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Cyclin-dependent kinase 9 is a therapeutic target for anti-TNF resistant inflammatory bowel disease

ABSTRACT: Cyclin-dependent kinase 9 is a therapeutic target for anti-TNF resistant inflammatory bowel disease

PROVIDER: PRJNA723035 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14276039_1.fastq.gz	Fastqsanger.gz
	SRR14276039_2.fastq.gz	Fastqsanger.gz
	SRR14276040_1.fastq.gz	Fastqsanger.gz
	SRR14276040_2.fastq.gz	Fastqsanger.gz
	SRR14276041_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Cyclin-dependent kinase 9 is a therapeutic target for anti-TNF resistant inflammatory bowel disease

Project description:The treatment of auto-inflammatory diseases is often limited by resistance to single cytokine blockade, primarily anti-TNF antibodies. This is a particularly important cause of treatment failure in inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis and is genetically linked to mucosal inflammation by causal variation in its binding sites. However, transcription factors such as T-bet are difficult to target therapeutically. Using CDK9 inhibitors, we show that modulation of P-TEFb (cyclinT1/CDK9), a transcriptional elongation factor downstream of T-bet, potently represses genes responsible for pro-inflammatory signalling, and in particular genes regulated by T-bet. Remarkably, CDK9 inhibition targets genes that are highly expressed in anti-TNF resistant IBD and that predict non-response to anti-TNF therapy. Collectively, our findings reveal CDK9 as a potential target in anti-TNF resistant IBD, which has the potential for rapid translation to the clinic.

2022-06-17 | GSE172372 | GEO

A multi-omics approach to understand and predict therapeutic success of anti-TNF and anti-integrin agents in inflammatory bowel disease

Project description:In this study we wanted to identify baseline predictors of successful anti-TNF and vedolizumab therapy in patients with inflammatory bowel disease (based on tissue transcriptomics and CD4/CD14 transcriptomics)

2023-10-31 | E-MTAB-7914 | biostudies-arrayexpress

Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling

Project description:Tumor necrosis factor (TNF) is one of the few cytokines successfully targeted by therapies against inflammatory diseases. However, blocking this well studied and pleiotropic ligand can cause dramatic side-effects. We reasoned that a systems-level proteomic analysis of TNF signaling could dissect its diverse functions and offer a base for developing more targeted therapies. Combining phosphoproteomics time course experiments with spatial and kinase inhibitor analysis clusters phosphorylations into functional modules. The majority of regulated phosphorylations could be assigned to an upstream kinase by inhibiting master kinases and spatial proteomics revealed phosphorylation-dependent translocations of hundreds of proteins upon TNF stimulation. Phosphoproteome analysis of TNF-induced apoptosis and necroptosis revealed a key role for transcriptional cyclin-dependent kinase (CDK) activity to promote cytokine production and prevent excessive cell death downstream of the TNF signaling receptor. Our comprehensive interrogation of TNF induced pathways and sites can be explored at http://tnfviewer.biochem.mpg.de/.

2021-10-11 | PXD021366 | Pride

Whole transcription profile of responders to anti-TNF drugs in pediatric inflammatory bowel disease

Project description:Background: In pediatric inflammatory bowel disease (IBD) up to 30% of patients do not respond to anti-TNF therapy. The aim was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. Methods: The study population included 29 responders and 9 non-responders to anti-TNF therapy patients aged <18 years with IBD who started treatment with infliximab or adalimumab. Whole gene expression profiles from total RNA isolated from whole-blood samples of 6 responders and 6 non-responders taken before biologic administration and after 2 weeks were analyzed by RNA next-generation sequencing. The expression of 6 selected genes was measured for validation in all of 38 patients recruited using qPCR; Results: Differentially expressed genes in non-responders versus responders to anti-TNF treatment were identified, 32 prior treatment initiation and 44 after 2 weeks (Log2FC (Fold change)>0.6 o <-0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B and GBP1 were overexpressed in non-responders after 2 weeks of anti-TNF treatment (Log2FC 1.05, 1.21 and 1.08, respectively, p value <0.05,); Conclusion: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.

