Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA299103 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Oxidative stress reduces haematopoietic stem cell (HSC) function with age, and increased reactive oxygen species (ROS) levels promote DNA damage, cell senescence, and haematopoietic dysfunction. DDO1002, an effective Keap1–Nrf2 inhibitor, may regulate antioxidant gene expression, however, its ability to alleviate impaired haematopoiesis following total body irradiation (TBI) or ageing remains unclear. Through both cellular and mouse models, we showed that DDO1002 upregulated Nrf2, activated the Nrf2-mediated antioxidant response element (ARE) signalling pathway, reduced intracellular ROS levels and delayed cellular senescence. Moreover, DDO1002 reduced DNA damage and HSC apoptosis, thereby increasing the number of HSCs, lymphoid-primed MPP4 cells, and B cells in peripheral blood. Therefore, DDO1002 alleviates TBI-induced haematopoietic injury. Similarly, DDO1002 treatment activated the expression of Nrf2 and Nrf2-mediated ARE signalling pathways in the bone marrow cells of naturally ageing mice. B and T cell proportions in the spleen were increased, as was the colony-forming ability of bone marrow cells. Single-cell sequencing analysis revealed that DDO1002 treatment attenuated intracellular inflammatory signalling pathways and reduced the ROS pathway in aged HSCs, suggesting an ability to restore aged-HSC viability. Thus, DDO1002 effectively activated Nrf2 to delay cell senescence and improved impaired haematopoiesis via the Nrf2–ARE pathway, showing potential for treating age-related haematopoietic disorders.
2025-01-29 | GSE275533 | GEO
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
2023-08-20 | GSE234421 | GEO
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
2023-08-20 | GSE234417 | GEO
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
2023-08-20 | GSE234420 | GEO
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
2023-08-20 | GSE234419 | GEO
Project description:Mutations in isocitrate dehydrogenase-1 (IDH1 R132) and -2 (IDH2 R140 and R172), which confer neomorphic enzymatic activity converting αKG (α-ketoglutarate) to D-2-hydroxyglutarate (D2HG), occur commonly in acute myeloid leukemia (AML). Mutant IDH1 alters epigenetics and increases haematopoietic progenitors in vivo, consistent with D2HG-mediated inhibition of TET2 5-methylcytosine hydroxylase. As TET2 mutations are mutually exclusive with IDH1/2 mutations and confer a similar phenotype, it has been widely believed that the oncogenicity of mutant IDH1/2 is due to TET2 inhibition. However, IDH1/2 mutations may have additional effects explaining the clinical features of MDS/MPN/AML. Here we show that mutant IDH1 downregulates ATM, thereby inhibiting DNA damage responses and increasing genomic instability. To investigate potential mechanisms of ATM downregulation, we examined ATM promoter DNA methylation in Vav-IDH1-KI long term haematopoietic stem cells (LT-HSC), short term haematopoietic stem cells (ST-HSC) and multipotent progenitors (MPP).
2017-08-23 | GSE66536 | GEO
Project description:DNA damage activates diverse cellular responses – either protective or deleterious –that ultimately promote or inhibit proliferation. How the distinct responses conferring crucial cell fate decisions are chosen is unclear. Using a systems approach, we demonstrate that the dynamic features of Atm dependent DNA double-strand break (DSB) signalling response dictate cellular outcome. Combining temporal phosphoproteome and nascent transcriptome analyses after low or high DNA-damage-load, we discovered that some responses, such as Tp53 activation, have an activation threshold and others arise independently of DNA-damage-load. Using DSB repair deficient cells, we show that persistent DSBs alter the kinetics – but not the amplitude – of Atm signalling. Thus, we demonstrate that pathway choices are dictated by the signalling dynamics and hence cell fate decisions are responsive to DNA-damage-load and repair capacity of the cells.
2023-01-18 | PXD013620 | Pride
Project description:To gain insight in the kinetics and interplay of the predominant transcriptional responses of DNA damage signalling pathways in undifferentiated cells, mouse embryonic stem cells were exposed to cisplatin at four different time points (2, 4, 8 and 24 hr) and concentrations (1, 2, 5 and 10 uM). RNA was isolated and subjected to genome-wide expression profiling.
2006-04-27 | E-TABM-89 | biostudies-arrayexpress
Project description:The underlying mechanisms which are responsible and govern early haematopoietic differentiation during development are poorly understood. Gene expression comparison between pluripotent human embryonic stem cells and earliest haematopoietic progenitors may reveal novel transcripts and pathways and provide crucial insight into early haematopoietic lineage specification and development. Understanding of transcriptional cues that direct differentiation of human embryonic stem cells (hESC) to defined and functional cell types is essential for their future clinical applications. In this study we have undertaken a comparative transcriptional approach of haematopoietic progenitors derived from hESC at various stages of a feeder and serum free differentiation method and have shown that the largest transcriptional changes occur during the first four days of differentiation. Data mining based on molecular function pointed to RhoGTPase signalling as key regulator of this differentiation. Inhibition of this pathway using a chemical inhibitor (Y26732) resulted in a significant downregulation of haematopoietic progenitors throughout the differentiation window, thus uncovering a previously unappreciated role for RhoGTPase signalling in differentiation of hESC to haematopoietic lineages. There are a total of 4 samples within this microarray experiment with 2 biological replicates for each sample. Pluripotent human embryonic stem cells (day 0) underwent haematopoietic differentiation and at various stages of development (day 4, day 6, day8) differentiated cells were FACS sorted for two key haemangioblast markers, CD31 and KDR.
2012-01-06 | E-GEOD-29115 | biostudies-arrayexpress
Project description:In chronic kidney disease (CKD) and with ageing, individuals lose regenerative capacity after renal injury and are predisposed to progressive fibrosis and cardiovascular disease. With ageing and CKD increased numbers of activated leukocytes are present in the circulation and within the kidney where they correlate with progressive fibrosis. The potential role of activated leukocytes in mediating progressive renal and systemic fibrosis remains incompletely understood. Here, we show that tumour necrosis factor alpha (TNFa) released with injury and aging promotes renal and cardiac fibrosis. We identify a Ubiquitin D expressing population of TNFa induced inflammatory proximal tubular epithelia (iPT) responsible for Indian Hedgehog release in aged and fibrotic kidneys. Indian Hedgehog production by iPT cells activates canonical Hedgehog signalling in Gli1+ stromal cells leading to activation, proliferation and fibrosis deposition. Our data links the immune activation seen in aging and chronic kidney disease to cardio-renal fibrosis. This provides multiple targets for antifibrotic therapies which we validate in murine models of aging and kidney disease.
2023-01-30 | GSE178109 | GEO