Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA271690 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Malaria is an infectious disease caused by parasites of the Plasmodium spp. In endemic areas, in approximately 1% of cases, almost exclusively in young children, malaria becomes severe resulting in nearly seven hundred thousand deaths each year in Africa alone. Cerebral malaria (CM) is a common form of severe malaria and one for which we have no effective adjunctive therapy. Although the cellular and molecular mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host’s immune response contribute to disease. Indeed, two hallmarks of CM are the sequestration of infected red blood cells in the brain vasculature and severe immune inflammation. The kinase, mammalian target of rapamycin (mTOR), through its regulation of cellular metabolism, is a central regulator of immune responses and drugs that inhibit the mTOR pathway have been shown to be antiparasitic, raising the possibility that mTOR inhibitors could be effective adjunctive therapies for CM. Here we show in a mouse model of CM, experimental CM (ECM), that the mTOR inhibitor rapamycin protects against ECM when administered within the first four days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood brain barrier and brain hemorrhaging, decreased the influx of both CD4+ and CD8+ T cells into the brain and the accumulation of parasitized red blood cells in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen and elevated the levels of peripheral parasitemia. These results open a new avenue for the development of highly selective adjunctive therapies for CM, by targeting pathways that regulate host and parasite metabolism
2018-01-06 | GSE64702 | GEO
Project description:Severe malaria encompasses a range of syndromes manifesting systemically or in diverse organs. These are believed to represent the end-stage processes of local parasite sequestration and inflammatory cascades. Classical anti-malarial drugs target parasites only. In treatment of severe disease, adjunctive therapies capable of controlling the inflammatory processes could be beneficial. Innate defense regulator (IDR) peptides display multiple immune modulatory activities. In this study, we assessed peptide IDR-1018, which shows promise as an anti-inflammatory drug, as a lead candidate for adjunctive host-directed therapy of established disease in the P. berghei ANKA model of experimental cerebral malaria (ECM). Intravenously administered IDR-1018 partially protected mice from ECM both prophylactically and in adjunctive treatment with classical anti-malarial drugs. We used transcriptional data from spleens and brains taken early in infection (day 3) of prophylactically treated mice to investigate the protective mechanisms. The microarrays compared spleens and brains from nine IDR-1018 i.v. treated, infected mice (IDR-1018-treated infected) with three saline i.v. treated infected mice (saline-treated infected) and three uninfected untreated control mice (controls). RNA samples were hybridized in randomized order to five Illumina WG-6 v2 BeadChips . No technical replicates were performed.
2012-04-08 | E-GEOD-32007 | biostudies-arrayexpress
Project description:Severe malaria encompasses a range of syndromes manifesting systemically or in diverse organs. These are believed to represent the end-stage processes of local parasite sequestration and inflammatory cascades. Classical anti-malarial drugs target parasites only. In treatment of severe disease, adjunctive therapies capable of controlling the inflammatory processes could be beneficial. Innate defense regulator (IDR) peptides display multiple immune modulatory activities. In this study, we assessed peptide IDR-1018, which shows promise as an anti-inflammatory drug, as a lead candidate for adjunctive host-directed therapy of established disease in the P. berghei ANKA model of experimental cerebral malaria (ECM). Intravenously administered IDR-1018 partially protected mice from ECM both prophylactically and in adjunctive treatment with classical anti-malarial drugs. We used transcriptional data from spleens and brains taken early in infection (day 3) of prophylactically treated mice to investigate the protective mechanisms.
2012-04-09 | GSE32007 | GEO
Project description:This research trial is testing a combination of two experimental drugs, MSC1936369B (Mitogen-activated protein extracellular signal-regulated kinase (MEK) Inhibitor) and SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR) inhibitor), in the treatment of locally advanced or metastatic solid tumors. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.
| 2109499 | ecrin-mdr-crc
Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes so there is great interest in understanding mTOR regulatory networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin only inhibits a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. To examine the complete spectrum of mTOR responsive cellular processes, we compared the transcriptional profiles of mammalian cells treated with rapamycin versus the ATP-competitive inhibitor PP242. Our analysis provides a genome-wide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin. Gene expression in mouse NIH3T3 cells was measured after 18 hour treatment with DMSO (control), 50 nM rapamycin, or 2 uM PP242. Four independent experiments were performed for each condition.
2011-03-15 | E-GEOD-27784 | biostudies-arrayexpress
Project description:<p>One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.</p>
| phs000535 | dbGaP
Project description:This is a mathematical describing the effect that DEP domain-containing mTOR-interacting protein (DEPTOR) has on the mammalian target of rapamycin (mTOR) signalling network.
2024-09-02 | BIOMD0000000823 | BioModels
Project description:The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibition has been shown to have clinical activity in patients with DLBCL, although overall response rates remain low. We therefore evaluated differences in the transcriptome between DLBCL cell lines with differential sensitivity to the mTOR inhibitor Rapamycin, to (A) identify gene-expression patterns(GEP) capable of identifying sensitivity to Rapamycin, (B) understand the underlying mechanisms of resistance to Rapamycin in DLBCL and (C) identify bioactive molecules likely to synergize with mTOR inhibitors. Using Affymetrix HuGene ST 1.0 microarrays, we were able to identify a gene expression signature capable of accurately predicting sensitivity and resistance to Rapamycin in DLBCL cell lines. Pathway analysis identified the serine/threonine kinase Akt as central to the differentially-expressed gene network. Connectivity mapping of our datasets identified compounds targeting the AKT pathway with a high likelihood of reversing the GEP associated with resistance to Rapamycin. Specifically, we evaluated the HIV protease inhibitor (PI) Nelfinavir, which is known to have anti-cancer and Akt-inhibitory properties, as well as the small molecule Akt inhibitor MK-2206, for their potential to synergize with to Rapamycin in DLBCL. Nelfinavir and MK-2206 caused profound inhibition of cell viability in combination with Rapamycin in DLBCL cell lines. Low nanomolar concentrations of Rapamycin inhibited phosphorylation of Akt and also downstream targets of activated mTOR when used in combination with these Akt inhibitors. These findings have the potential to significantly improve patient selection for mTOR inhibitor therapy, and to improve rates and depths of response. More broadly, they support the use of global RNA expression and connectivity mapping to improve patient selection and identify synergistic drug combinations for cancer therapy. DLBCL cell lines were tested for Rapamycin sensitivity and classified as "sensitive" or "resistant." Genome-wide analysis of all cell lines were performed using the Affymetrix HuGene ST 1.0 Array Platform. Genes with differential expression between sensitive and resistant cell lines were analyzed using Statistical Analysis of Microarrays (SAM) software, and a signature of genes determnined. This signature was found to accurately predict sensitivity or resistance of other DLBCL cell lines, and to identify the protein kinase Akt as central to resistance.
2012-04-29 | E-GEOD-27255 | biostudies-arrayexpress
Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes so there is great interest in understanding mTOR regulatory networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin only inhibits a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. To examine the complete spectrum of mTOR responsive cellular processes, we compared the transcriptional profiles of mammalian cells treated with rapamycin versus the ATP-competitive inhibitor PP242. Our analysis provides a genome-wide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin.
2011-03-15 | GSE27784 | GEO
Project description:The PI3K/mammalian target of rapamycin (mTOR) pathway is dysregulated in over 50% of human GBM but remains a challenging clinical target. Inhibitors against PI3K/mTOR mediators have limited clinical efficacy as single agents. Gene expression profiling after PI3K/mTOR inhibition treatment was analyzed by Affymetrix microarrays.
2016-05-20 | GSE79316 | GEO