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GSE119559
Homo sapiens
2 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The discovery of mammalian cardiac progenitor cells has suggested that the heart consists of not only terminally differentiated beating cardiomyocytes, but also a population of self-renewing stem cells with the potential to generate new cardiomyocytes (Anderson, Self et al. 2007; Bearzi, Rota et al. 2007; Wu, Chien et al. 2008). A consequence of longevity is continual exposure to environmental and xenobiotic stresses, and recent literature suggests that hematopoietic stem cell pools tightly control cell health through upregulation of the integrated stress response and consequent cellular mechanisms such as apoptosis. However, whether or not this biological response is conserved in progenitor cells for later lineages of tissue specific stem cells is not well understood. Using human induced pluripotent stem cells (iPSC) of both cardiac progenitor and mature cardiomyocyte lineages, we found that the integrated stress response was upregulated in the iPSC cardiac progenitors leading to an increased sensitivity for apoptosis relative to the mature cardiomyocytes. Of interest, C/EBP homologous protein (CHOP) signaling plays a mechanistic role in the cell death phenotype observed in iPSC progenitors, by which depletion of CHOP prevents cell death following cellular stress by thapsigargin exposure. Our studies suggest that the integrated stress response plays a unique role in maintaining iPSC cardiac progenitor cellular integrity by removing unhealthy cells via apoptosis following environmental and xenobiotic stresses, thus preventing differentiation and self-renewal of damaged cells.
Publication Title
The Integrated Stress Response Regulates Cell Health of Cardiac Progenitors.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Rattus norvegicus
- 51 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the TXG-MAP). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses compliment traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.
Publication Title
Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 364 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPAR ligands.
Publication Title
Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization.
Sample Metadata Fields
Specimen part, Subject
View Samples- Rattus norvegicus
- 53 Downloadable Samples
- Affymetrix Rat Expression 230A Array (rae230a)
Description
We characterized the insulin sensitivity and multi-tissue gene expression profiles of lean and insulin resistant, obese Zucker rats untreated or treated with one of four PPAR ligands (pioglitazone, rosiglitazone, troglitazone, and AG035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand insulin-sensitizing potency was related to ligand-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats, albeit to varying degrees.
Publication Title
Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
IlluminaHiSeq2000
Description
The goal of this study was to determine the transcriptional changes associated with breast cancer cells undergoing vascular mimicry in a 3D assay. Two breast cancer cell lines were plated on matrigel in the presence or absence of serum. MDA-MB-231 cells undergo vascular mimicry on matrigel in the absence of serum, MDA-MB-453 cells do not. Overall design: Four samples were analyzed. MDA-MB-231 and MDA-MB-453 cells were plated for 24 hours on matrigel in the presence or absence of serum. MDA-MB-231 cells undergo vascular mimicry when plated on matrigel in the absence of serum, while MDA-MB-453 cells do not.
Publication Title
ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 5 Downloadable Samples
- IlluminaHiSeq2000
Description
Inhibition of SET by siRNA or SET antagonist and CIP2A by siRNA can downregulate c-MYC and c-MYC target genes. Overall design: Cells were treated with a SET antagonist (1µMOP449) for 12 hours, or siRNA for 48 hours.
Publication Title
Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 35 Downloadable Samples
- Illumina HiSeq 2500
Description
Retinopathy of prematurity (ROP) is the most common cause of childhood blindness worldwide and is caused by oxygen therapy necessary to prevent mortality after premature birth. We have previously demonstrated the efficacy of systemic hypoxia inducible factor (HIF) stabilization through HIF prolyl hydroxylase inhibition (HIF PHi) in protecting retinal vasculature from oxygen toxicity in a mouse model of ROP or oxygen induced retinopathy (OIR). We definitively demonstrated that hepatic HIF-1 can be activated to confer this protection using systemic dimethyloxalylglycine (DMOG) to prevent HIF-1a degradation. In this study we compare Roxadustat, a small molecule stabilizer of HIF-1 currently in phase 3 clinical trials for increasing erythropoiesis in adult patients with chronic kidney disease, to DMOG. We demonstrate that Roxadustat induces vascular protection during hyperoxia to induce the coordinated sequential growth of retinal vasculature with a 3-fold reduction in oxygen induced capillary loss (p-=0.001). In order to define the molecular mechanism of protection, we further compared the transcriptome of both liver and retina after systemic treatment with Roxadustat or DMOG. Similar gene expression profiles were identified in liver but very different effects on transcription were found in retinal tissues because Roxadustat, in contrast to DMOG, directly targets retina, confirmed by western blot and by rescue of the hepatic HIF-1 KO, two criteria