Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA563773 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11470685_1.fastq.gz | Fastqsanger.gz | |||
| SRR11470685_2.fastq.gz | Fastqsanger.gz | |||
| SRR11470686_1.fastq.gz | Fastqsanger.gz | |||
| SRR11470686_2.fastq.gz | Fastqsanger.gz | |||
| SRR11470687_1.fastq.gz | Fastqsanger.gz |
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Project description:Diabetes onset is accompanied with β-cell deficiency, and thus restoring functional β-cell mass is a promising therapy for those with diabetes. However, the mechanisms of β-cell mass regulation are not fully understood. Previously, we demonstrated that Sox4 is required for β-cell proliferation during prediabetes. Here, we report that Sox4 regulates β-cell mass through modulating expression of the type 2 susceptibility gene GRK5. Newly generated β-cell specific Grk5 knockout mice showed impaired glucose tolerance with reduced β-cell mass. In agreement with this phenotype, cell cycle inhibitor genes, Cdkn1a and Ccng1 were upregulated in Grk5 knockout islets. Furthermore, we found that Grk5 positively regulates β-cell mass through phosphorylation of HDAC5 and subsequent transcription of immediate early genes (IEGs) such as Nr4a1, Fosb, Junb, Arc, Egr1 and Srf. Together, these studies suggest GRK5 is linked to type 2 diabetes through regulation of β-cell mass. GRK5 could become a potential target of cell therapy to preserve functional β cells during the progression towards frank diabetes.
2023-07-31 | GSE221716 | GEO
Project description:The immediate early gene product activity-regulated cytoskeleton-associate protein (Arc or Arg3.1) is a major regulator long-term synaptic plasticity with critical roles in postnatal cortical development and memory formation. However, the molecular basis of Arc function is not defined. Arc is a hub protein with interaction partners in the postsynaptic neuronal compartment and nucleus. In vitro biochemical and biophysical analysis of purified recombinant Arc show formation of low-order oligomers and larger particles including retrovirus-like capsids. Here, we provide evidence for naturally occurring Arc oligomers in mammalian brain. Using in situ protein crosslinking to trap weak Arc-Arc interactions, we identified in various preparations a prominent Arc immunoreactive band on SDS-PAGE of molecular mass corresponding to a dimer. While heavier Arc species or putative trimers and tetramers were detected, they were of lower abundance. In the dentate gyrus (DG) of adult anesthetized rats, induction of long-term potentiation (LTP) by high-frequency stimulation (HFS) of medial perforant synapses or by brief intrahippocampal infusion of BDNF led to a massive increase in Arc dimer expression. Arc immunoprecipitation of crosslinked DG tissue showed enhanced expression of dimer during four hours of LTP maintenance. Mass spectrometric proteomic analysis of immunoprecipitated, gel-excised bands corroborated detection of Arc dimer. Furthermore, Arc dimer was constitutively expressed in naïve cortical, hippocampal and DG tissue, with lowest levels in the DG. Taken together the results implicate Arc dimers as the predominant low-oligomeric form in mammalian brain, exhibiting regional differences in its constitutive expression and pronounced enhanced expression during DG LTP.
2023-07-20 | PXD039612 | Pride
Project description:ARC (NSC 188491, SMA-491), 4-amino-6-hydrazino-7-beta-d-ribofuranosyl-7H-pyrrolo-(2,3-d)-pyrimidine-5-carboxamide, is a nucleoside analog with profound in vitro anti-cancer activity. First identified in a high-throughput screen for inhibitors of p21 mRNA expression, subsequent experiments showed that ARC also repressed expression of hdm2 and survivin, leading to its classification as a global inhibitor of transcription 1. The following Hu U133 plus 2.0 arrays represent single time point (24 hour) gene expression analysis of transcripts altered by ARC treatment. Arrays for the other compounds (sangivamycin and doxorubicin) are included as comparators. Experiment Overall Design: MCF7 cells treated with ARC, Sangivamycin or Doxorubicin for 24 hours.
2008-11-15 | E-GEOD-13477 | biostudies-arrayexpress
Project description:Although persistent elevations in circulating glucose concentrations promote compensatory increases in pancreatic islet mass, unremitting insulin resistance causes a deterioration in beta cell function that disrupts glucose balance and signals the progression to diabetes 1. Glucagon like Peptide 1 (GLP1) agonists improve glucose tolerance in insulin resistance, although some individuals are unresponsive to treatment. Here we show that increases in GLP1 during feeding promote beta cell function in part through the PKA-mediated activation of CREB and its coactivator CRTC2 2. Mice with a knockout of CRTC2 in beta cells have impaired oral glucose tolerance due to decreases in circulating insulin concentrations. CRTC2 was found to promote beta cell function in part by stimulating the expression of the transcription factor MafA. Chronic hyperglycemia associated with high fat or high carbohydrate diet feeding disrupted cAMP signaling in pancreatic islets. Indeed, prolonged elevations in circulating glucose concentrations interfered with CREB signaling by activating the mTOR pathway and triggering the hypoxia inducible factor (HIF1)-dependent induction of the Protein Kinase A Inhibitor beta (PKIB), a potent inhibitor of PKA catalytic activity 3. As disruption of the PKIB gene restored glucose tolerance and insulin secretion in obesity, our results demonstrate how cross-talk between nutrient and hormonal pathways contributes to loss of pancreatic islet function in insulin resistance. Rat insulinoma cells were used to interrogate the impact of glucose exposure and CREB activity on cAMP dependent gene regulation in the pancreatic beta cells
2015-02-23 | E-GEOD-60158 | biostudies-arrayexpress
Project description:AIMS/HYPOTHESIS: Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. METHODS: Rkip1 (also known as Pebp1) knockout (Rkip1 (-/-)) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 (-/-) mice after streptozotocin treatment. RESULTS: Rkip1 (-/-) mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 (-/-) mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice. CONCLUSIONS/INTERPRETATION: These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration. Pancreatic gene expression of Rkip-1 (Raf kinase inhibitor 1) knockout (KO) and wild type (WT) mice, including three biological replicates in each group.
