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ABSTRACT:
PROVIDER: PRJNA448054 | ENA |
REPOSITORIES: ENA
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Project description:Primary familial brain calcification (PFBC) is a rare neurodegenerative and neuropsychiatric disorder characterized by bilateral and symmetric brain calcification along the microvessels or inside neuronal cells in the basal ganglia, thalamus, and cerebellum. Neurological symptoms typically include movement disorders, cognitive impairment, and neuropsychiatric signs. Slc20a2 homozygous (HO) knockout mice can simulate the phenotype of brain calcification observed in humans. However, the cellular and molecular mechanisms associated with brain calcification, particularly at an extremely early stage (before calcification emerges), remain largely unknown. Herein, we quantified central nervous system (CNS)-infiltrating immune cells in different age groups and found that CD45+CD3+ T cells were significantly increased in the brain parenchyma even in the pre-calcification stage of 1-month-old Slc20a2-HO mice. Further immunophenotyping demonstrated that CD3+CD4-CD8- and CD3+CD4+ T cells were the two main subtypes increased in the brain. The accumulation of total T cells appears to be associated with the severity of brain calcification. Paracellular and transcellular permeability of the blood-brain barrier increased in endothelial cells of brain microvessels in Slc20a2-HO mice. The expression of endothelial cell adhesion molecules was increased, while that of tight and adherens junction proteins was decreased, reflecting the molecular basis of T cell recruitment to endothelial cells and paracellular migration into the brain. IgG and albumin assays revealed an increased leakage of endothelial cells and the process of T cell transcellular migration was captured by immunoelectron microscopy, suggesting the enhancement of transcytosis or endocytosis in brain endothelial cells of Slc20a2-HO mice. The sphingosine 1-phosphate receptor modulator, FTY720, could significantly inhibit brain calcification, probably by reducing the CNS infiltration of T cells, subsequently modulating neuroinflammation, and enhancing the phagocytosis of CNS resident immune cells. This study demonstrated that CNS-infiltrating T cells were associated with the progression of brain calcification and suggested that the impairment of blood-brain barrier permeability, which was closely related to T cell invasion into the CNS, could be explained by an increase in the paracellular and transcellular pathways of brain endothelial cells in Slc20a2-HO mice. Moreover, FTY720 was a potential drug that could be used to treat patients with PFBC in the future
2022-11-23 | GSE218335 | GEO
Project description:The role of microglia in the formation of brain capillary calcification was investigated in a platelet-derived-growth factor B (PDGFB) hypomorph - Pdgfb ret/ret mouse model of human primary familial brain calcification.
2020-12-31 | GSE135449 | GEO
Project description:Mutations in isocitrate dehydrogenase 2 (IDH2) occur in many cancers including Acute Myeloid Leukemia (AML). In preclinical models mutant IDH2 causes partial hemopoietic differentiation arrest. Recently, we showed that single agent Enasidenib, a first-in-class, selective mutant IDH2 inhibitor, produces a 40% response in relapsed/refractory AML patients by promoting differentiation. Yet, the rate, extend and duration of the clinical benefits of Enasidenib vary from one patient to another. To investigate how the genetic mutational landscape, at baseline or at relapse, contributes in modulating response to Enasidenib, WES analyses on FACS-sorted blasts from baseline, best response and/or relapse samples from 16 Enasidenib-treated patients were performed. WES analyses were also performed on the CD3+ cells from the same patients, which may be used as germinal control samples.
2018-08-13 | E-MTAB-6299 | biostudies-arrayexpress
Project description:Blood samples from patients with myeloid malignancies were analyzed using whole exome sequencing (WES). Data set from genotyping by microarray of the same samples has been deposited in ArrayExpress under accession number E-MTAB-1845 (https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1845/).
2013-11-01 | E-MTAB-1850 | biostudies-arrayexpress
Project description:WES and RNAseq from tumor samples of patients treated on clinical trial
2021-08-20 | GSE174765 | GEO
Project description:Aims/hypothesis. Ectopic calcification is a typical feature of diabetic vascular disease and resembles an accelerated aging phenotype. We previously found an excess of myeloid calcifying cells (MCCs) in diabetic patients. We herein examined molecular and cellular pathways linking atherosclerotic calcification with calcification by myeloid cells in the diabetic milieu. Methods. We first examined the associations among coronary calcification, MCC levels, and mononuclear cell gene expression in a cross-sectional study of 87 type 2 diabetic patients undergoing elective coronary angiography. Then, we undertook in vitro studies on mesenchymal stem cells (MSCs) and on the THP-1 myeloid cells line to verify the causal relationships of the observed associations. Results. Coronary calcification was associated with 2.8-times higher MCC levels (p=0.037) and 50% elevated expression of the osteogenic gene RUNX2 in mononuclear cells, whereas expression of Sirtuin-7 (SIRT7) was inversely correlated with calcification. In standard differentiation assays of MSCs, SIRT7 knockdown activated the osteogenic program and worsened calcification, especially in the presence of high (20 mM) glucose. In the monocytic cell line THP-1, SIRT7 downregulation drove a pro-calcific phenotype, whereas SIRT7 overexpression prevented high-glucose induced calcification. Through the JAK/STAT pathway, high glucose induced miR-125b-5p, which in turn targeted SIRT7 in myeloid cells and was directly associated with coronary calcification. Conclusions/interpretation. We describe a new pathway elicited by high glucose trough the JAK/STAT cascade, involving regulation of SIRT7 by mir-125b-5p driving calcification by myeloid cells. This pathway is associated with coronary calcification in diabetic patients and may be a target to tackle diabetic vascular disease.
2022-01-15 | GSE193510 | GEO
Project description:In this study, we analyze DNA whole-exome sequencing (WES) data from 3 patients with m.14487T>C mutation to detect rare candidate SNVs.
2020-05-19 | GSE131740 | GEO
Project description:Vascular calcification contributes to high cardiovascular mortality in chronic kidney disease (CKD) patients. An association between the uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) and cardiovascular disease has been suggested. This study provides strong etiological evidence for indoxyl sulfate and p-cresyl sulfate as major contributors to vascular calcification in chronic kidney disease patients. Continuous exposure to indoxyl sulfate or p-cresyl sulfate in rats with chronic kidney disease promotes moderate to severe calcification in the aorta and peripheral vessels. Unbiased proteomic analyses of arterial samples coupled to functional bioinformatics annotation analysis revealed that calcification events were associated with acute phase response signaling, coagulation and glucometabolic signaling pathways, while escape from toxin-induced calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Activation of inflammation and coagulation pathways in the arterial wall plays a pivotal role in toxin-induced calcification and strongly associates with hyperglycemia and insulin resistance. These findings reveal new perspectives to establish novel therapeutic targets to prevent, halt progression or cure vascular calcification.
2019-06-13 | PXD012582 | Pride