Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA563529 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10187288.fastq.gz | Fastqsanger.gz | |||
| SRR10187291.fastq.gz | Fastqsanger.gz | |||
| SRR10187295.fastq.gz | Fastqsanger.gz | |||
| SRR10187297.fastq.gz | Fastqsanger.gz |
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Project description:anti-CD3 + anti-CD46 stimulation for 2hr Patient has a mutation in CD46 that leads to reduced cell surface CD46 expression and suffers from episodes of atypical hemolytic uremic syndrome (aHUS), common variable immune deficiency (CVID) and recurrent infections
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Project description:Highly pathogenic avian influenza viruses (HPAIV) induce severe inflammation in poultry and men. There is still an ongoing threat that these viruses may acquire the capability to freely spread as novel pandemic virus strains that may cause major morbidity and mortality. One characteristic of HPAIV infections is the induction of a cytokine burst that strongly contributes to viral pathogenicity. It has been suggested, that this cytokine overexpression is an intrinsic feature of infected cells and involves hyperinduction of p38 mitogen activated protein kinase (MAPK). Here we investigate the role of MAPK p38 signaling in the antiviral response against HPAIV in mice as well as in endothelial cells, the latter a primary source for cytokines during systemic infections. Global gene expression profiling of HPAIV infected endothelial cells in the presence of the MAP kinase p38-specific inhibitor SB202190 revealed, that inhibition of MAPK p38 leads to reduced expression of interferon (IFN) and other cytokines after A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Bratislava/79 (H7N7) infection. Furthermore, the expression of interferon stimulated genes (ISGs) after treatment with IFN or conditioned media from HPAIV infected cells was decreased when the target cells were preincubated with SB202190. Finally, promoter analysis confirmed a direct impact of p38 MAPK on the IFN-enhanceosome and ISG-promoter activity. In vivo inhibition of MAP kinase p38 greatly diminishes virus induced cytokine expression concomitant with reduced viral titers, thereby protecting mice from lethal infection. These observations show, that MAPK p38 acts on two levels of the antiviral IFN response: Initially the kinase regulates IFN induction and at a later stage MAPK p38 controls IFN signaling and thereby expression of IFN-stimulated genes. Thus, inhibition of MAP kinase p38 may be an antiviral strategy that significantly protects mice from lethal influenza via suppression of overshooting cytokine expression. HUVEC were infected with FPV in the presence or absence of a p38 MAP kinase inhibitor
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Project description:Transcriptome analysis of human coronary arterial endothelial cells (HCAEC) primary cultures exposed to uremic serum from patients with stage 4-5 cardiovascular diseases (CKD) without myocardial infarction (USI) and stage 4-5 CKD with myocardial infarction (UCI). Gene expression profile of human coronary arterial endothelial cells (HCAEC) primary cultures exposed to uremic serum from of patients with chronic kidney disease (CKD) that explore which pathways are involved in in the development of cardiovascular disease. The metabolic pathway significantly represented was the MAPK signaling pathway, suggesting that the effects of uremic toxins present in patients with CDK, on the primary cultures of HCAEC provides a more informative model for the study of molecular mechanisms that lead to the development of endothelial dysfunction secondary to CKD.
