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GSE13035
Mus musculus
18 Downloadable Samples
Affymetrix Mouse Expression 430A Array (moe430a)
Description
Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here we demonstrate that loss of HtrA2 results in transcriptional up-regulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinsons disease patients brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases.
Publication Title
Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here we demonstrate that loss of HtrA2 results in transcriptional up-regulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinsons disease patients brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases.
Publication Title
Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here we demonstrate that loss of HtrA2 results in transcriptional up-regulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinsons disease patients brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases.
Publication Title
Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 9 Downloadable Samples
Illumina MouseRef-8 v2.0 expression beadchip
Description
We found that AhR, a unique chemical sensor, is critical in controlling mast cell differentiation, growth and function in vitro and in vivo. This study seeks to further the understanding of the mechanisms of how AhR control mast cell homeostasis.
Publication Title
Aryl hydrocarbon receptor controls murine mast cell homeostasis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 70 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The primary goal of toxicology and safety testing is to identify agents that have the potential to cause adverse effects in humans. Unfortunately, many of these tests have not changed significantly in the past 30 years and most are inefficient, costly, and rely heavily on the use of animals. The rodent cancer bioassay is one of these safety tests and was originally established as a screen to identify potential carcinogens that would be further analyzed in human epidemiological studies. Today, the rodent cancer bioassay has evolved into the primary means to determine the carcinogenic potential of a chemical and generate quantitative information on dose-response behavior in chemical risk assessments. Due to the resource-intensive nature of these studies, each bioassay costs $2 to $4 million and takes over three years to complete. Over the past 30 years, only 1,468 chemicals have been tested in a rodent cancer bioassay. By comparison, approximately 9,000 chemicals are used by industry in quantities greater than 10,000 lbs and nearly 90,000 chemicals have been inventoried by the U.S. Environmental Protection Agency as part of the Toxic Substances Control Act. Given the disparity between the number of chemicals tested in a rodent cancer bioassay and the number of chemicals used by industry, a more efficient and economical system of identifying chemical carcinogens needs to be developed.
Publication Title
Application of genomic biomarkers to predict increased lung tumor incidence in 2-year rodent cancer bioassays.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
A cross-platform genome-wide comparison of the relationship of promoter DNA methylation to gene expression.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Transcriptional profiling of IAS subjects
Publication Title
A cross-platform genome-wide comparison of the relationship of promoter DNA methylation to gene expression.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Two-year rodent bioassays play a central role in evaluating both the carcinogenic potential of a chemical and generating quantitative information on the dose-response behavior for chemical risk assessments. The bioassays involved are expensive and time-consuming, requiring nearly lifetime exposures (two years) in mice and rats and costing $2 to $4 million per chemical. Since there are approximately 80,000 chemicals registered for commercial use in the United States and 2,000 more are added each year, applying animal bioassays to all chemicals of concern is clearly impossible. To efficiently and economically identify carcinogens prior to widespread use and human exposure, alternatives to the two-year rodent bioassay must be developed. In this study, animals were exposed for 13 weeks to two chemicals that were positive for lung tumors in the two-year rodent bioassay, two chemicals that were negative for tumors, and two vehicle controls. Gene expression analysis was performed on the lungs of the animals to assess the potential for identifying gene expression biomarkers that can predict tumor formation in a two-year bioassay following a 13 week exposure.
Publication Title
A comparison of transcriptomic and metabonomic technologies for identifying biomarkers predictive of two-year rodent cancer bioassays.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Two-year rodent bioassays play a central role in evaluating both the carcinogenic potential of a chemical and generating quantitative information on the dose-response behavior for chemical risk assessments. The bioassays involved are expensive and time-consuming, requiring nearly lifetime exposures (two years) in mice and rats and costing $2 to $4 million per chemical. Since there are approximately 80,000 chemicals registered for commercial use in the United States and 2,000 more are added each year, applying animal bioassays to all chemicals of concern is clearly impossible. To efficiently and economically identify carcinogens prior to widespread use and human exposure, alternatives to the two-year rodent bioassay must be developed. In this study, animals were exposed for 13 weeks to two chemicals that were positive for liver tumors in the two-year rodent bioassay, two chemicals that were negative for liver tumors, and two vehicle controls. Gene expression analysis was performed on the livers of the animals to assess the potential for identifying gene expression biomarkers that can predict tumor formation in a two-year bioassay following a 13 week exposure.
Publication Title
A comparison of transcriptomic and metabonomic technologies for identifying biomarkers predictive of two-year rodent cancer bioassays.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Rattus norvegicus
- 418 Downloadable Samples
- Affymetrix Rat Expression 230A Array (rae230a)
Description
The carcinogenic potential of chemicals is currently evaluated with rodent life-time bioassays, which are time consuming, and expensive with respect to cost, number of animals and amount of compound required. Since the results of these 2-year bioassays are not known until quite late during development of new chemical entities, and since the short-term test battery to test for genotoxicity, a characteristic of genotoxic carcinogens, is hampered by low specificity, the identification of early biomarkers for carcinogenicity would be a big step forward. Using gene expression profiles from the livers of rats treated up to 14 days with genotoxic and non-genotoxic carcinogens we previously identified characteristic gene expression profiles for these two groups of carcinogens. We have now added expression profiles from further hepatocarcinogens and from non-carcinogens the latter serving as control profiles. We used these profiles to extract biomarkers discriminating genotoxic from non-genotoxic carcinogens and to calculate classifiers based on the support vector machine (SVM) algorithm. These classifiers then predicted a set of independent validation compound profiles with up to 88% accuracy, depending on the marker gene set. We would like to present this study as proof of the concept that a classification of carcinogens based on short-term studies may be feasible.
Publication Title
Cross-platform toxicogenomics for the prediction of non-genotoxic hepatocarcinogenesis in rat.
Sample Metadata Fields
Specimen part
View Samples