Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Response of the EPI-200 human 3-D skin model to high and low doses of protons

ABSTRACT: Accumulating data suggest that the biological responses to high and low doses of radiation are qualitatively different, necessitating the direct study of low dose responses. Most such studies have utilized 2-dimensional culture systems, which may not fully represent responses in 3-dimensional tissues. To gain insight into low dose responses in tissue, we have profiled global gene expression in EPI-200, a 3-dimensional tissue model from MatTek that imitates the structure and function of human epidermis, at 4, 16 and 24 hours after exposure to high (2.5 Gy) and low (0.1 Gy) doses of low LET protons. Untreated controls and samples exposed to 10 cGy or to 2.5 Gy were analyzed at three different times (4, 16 or 24 hours after exposure). Three biological repeats were performed for each condition

ORGANISM(S): Homo sapiens

SUBMITTER: Sally Amundson

PROVIDER: E-GEOD-16935 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Global gene expression responses to low- or high-dose radiation in a human three-dimensional tissue model.

Mezentsev Alexandre A Mezentsev Alexandre A Amundson Sally A SA

Radiation research 20110412 6

Accumulating data suggest that the biological responses to high and low doses of radiation are qualitatively different, necessitating the direct study of low-dose responses to better understand potential risks. Most such studies have used two-dimensional culture systems, which may not fully represent responses in three-dimensional tissues. To gain insight into low-dose responses in tissue, we have profiled global gene expression in EPI-200, a three-dimensional tissue model that imitates the stru ...[more]

PMID: 21486161

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Project description:Biological response X-rays traditionally serves as a standard in comparative analysis of different qualities of ionizing radiation. Most such studies have utilized 2-dimensional culture systems, which may not fully represent responses in 3-dimensional tissues. To gain insight into biological responses to X-rays in tissue, we have profiled global gene expression in EPI-200, a 3-dimensional tissue model that imitates the structure and function of human epidermis, at 4, 16 and 24 hours after exposure to 2.5 Gy of X-rays. The most significant gene ontology groups were associated with cell cycle, cytokinesis, establishment and maintenance of chromatin architecture. Remarkably, genes with a role in cell cycle were predominantly downregulated at all time points while genes involved in the cell defense response - upregulated. Methyltransferases were predominantly upregulated at 4 and 16h while transcription factors - at 16h and 24h suggesting remodeling of the chromatin. Among the genes with a role in signal transduction, irradiation affected kinase modulators and microtubule binding motor proteins at all time points. Kinases, especially non-receptor serine/threonine protein kinases were predominantly upregulated at 16 and 24h suggesting a rearrangement in the signaling pathways. The results also confirm involvement in the biological response of the genes participating in p53 pathway that were overrepresented at 4 and 16h in the set of upregulated genes and ubiquitin proteasome pathway that were predominantly downregulated at 16h and 24h In the same time, growing numbers of altered in expression genes: 449 at 4h; 720 and 3986 genes - at 16 and 24h postirradiation, accordingly suggested that ionizing radiation caused long term changes in the gene expression the exceeded the time frame proposed for this study. Radiation induced gene expression in 3-dimensional tissue model, Epi-200, was measured at 4, 16 and 24 hours after exposure to the dose of 2.5 Gy of X-rays. Three independent experiments were performed in the each time point using one tissue sample per a data point.

