2019-03-18 | GSE94974 | GEO
Project description:IDH1-R132H is expressed in Low Grade Glioma (LGG) in combination with loss of function mutation in ATRX and TP53 genes. IDH1-R132H results in gain of function with production of 2-hydroxygluatrate, that in turn generates a hypermethylated phenotype in DNA and histone with consequences in epigenetic regulation of gene expression. Here we will compare the gene expression profile between IDH1-R132H and IDH1 Wt LLG moribund animal brain tumors and identify key genes responsible for the phenotype of this subtype of glioma.
2018-02-10 | GSE94902 | GEO
Project description:IDH1-R132H is expressed in Low Grade Glioma (LGG) in combination with loss of function mutation in ATRX and TP53 genes. IDH1-R132H results in gain of function with production of 2-hydroxygluatrate, that in turn generates a hypermethylatyed phenotype in DNA and histone with consequences in epigenetic regulation of gene expression. Here we will compare the gene expression profile between IDH1-R132H and IDH1 Wt LLG animal brain tumors in reponse to radiation
2019-03-18 | GSE94975 | GEO
Project description:IDH1-R132H Low Grade Glioma animal brain tumors
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Project description:The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA-cycle are associated with IDH1 mut. Here we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, in order to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism and the TCA-cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA cycle activity in IDH1 mut gliomas.
2020-03-09 | PXD016697 | Pride
Project description:The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA-cycle are associated with IDH1 mut. Here we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, in order to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism and the TCA-cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA cycle activity in IDH1 mut gliomas.
2020-03-09 | PXD016698 | Pride
Project description:The R132H mutation in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is the most important prognostic factor for survival of glioma patients. This resulted in many studies investigating the effects of this mutation, including those on energy metabolism. This led to the discovery of a panel of enzymes mainly involved in glutamate anaplerosis and aerobic glycolysis that change in abundance as a result of the IDH1 mutation. To further study these changes and investigate the therapeutic value of inhibitors of IDH1 R132H-associated metabolic pathways, appropriate glioma models are required that mimic in vivo metabolism as good as possible. To investigate how metabolism is affected by in vitro cell culture, we here compared surgically obtained snap frozen glioma tissues with their corresponding primary glioma cell culture models with a previously developed targeted mass spectrometry proteomic assay. We determined the relative abundance of a panel of metabolic enzymes. Results confirmed increased glutamate use and decreased aerobic glycolysis in resected IDH1 R132H glioma tissue samples. However, these metabolic profiles were not reflected in the paired glioma culture samples. Analysis of orthotopic glioma xenograft samples with and without the IDH1 mutation revealed metabolic profiles that more closely resembled clinical counterparts. We suggest that culture conditions and tumor microenvironment play a crucial role in maintaining the in vivo metabolic situation in cell culture models. For this reason, new models that more closely resemble the in vivo microenvironment, such as 3-dimensional cell co-cultures or organotypic multicellular spheroid models, need to be developed and investigated.
2022-02-14 | PXD024009 | Pride
Project description:The R132H mutation in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is the most important prognostic factor for survival of glioma patients. This resulted in many studies investigating the effects of this mutation, including those on energy metabolism. This led to the discovery of a panel of enzymes mainly involved in glutamate anaplerosis and aerobic glycolysis that change in abundance as a result of the IDH1 mutation. To further study these changes and investigate the therapeutic value of inhibitors of IDH1 R132H-associated metabolic pathways, appropriate glioma models are required that mimic in vivo metabolism as good as possible. To investigate how metabolism is affected by in vitro cell culture, we here compared surgically obtained snap frozen glioma tissues with their corresponding primary glioma cell culture models with a previously developed targeted mass spectrometry proteomic assay. We determined the relative abundance of a panel of metabolic enzymes. Results confirmed increased glutamate use and decreased aerobic glycolysis in resected IDH1 R132H glioma tissue samples. However, these metabolic profiles were not reflected in the paired glioma culture samples. Analysis of orthotopic glioma xenograft samples with and without the IDH1 mutation revealed metabolic profiles that more closely resembled clinical counterparts. We suggest that culture conditions and tumor microenvironment play a crucial role in maintaining the in vivo metabolic situation in cell culture models. For this reason, new models that more closely resemble the in vivo microenvironment, such as 3-dimensional cell co-cultures or organotypic multicellular spheroid models, need to be developed and investigated.
2022-02-16 | PXD024019 | Pride
Project description:A phase-1, multi-center study in recurrent non-enhancing gliomas with IDH1 R132H mutation for patients who require surgery. The purpose of this study is to evaluate the suppression of 2-HG (2-hydroxyglutarate) by comparing the concentration of 2-HG in resected tumors from IDH1 mutant glioma subjects following AG-120 or AG-881 treatment with the 2-HG concentration in untreated, control tumors. The safety, tolerability, PK/PD, and anti tumor activity data from the study in subjects with recurrent non-enhancing Grade 2/3 LGG with an IDH1 R132H mutation for whom surgical resection is indicated will identify the recommended dose of AG-120 and AG-881 for future studies in glioma. Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDHglioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration ofD-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1–97.6) and 91.1% (95% CrI, 72.0–97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of ‘proneural’ and ‘stemness’ gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDHLGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.
2023-05-11 | GSE232312 | GEO
Project description:Pilot study aimed at comparing miRNA profiles of human glioma cells with and without the R132H IDH1 mutation.
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