2012-11-19 | E-GEOD-31150 | biostudies-arrayexpress
Project description:Pancreatic beta-cell dysfunction and death are central in the pathogenesis of type 2 diabetes. Saturated fatty acids cause beta-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA-sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling beta-cell phenotype including PAX4 and GATA6. 59 type 2 diabetes candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. DAVID analysis of transcription binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced beta-cell dysfunction and death. The data point to crosstalk between metabolic stress and candidate genes at the beta-cell level. 5 human islet of Langerhans preparations examined under 2 conditions (control and palmitate treatment)
2014-01-09 | E-GEOD-53949 | biostudies-arrayexpress
Project description:Type 1 diabetes (T1D) is a chronic autoimmune disease that involves immune mediated destruction of β cells. How β cells respond to immune attack is unknown. We identified a population of β cells during the progression of T1D in non-obese diabetic (NOD) mice that survives immune attack. This population develops from normal β cells confronted with islet infiltrates. Pathways involving cell movement, growth and proliferation, immune responses, and cell death and survival are activated in these cells. There is reduced expression of β cell identity genes and diabetes antigens and increased immune inhibitory markers and stemness genes. This new subpopulation is resistant to killing when diabetes is precipitated with cyclosphosphamide. Human β cells show similar changes when cultured with immune cells. These changes may account for the chronicity of the disease and the long term survival of β cells in some patients.
2017-02-02 | GSE94382 | GEO
Project description:Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell function. Here, we assessed the global protein and individual PTP profile in the pancreas from diabetic NOD mice treated with anti-CD3 monoclonal antibody and IL-1 receptor antagonist (IL-1RA). The treatment reversed hyperglycemia compared to the anti-CD3 alone control group. We observed enhanced expression of PTPN2, a T1D candidate gene, and endoplasmic reticulum (ER) chaperones in islets from mice with reversed diabetes. To address the functional role of PTPN2 in β-cells, we generated PTPN2 deficient stem cell-derived β-like and human EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates the type I and type II IFN signalling networks, and the potential progression towards autoimmunity. Moreover, we established the capacity of PTPN2 to modulate the Ca2+-dependent unfolded protein response in β-cells. Adenovirus-induced overexpression of PTPN2 decreased BiP expression and partially protected from ER-stress induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.
2022-01-21 | GSE172148 | GEO
Project description:During Type 1 diabetes development, T lymphocytes infiltrate pancreatic islets and induce the destruction of the insulin-producing cells within the islets, the beta-cells. T lymphocytes are known to secrete pro-inflammatory cytokines but also exosomes that could contribute to the mechanisms leading to beta-cell death. In this project, we wanted to investigate the effect of exosomes released from T lymphocytes on beta-cell gene expression.
2018-09-11 | GSE92439 | GEO
Project description:Beta-endorphinergic neurons in the hypothalamic arcuate nucleus (ARC) synthesize beta-endorphin (β-EP) to alleviate nociceptive behaviors, although the underlying regulatory mechanisms remain unknown. Here, we elucidated a novel epigenetic pathway driven by microRNA regulation of beta-endorphin synthesis in ARC neurons to control neuropathic pain. In pain-injured rats miR-203a-3p was the most highly upregulated miRNA in the ARC. A similar increase was identified in the cerebrospinal fluid of trigeminal neuralgia patients. Mechanistically, histone deacetylase 9 downregulation increased acetylation of histone H3 lysine-18, facilitating the binding of NR4A2 transcription factor to the miR-203a-3p gene promoter increasing miR-203a-3p expression following nerve injury. Further, increased miR-203a-3p was found to maintain neuropathic pain by targeting proprotein convertase 1, an endopeptidase necessary for the cleavage of proopiomelanocortin, the precursor of β-EP. Our findings highlight an epigenetic regulatory pathway for β-EP synthesis that contributes to neuropathic pain development and maintenance mechanisms providing for new therapeutic targets for neuropathic pain treatment.
2023-10-17 | GSE216965 | GEO