Project description:Bystander mechanisms that originate in the areas surrounding a tissue damage presumably play an important role participating in wound healing and tissue remodeling. Thus, identification and characterization of bystander mechanisms will help to development of new treatments of patients with a radiation exposure. In the present study, we irradiated 3-dimensional tissue model of human epidermis, Epi-200 (Mat-Tek, Ashland, MA), with 2.5 Gy protons. By exposing only a thin strip across the center of the EPI-200 tissue, we have been able to measure global gene expression responses in directly irradiated and bystander cells located at 0.125-0.375, 0.375-0.625, 0.625-875 mm from the irradiation line. The data were analyzed using BRB-Array Tools (NIH), and further gene ontology analysis and network analysis was performed with Panther (Applied Biosystems) and IPA (Ingenuity), accordingly. Significantly responding genes were identified at all distances and included sets common to both direct and bystander responses. False discovery rate in bystander samples did not exceed 20% (p=0.001) and was sufficiently low in the samples obtained after the whole tissue exposure (0.06-1.16%). Analysis of the fragments cut at the same distance revealed 52, 54 and 88 differentially expressed genes. These gene lists overlapped each other had from 3 to 12 genes in common including CLED2, S100A7A. Samples obtained after the whole tissue exposure discovered 949 differentially expressed genes. Moreover, the performed gene ontology analysis showed there overrepresentation of TP53 pathway (pathways, p=2.04E-02), a common marker of direct irradiation response, and also overrepresentation of the following groups of genes: signal transduction (p=4.52E-04), cell communication (p=1.24E-04) and cell cycle in the category of biological processes; DNA helicase activity (p=2.54E-07), receptor binding (p=6.19E-04), calcium ion binding proteins (p=2.57E-03) as the molecular functions. Differentially expresses genes of bystander samples had few categories in common such as cell communication (p=2.36E-03) and signal transduction (p=2.42E-03) among the biological processes and receptor activity (p=4.54E-03) among the molecular functions. Categories specific for the bystander samples included G-protein coupled receptors (p=7.24E-03) and ligand-gated ion channels (p=4.16E-03) suggesting a role of external stimulation and ion trafficking in bystander mechanisms. Radiation induced gene expression in 3-dimensional tissue model, Epi-200, was measured in 16 hours after exposure to 2.5 Gy of protons. Four independent experiments were performed for the samples collected at different distances from the irradiation line (125-375, 375-625 and 625-875 micrometers) using three tissue fragments per a data point. Moreover, three sets of whole tissue irradited samples were also generated for 0 and 2.5 Gy (6 samples total) and used for comparison of bystander and direct responses.

Project description:Measuring global gene expression using cDNA or oligonucleotide microarrays is an effective approach to understanding the complex mechanisms of the effects of radiation. However, few studies have been carried out that investigate gene expression in vivo after prolonged exposure to low-dose-rate radiation. In this study, C57BL/6J mice were continuously irradiated with ?-rays for 485 days at dose-rates of 0.032 – 13 ?Gy/min. Gene expression profiles in the kidney and testis from irradiated and unirradiated mice were analyzed, and differentially expressed genes were identified. A combination of pathway analysis and hierarchical clustering of differentially expressed genes revealed that expression of genes involved in mitochondrial oxidative phosphorylation was elevated in the kidney after irradiation at the dose-rates of 0.65 ?Gy/min and 13 ?Gy/min. Expression of cell cycle-associated genes was not profoundly modulated in the kidney, in contrast to the response to acute irradiation, suggesting a threshold in the dose-rate for modulation of the expression of cell cycle-related genes in vivo following exposure to radiation. We demonstrated that changes to the gene expression profile in the testis were largely different from those in the kidney. The Gene Ontology categories “DNA metabolism”, “response to DNA damage” and “DNA replication” overlapped significantly with the clusters of genes whose expression decreased with an increase in the dose-rate to the testis. These observations provide a fundamental insight into the organ-specific responses to low-dose-rate radiation. Key Words: kidney, low-dose-rate, radiation, microarray, mitochondrial oxidative phosphorylation, testis 3 biological replicates for each experimental group were analysed. GSE14290_Kidney_raw_data.csv contains the raw data for GSM357146, GSM357425, GSM357426, GSM357452 to GSM357460. GSE14290_Testis_raw_data.csv contains the raw data for GSM357471 to GSM357482. In these files, the sample identifiers are included in the column headers.

Dataset Information

Response of the EPI-200 human 3-D skin model to high and low doses of protons

Publications

Global gene expression responses to low- or high-dose radiation in a human three-dimensional tissue model.

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