that DMOG treatment is unable to fulfill. Systems pharmacologic analysis demonstrates that Roxadustat induces typical HIF regulated genes critical to aerobic glycolysis in liver and retinal tissues whereas DMOG, acting through either secreted hepatokines or by influence of systemic DMOG, downregulates cell adhesion/extracellular matrix interaction pathways while increasing expression of histone cluster genes. Stratification of liver transcriptomes to secreted gene products again shows close consensus of hepatic genes induced by both small molecules, and includes upregulation of a plethora of angiogenic proteins such as plasminogen activator inhibitor (PAI-1), erythropoietin (EPO), and orosomucosoid 2 (ORM2). Secondary validation of these transcripts by serum ELISA confirms secretion of EPO and PAI-1 into blood from liver. These findings definitively demonstrate that HIF stabilization can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect, hepatic HIF-1 stabilization and increased serum angiokines. Systems pharmacology analysis therefore explains why intermittent, low dosage of small molecule HIF stabilizers creates a profound protective phenotype, because both pathways can take advantage of cytoprotection induced by the liver and by retina synergistically. These data provide a rationale for considering low dose, intermittent systemic administration of Roxadustat, currently in phase 3 trials in adults with chronic kidney disease, to eradicate ROP in children. Overall design: RNA-Seq of mice treated with PBS (control), DMOG, or Roxadustat from liver or retina.
Publication Title
Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Cigarette smoking is the leading cause of emphysema in the United States. Alveolar macrophages play a critical role in the inflammation-mediated remodeling of the lung parenchyma in emphysema. However, the exact gene pathways and the role of DNA methylation in moderating this pathological transformation are not known. In order to more exactly understand this process, we compared genome-wide expression and methylation signatures of alveolar macrophages isolated from heavy smokers with those isolated from non-smoking controls. We found enrichment of differential methylation in genes from immune system and inflammatory pathways as determined by standard pathway analysis. Consistent with recent findings, significant methylation changes were particularly enriched in the areas flanking CpG islands (CpG shores). Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune system and inflammatory pathways. We conclude that alveolar macrophages from the lungs of smokers demonstrate coordinated changes in DNA methylation and gene expression that link to inflammation pathways. We suggest that further studies of DNA methylation in immune and inflammation-related gene expression are needed to understand the pathogenesis of emphysema and other smoking-related diseases.
Publication Title
Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression.
Sample Metadata Fields
Specimen part, Disease
View Samples- Macaca mulatta
- 10 Downloadable Samples
- Affymetrix Rhesus Macaque Genome Array (rhesus)
Description
The majority of transplanted organs are recovered from deceased donors after brain death (BD). BD has been hypothesized to compromise organ quality in part from the activation of systemic inflammation. The objective of this study was to characterize the immune response induced by BD in a well controlled non-human primate (NHP) model. Assessment of physiologic parameters (blood pressure, heart rate, urinary output, catecholamines, and cerebral angiograms) was used to confirm BD. After 6h of BD, we monitored changes in the peripheral blood by flow cytometry, liver gene expression by microarray and liver protein expression by Western blotting and immunohistochemistry (IHC). BD was indicated by a rapid increase in blood pressure followed by hemodynamic instability, hypotension, diabetes insipidus and the absence of cerebral blood flow and brain stem reflexes. Within the peripheral blood IL-6 levels and neutrophils increased and myeloid dendritic cells decreased in BD NHP when compared to living donor controls. Genes related to innate inflammatory response and apoptosis were significantly upregulated in BD NHP. BD livers showed increased expression of suppressor of cytokine signaling 3 (SOCS3) protein and the danger associated molecular pattern protein S100A9. Increased expression of intracellular cellular adhesion molecule 1 (ICAM-1) and major histocompatibility complex (MHC) II, neutrophil accumulation, and products of oxidative stress (carboxy methyl lysine (CML) and hydroxynonenal (HNE)) were detected by IHC in livers. Conclusion: These data indicate that BD leads to the rapid activation of an inflammatory response within the liver involving components of the innate immune response at the gene and protein levels. The activation of these inflammatory pathways may provide one explanation for the reduced post-transplant function of organs from brain dead donors.
Publication Title
Early activation of the inflammatory response in the liver of brain-dead non-human primates.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 2 Downloadable Samples
- Illumina Genome Analyzer II
Description
Examination of Pin1-regulated Myc target genes in a human breast epithelial cell line. Overall design: Two samples: control GFP-expressing MCF10A-Myc cells and Pin1-expressing MCF10A-Myc cells.
Publication Title
Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples