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GSE17933
Mus musculus
190 Downloadable Samples
Description
The process for evaluating chemical safety is inefficient, costly, and animal intensive. There is growing consensus that the current process of safety testing needs to be significantly altered to improve efficiency and reduce the number of untested chemicals. In this study, the use of short-term gene expression profiles was evaluated for predicting the increased incidence of mouse lung tumors. Animals were exposed to a total of 26 diverse chemicals with matched vehicle controls over a period of three years. Upon completion, significant batch-related effects were observed. Adjustment for batch effects significantly improved the ability to predict increased lung tumor incidence. For the best statistical model, the estimated predictive accuracy under honest five-fold cross-validation was 79.3% with a sensitivity and specificity of 71.4 and 86.3%, respectively. A learning curve analysis demonstrated that gains in model performance reached a plateau at 25 chemicals, indicating that the size of the current data set was sufficient to provide a robust classifier. The classification results showed a small subset of chemicals contributed disproportionately to the misclassification rate. For these chemicals, the misclassification was more closely associated with genotoxicity status than efficacy in the original bioassay. Statistical models were also used to predict dose-response increases in tumor incidence for methylene chloride and naphthalene. The average posterior probabilities for the top models matched the results from the bioassay for methylene chloride. For naphthalene, the average posterior probabilities for the top models over-predicted the tumor response, but the variability in predictions were significantly higher. The study provides both a set of gene expression biomarkers for predicting chemically-induced mouse lung tumors as well as a broad assessment of important experimental and analysis criteria for developing microarray-based predictors of safety-related endpoints.
Publication Title
Use of short-term transcriptional profiles to assess the long-term cancer-related safety of environmental and industrial chemicals.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Subject
View Samples- Mus musculus
- 2 Downloadable Samples
Description
Liver undergoes both size increase and differentiation during postnatal period, which in mice is approximately first 30 days. The mechanisms of simultaneous postnatal liver cell proliferation and maturation are not clear. In these experiments, role of yes associated protein (Yap), the downstream effector of Hippo Kinase signaling pathway was investigated.
Publication Title
Yes-associated protein is involved in proliferation and differentiation during postnatal liver development.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 11 Downloadable Samples
Description
Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and of its proteolytic fragments are still poorly understood. The secreted APPs ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The -secretase generated APP intracellular domain, AICD, functions as a transcriptional regulator in heterologous reporter assays although its role for endogenous gene regulation has remained controversial. Previously, we have generated APPs knockin (KI) mice expressing solely the secreted ectodomain APPs. Here, we generated double mutants (APPs-DM) by crossing APPs-KI mice onto an APLP2-deficient background and show that APPs rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPs-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP. To gain further mechanistic insight into which domains/proteolytic fragments are crucial for hippocampal APP/APLP2 mediated functions, we performed a DNA microarray transcriptome profiling of prefrontal cortex and hippocampus of adult APLP2-KO (APLP2-/-) and APPs-DM mice (APP/APLP2-/- mice).Interestingly, this analysis failed to reveal major genotype-related transcriptional differences. Expression differences between cortex and hippocampus were, however, readily detectable.
Publication Title
APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
Description
We used an in vitro cardiomyocyte differentiation system with inducible Hey1 or Hey2 expression to study target gene regulation in cardiomyocytes (CM) generated from murine embryonic stem cells (ESC). The effects of Hey1 and Hey2 are largely redundant, but cell type specific. The number of regulated genes is comparable between ESC and CM, but the total number of binding sites is much higher, especially in ESC, targeting mainly genes involved in transcriptional regulation and developmental processes. Repression by Hey generally correlates with the extent of Hey-binding to target promoters, subsequent Hdac recruitment and lower histone acetylation. Functionally, treatment with the Hdac inhibitor TSA abolished Hey target gene regulation. However, in CM the repressive effect of Hey-binding is lost for a subset of genes. These lack Hey-dependent histone deacetylation in CM and are enriched for binding sites of cardiac specific activators like Srf, Nkx2-5, and Gata4.
Publication Title
Mechanisms of epigenetic and cell-type specific regulation of Hey target genes in ES cells and cardiomyocytes.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 36 Downloadable Samples
Description
In this study, we aim to identify candidate biomarkers which may be useful as surrogate indicators of toxicity for pre-clinical development of panPPAR-agonist drug candidates. Gene expression microarray, histopathology and clinical chemistry data were generated from liver, heart, kidney and skeletal muscles of three groups of mice administered with three different dosages of an experimental pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, PPM-201, for 14 days. The histopathology and clinical chemistry data were compared with the gene expression analysis and candidate biomarker genes were identified.
Publication Title
Simultaneous non-negative matrix factorization for multiple large scale gene expression datasets in toxicology.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 8 Downloadable Samples
Description
Dominant RUNX1 inhibition has been proposed as a common pathway for CBF-leukemia. CBFb-SMMHC, a fusion protein in human acute myeloid leukemia (AML), dominantly inhibits RUNX1 largely through its RUNX1 high-affinity binding domain (HABD). We generated knock-in mice expressing CBFb-SMMHC with a HABD deletion, CBFb-SMMHCd179-221. These mice developed leukemia highly efficiently, even though hematopoietic defects associated with Runx1-inhibition were partially rescued.
Publication Title
Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
Description
Glucocorticoids (GC) are used as first line therapies for generalized suppression of inflammation (e.g. allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work has revealed that GC induced a stable anti-inflammatory phenotype in monocytes, the glucocorticoid-stimulated monocytes (GCsM) that we now exploited for targeted GC-mediated therapeutic effects.
Publication Title
Immune suppression via glucocorticoid-stimulated monocytes: a novel mechanism to cope with inflammation.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 62 Downloadable Samples
Description
In order to elucidate the molecular mechanisms underlying individual variation in sensitivity to ethanol we profiled the prefrontal cortex transcriptomes of two inbred strains that exhibit divergent responses to acute ethanol, the C57BL6/J (B6) and DBA/2J (D2) strains, as well as 27 members of the BXD recombinant inbred panel, which was derived from a B6 x D2 cross. With this dataset we were able to identify several gene co-expression networks that were robustly altered by acute ethanol across the BXD panel. These ethanol-responsive gene-enriched networks were heavily populated by genes regulating synaptic transmission and neuroplasticity, and showed strong genetic linkage to discreet chromosomal loci. Network-based measurements of node importance identified several hub genes as established regulators of ethanol response phenotypes, while other hubs represent novel candidate modulators of ethanol responses.
Publication Title
Genetic dissection of acute ethanol responsive gene networks in prefrontal cortex: functional and mechanistic implications.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
Description
FLT3-ITDs Introduce a Myeloid Differentiation and Transformation Bias in Lympho-myeloid Multipotent Progenitors
Publication Title
FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 101 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Canonical and atypical E2Fs regulate the mammalian endocycle.
Sample Metadata Fields
Age, Specimen part
View Samples