Effect of BTK and GSK3 inhibition on gene expression in primary peripheral human B cells
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ABSTRACT:
PROVIDER: PRJNA848850 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the BTK and GSK3 in the regulation of human B cell biology, we treated B cells from peripheral blood with either vehicle or BTK inhibitor or GSK3 in presence or absence of BCR cross-linking antibodies. We then performed gene expression profiling analysis using data obtained from RNA-seq of those samples at 24hrs.
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Project description:Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. While BTK inhibition does not impact humoral memory survival, antigen-driven clonal expansion of memory B cells and antibody secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of BTK inhibition. We used Affymetrix genechips to profile the transcriptional changes downstream of BTK inhibition after in vivo B-cell activation by anti-IgD Mice were injected with the novel BTK inhibitor PF-303 2 hours prior to anti-IgD mediated in vivo B-cell activation; B-cells where harvested 2 hours after anti-IgD activation and RNA isolated.
2014-08-01 | E-GEOD-56483 | biostudies-arrayexpress
Project description:Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. While BTK inhibition does not impact humoral memory survival, antigen-driven clonal expansion of memory B cells and antibody secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of BTK inhibition. We used Affymetrix genechips to profile the transcriptional changes downstream of BTK inhibition after in vivo B-cell activation by anti-IgD
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Project description:HeLa cell extracts with or without GSK3 enzyme inhibition were assayed using protein microarrays in order to detect GSK3-dependent changes in protein polyubiquitination.
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Project description:HeLa cell extracts with or without GSK3 enzyme inhibition were assayed using protein microarrays in order to detect GSK3-dependent changes in protein polyubiquitination. HeLa lysates in triplicates were supplemented with ubiquitin and incubated on protein microarrays (ProtoArray 5.0; Invitrogen) in the presence or absence of the GSK3 inhibitor SB-216763. Polyubiquitination of the arrayed proteins was detected using specific antibodies. ProtoArray 5.0 contains over 9,000 full-length human proteins purified and arrayed in duplicate under native conditions to maximize functionality.
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Project description:To compare transcriptional changes of germinal center B cells upon GSK3 inhibition, induced GC B cells were treated with GSK3 inhibitor, CHIR99021. 407 differentially expressing genes were identified
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Project description:We identified GSK3 as a regulator of GBM cell survival using microarray analysis, small molecule and genetic inhibitors of GSK3 activity. Various molecular and genetic approaches were then employed to dissect out the molecular mechanisms responsible for GSK3 inhibition-induced cytotoxicity. Keywords: time course
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Project description:Bruton's tyrosine kinase (Btk) is important for B lymphocyte development. To identify genes that are differentially expressed in primary B cells lacking functional Btk, splenocytes from X-linked immunodeficiency (Xid), Btk knockout (KO) and immunocompetent CBA mice, were used in microarrays containing more than 12,000 genes and expressed sequence tags (ESTs). We found 4515 transcripts expressed in duplicate experiments in all three strains. Out of these, 38 were differentially expressed genes (21 up-regulated >2 fold and 17 down-regulated <-2 fold) between CBA and Btk defective mice. Ten out of these genes were selected and quantitative Real-Time PCR was conducted for validation and further investigation. Real-Time experiments correlated nicely with the microarray data. No definitive phenotypic difference has previously been reported between Xid and Btk KO mice. We found 7 genes, whose expression differed (>2 fold) between the two strains. Moreover, when the 38 genes, which differed between immunocompetent CBA and Btk defective mice were ranked according to fold-increase, the levels in Btk KO mice were significantly more altered. This suggests that the defect in Btk KO mice is more severe and demonstrates that the mutant Btk protein in Xid mice does not generally function as dominant negative form. Experiment Overall Design: 6 Affymetrix U74Av2 GeneChip arrays was run. Three initially with CBA, Xid and Btk KO mice and then additional three chips with new RNA preperations from new CBA, Xid and Btk KO mice.
2007-08-31 | E-GEOD-2826 | biostudies-arrayexpress
Project description:We describe a previously unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcgR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment nor lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.
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Project description:The goal of this study was to determine how GSK3 inhibition/beta Catenin stabilisation affects the transcription profile of pre B cells
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