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Project description:Changes in endothelial phenotype induced by E. coli-derived Shiga toxins (Stx) are believed to play a critical role in the pathogenesis of hemolytic uremic syndrome. Stx inactivate host ribosomes, but also alter gene expression at concentrations that minimally affect global protein synthesis. The effect of Stx on the gene expression profile of human microvascular endothelial cells was examined using the Affymetrix HG-U133A platform. Data were processed using 13 different methods and revealed 369 unique differentially expressed genes, 318 of which were up-regulated and 51 of which were down-regulated. These studies implicated activation of the CXCR4/CXCR7/SDF-1 chemokine pathway in Stx-mediated pathogenesis. Primary human dermal microvascular endothelial cells were treated with vehicle or Shiga toxin (10 fM, 24 h, n = 6) and changes in steady-state mRNA levels were determined by hybridization to Affymetrix HG-U133A arrays
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Project description:Medial artery calcification and calcific uremic arteriolopathy (CUA) are observed in patients with chronic kidney disease (CKD). They are strongly associated with increased morbidity and mortality, yet the underlying mechanisms are poorly understood, and no effective drug targets have been developed. Herein, we observed that a high phosphate, low protein (HPi-Lp) diet induced medial artery and skin arteriolar calcification in 5/6 nephrectomy (5/6 Nx) CKD mice. We further determined that p38 MAPK signaling was critical in this vasculopathy. Calcification was examined using a micro-CT scan, Alizarin Red staining, Von Kossa staining, and calcium assay. Additionally, we found that the HPi-Lp diet feeding aggravated glomerulus impairment and renal fibrosis in 5/6 Nx mice. Using RNA-Seq analysis, we identified that p38 MAPK signaling was specifically activated in the 5/6 Nx-HPi-Lp mice. Inactivation of p38 MAPK signaling using a pharmacological inhibitor SB203580 significantly reduced medial artery calcification, skin arteriolar calcium deposits, and kidney fibrosis. Collectively, our data suggest that 5/6 Nx mice fed a HPi-Lp diet can be used as a reliable mouse model for studying medial artery and CUA arteriolar calcification. Additionally, targeting p38 MAPK signaling could be a promising therapeutic strategy to mitigate these vascular disorders in patients with CKD.
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Project description:Recent data indicate that intracellularly activated and autocrine-functioning complement activation fragments - in conjunction with an NLRP3 inflammasome - is critical for normal human Th1 induction and contraction. More specifically, engagement of of the C3aR and CD46 by autocrine generated C3a and C3b, respectively, drives the metabolic reprogramming needed for IFN-gamma secrtion by human CD4+ T cells. It was not clear whether autocrine complement and/or the NLRP3 inflammasome are also needed for normal human cytotoxic CD8+ T cell (CTL) responses. During this study, we used CTLs isolated from patients with either CD46 deficiency or with NLRP3 hyperactivity to determine that CD46 is also required for normal IFN-gamma secretion as well as killing activity in CTLs, whilst a canonical NLRP3 inflammasome is not required for these key functions. The CD46-deficient patient utilized in this study has a mutation in the CD46 gene that leads to reduced cell surface CD46 expression and a dysfunction in Th1 induction. The patient suffers from episodes of atypical hemolytic uremic syndrome (aHUS) and common variable immune deficiency (CVID) and recurrent infections.
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Project description:Changes in endothelial phenotype induced by E. coli-derived Shiga toxins (Stx) are believed to play a critical role in the pathogenesis of hemolytic uremic syndrome. Stx inactivate host ribosomes, but also alter gene expression at concentrations that minimally affect global protein synthesis. The effect of Stx on the gene expression profile of human microvascular endothelial cells was examined using the Affymetrix HG-U133A platform. Data were processed using 13 different methods and revealed 369 unique differentially expressed genes, 318 of which were up-regulated and 51 of which were down-regulated. These studies implicated activation of the CXCR4/CXCR7/SDF-1 chemokine pathway in Stx-mediated pathogenesis.
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Project description:In this experiment, we explore if circulating microRNAs are altered in patients with atypical hemolytic uremic syndrome (aHUS). To do so, we analyze 4 different pooled samples of aHUS (Pool 1-4) in the arrays and 2 pools of age and gender-matched control samples (Pool F and Pool M). aHUS pools consist of patients samples with different characteristics regarding the presence of complement gene mutations: Pool 1: patients without identified mutations (n=5) Pool 2: patients with mutations in CFH (n=5) Pool 3: patients with mutations in MCP (n=5) Pool 4: patients with mutations in C3 or CFB (n=5) In the case of the control samples, pool F consists of 10 samples of healthy women and pool M consists of 10 samples of healthy men. In conclusion, circulating miRNAs levels are altered in aHUS compared with controls. This alteration is variable and could be mediated by the presence of the complement genetic defect.
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