2021-01-14 | GSE159034 | GEO

A divergent cyclin/cyclin-dependent kinase complex controls progression through the atypical replicative cycles during Plasmodium berghei gametogony

Project description:A divergent cyclin/cyclin-dependent kinase complex controls progression through the atypical replicative cycles during Plasmodium berghei gametogony

| PRJNA604771 | ENA

A divergent cyclin/cyclin-dependent kinase complex controls progression through the atypical replicative cycles during Plasmodium berghei gametogony

Project description:Cell-cycle transitions are generally triggered by variations in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria-causing parasites have evolved unique cell-cycles with a repertoire of ancestral CDKs and cyclins whose functions and interdependency remain elusive. Here, we show that the divergent Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical cell-cycle regulator of gametogony required for transmission to the mosquito. It phosphorylates canonical CDK motifs on components of the pre-replicative complex and is essential for DNA replication. We also provide evidence for indirect regulation of the concomitant progression through M-phase. Over a replicative cycle, CRK5 stably interacts with a single Plasmodium-specific cyclin (SOC2) with no evidence of SOC2 cycling through transcription, translation nor degradation. Our results present evidence that during Plasmodium gametogony, a unique and divergent cyclin/CDK pair evolved to fulfil the functional space of multiple eukaryotic cell-cycle kinases controlling S-phase entry and progression through M-phase.

2020-06-17 | GSE144743 | GEO

A multi-omics approach to understand and predict therapeutic success of anti-TNF and anti-integrin agents in inflammatory bowel disease

Project description:A multi-omics approach to understand and predict therapeutic success of anti-TNF and anti-integrin agents in inflammatory bowel disease

| PRJEB32332 | ENA

A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding

Project description:A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding

| PRJNA873102 | ENA

Sustained expression of cyclin D1 or cyclin D1/KE in mouse mammary gland

Project description:Analysis of mammary glands from tet-inducible(rtTA) transgenic mice expressing cyclin D1 using Affymetrix Mouse Gene 1.0 ST GeneChip arrays. MMTV-rtTA transgenic mice (MMTV-Mouse Mammary Tumor Virus promoter) were cross-mated to cyclin D1 transgenic mice under control of tet operon. 8-week-old tetracycline-inducible cyclin D1/rtTA bi-transgenic pregnant female mice (12 days postcoitus) were treated with doxycycline through drinking water supplementation at a final concentration of 2 mg/ml. Control mice were rtTA transgenics alone and treated in the same manner. After 7 days of doxycycline treatment, the mice were sacrificed and mammary glands taken for RNA isolation. Results provide insight into the in vivo gene expression pattern regulated by cyclin D1 through acute induction. Analysis of mammary glands from MMTV-cyclin D1/WT and MMTV-cyclin D1/KE using Affymetrix Mouse 430A v2.0 GeneChip arrays. Cyclin D1 point mutant, cyclin D1/KE K112E (K112E) contains a lysine to glutamine substitution at amino acid position 112. cyclin D1. The cyclin D1/KE mutant fails to induce cyclin D1-dependent kinase activity. Female MFD1, MFD1-KE, and WT mice were monitored twice weekly, up to 760 days, for the development of palpable tumors. Those developing palpable tumors were sacrificed within a week of tumor detection. Tumors were dissected and portions snap frozen for RNA isolation. Results provide insight into the in vivo gene expression pattern regulated by cyclin D1 that is kinase independent. Two separate control mice were positive for MMTV-rtTA transgene compared to 3 separate cyclin D1/rtTA bitransgenic female mice and 3 separate cyclin D1 KE mutant/rtTA bitransgenic female mice (Mouse Gene 1.0 ST arrays). Three separate control WT FvBmice were compared to three MMTV-cyclin D1/WT and 3 MMTV-cyclin D1/KE mice (Mouse 430A v2.0 arrays).

2013-12-31 | E-GEOD-43216 | biostudies-arrayexpress

Therapeutic TNF Inhibitors Exhibit Differential Levels of Efficacy in Accelerating Cutaneous Wound Healing

Project description:Adalimumab is the only FDA- and EMA-approved treatment for moderate-to-severe hidradenitis suppurativa (HS), suggesting that the mechanism of action of adalimumab is distinct in HS and may contribute to improved wound healing. We have demonstrated that adalimumab, but neither etanercept nor certolizumab-pegol, induces a wound healing profile in vitro, which may underlie the differences in efficacy between various anti-TNF agents. To examine and compare the efficacy of therapeutic TNF inhibitors in chronic cutaneous wound healing in vivo, a human TNF knock-in Leprdb/db mouse model was established. The vehicle group exhibited severe impairments in cutaneous wound healing. In contrast, adalimumab significantly accelerated healing, confirmed by both histologic assessment and a unique healing transcriptional profile. Moreover, adalimumab and infliximab showed similar levels of efficacy, but golimumab was less effective, along with etanercept and certolizumab-pegol. In line with histologic assessments, proteomics analyses from healing wounds exposed to various TNF inhibitors revealed distinct and differential wound healing signatures that may underlie the differential efficacy of therapeutic inhibitors in accelerating chronic wound healing.

2023-09-11 | PXD040275 | Pride

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