Serum miRNA expression in mice exposed to a high dose of ionizing radiation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE288305 | GEO | 2025/01/29
REPOSITORIES: GEO
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Project description:Abstract Purpose: There is a recognised need to develop new methods of high throughput, rapid and minimally invasive individual dose assessment for radiation exposure. The aim of this work is to establish a panel of highly radiation responsive genes suitable for biological dosimetry and to explore inter-individual variation in response to ionising radiation exposure.Materials and method: Analysis of gene expression in response to radiation was carried out using three independent techniques (microarray, Multiplex Quantitative RT-PCR and nCounter Analysis System) in human lymphocytes in culture and circulating blood exposed ex vivo from the same donors. Results: Variations in transcriptional response to exposure to ionising radiation analysed by microarray allowed the identification of genes which can be validated and measured accurately as biomarkers of radiation exposure using other techniques. We have identified genes which are consistently up-regulated following exposure at different time points to either 2 or 4 Gy of X-rays, for all individuals in blood and cultured lymphocytes. Most down-regulated genes including cyclins, centromeric and mitotic checkpoints proteins, particularly those associated with chromosome instability and cancer can only be detected in dividing cells. Conclusions: The data provides evidence that there are a number of genes which seem suitable for biological dosimetry, like SESN1, GADD45A, CDKN1A, CCNG1, FDXR, BBC3 and MDM2. ÊThese biomarkers could potentially be used for triage after large-scale radiological incidents. Variations in transcriptional response accurately measured by MQRT-PCRæ may allow the identification of biomarkers of radiation sensitivity and individual susceptibility and therefore being useful in radiation oncology.
2011-10-20 | E-TABM-1083 | biostudies-arrayexpress
Project description:Acute radiation syndrome (ARS) is a severe condition that develops after exposure to high doses of ionizing radiation that features immune suppression and organ failure. Currently, there are no diagnostics to identify the occurrence or severity of radiation exposure. There are also no current treatments or preventative strategies to mitigate ARS. Extracellular vesicles (EVs) are mediators of intercellular communication that contribute to immune dysfunction across diseases. We investigated if EV cargo would be able to identify whole body irradiation (WBIR) exposure and if EVs promote ARS immune dysfunction. We hypothesized that beneficial EVs derived from mesenchymal stem cells (MSC-EVs) would blunt ARS immune dysfunction and might serve as prophylactic radioprotectants. Mice received WBIR (2 or 9 Gy) with assessment of EVs at 3 and 7 days after exposure. LC-MS/MS proteomic analysis of WBIR-EVs found dose-related changes as well as candidate proteins that were increased with both doses and timepoints (34 total) such as Thromboxane-A Synthase and lymphocyte cytosolic protein 2. Suprabasin and Sarcalumenin were increased only after 9 Gy suggesting these proteins may indicate high dose/lethal exposure. Analysis of EV miRNAs identified miR-376 and miR-136, which were increased up to 200- and 60-fold respectively by both levels of WBIR and select miRNAs such as miR-1839 and miR-664 that were increased only with 9 Gy. WBIR-EVs (9 Gy) were biologically active and blunted immune responses to LPS in RAW264.7 macrophages, inhibiting canonical signaling pathways associated with wound healing and phagosome formation. Accordingly, WBIR-EVs also blunted RAW macrophage phagocytosis. When given 3 days after exposure, MSC-EVs slightly modified immune gene expression changes in the spleens of mice in response to WBIR and a combined radiation plus burn injury exposure (RCI). MSC-EVs normalized the expression of certain key immune genes such as NFκBia and Cxcr4 (WBIR), Map4k1, Ccr9 and Cxcl12 (RCI) lowered plasma TNFα cytokine levels after RCI, though most gene changes were not influenced. When given prophylactically (24 and 3 hours before exposure), MSC-EVs prolonged survival to the 9 Gy lethal exposure. Thus, EVs are important participants in ARS. EV cargo might be used to diagnose WBIR exposure, and MSC-EVs might serve as radioprotectants to blunt the impact of toxic radiation exposure.
2023-06-30 | PXD041837 | Pride
Project description:Rapid and reliable methods for conducting biological dosimetry are a necessity in the event of a large-scale nuclear event. Timely and accurate methods are thus critical in order to correctly evaluate and identify radiation dose exposure and triage appropriately. Alterations in microRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have been reported in cells/tumors subjected to radiation exposure, implying that miRNAs play an important role in cellular stress response to radiation. To examine the possibility of using microRNA as stable blood based biomarkers for radiation response, we have used microRNA microarray analysis. Differential microRNA expression pattern was evaluated (>1.5 fold and p value <0.05) at 6, 24, 48 h and 7day time points in whole blood from mice exposed to 2, 4, 8, 12 and 15Gy irradiation. More differentially expressed microRNAs (up and down) were seen after higher dose of radiation and later time points. Among the significantly upregulated microRNAs, miR-193b-3p and mir-92a-3p were consistently upregulated for all doses at earlier time points. We observed significant downregulation of several members of the miR-17 family (miR-17-5p, miR-20a-5p, miR-93-5p and miR-106b-5p) in response to radiation from 2 Gy onwards at 24 h, 48 h and at higher doses for the 7 d time-point. Whereas miR-34a, which regulates G1/S cell cycle checkpoint activation in response to radiation induced DNA damage, showed consistent upregulation for both low and high doses at later time points up to one week after exposure. Significant down regulation of miR-150-5p, miR-101, miR-140, miR-29b, miR-193b and miR-30 family of microRNAs were seen for low and high doses of radiation for all time points up to 7day. Low dose radiation (2Gy) exposure also resulted in down regulation of a group of microRNAs after one week; whereas these microRNAs showed upregulation after high dose exposure (8, 12 and 15Gy) up to one week. This dose and time dependent differential microRNA expression pattern might be useful in evaluating radiation response during and after therapeutic radiation treatment in patients. Ultimately, a combined approach of identifying biomarkers by assessing functional miRNA, target mRNAs and the resulting proteins to assess radiation exposure after mass-casualty incidents could provide a valuable tool in developing and implementing effective and timely medical countermeasures.
2018-07-01 | GSE107057 | GEO
Project description:Dose-dependent (phospho) proteome responses of mouse embyronic stem cells to ionising radiation. Quantitative SILAC- and mass spectrometry-based proteomics and phosphoproteomics experiments were performe at half an hour (0.5h) and four hours (4h) after exposure to LD (0.1 Gy) and high doses (HD; 1 Gy) of IR.
2022-03-18 | PXD025343 | Pride
Project description:Long non-coding RNAs (lncRNAs) are emerging as key molecules in regulating many biological processes and have been implicated in development and disease pathogenesis. Biomarkers of cancer and normal tissue response to treatment are of great interest in precision medicine and for public health and medical management of disasters such as assessing radiation injury following accidental or intentional exposure. Circulating and functional RNAs, including microRNAs (miRNAs) and lncRNAs, in whole blood and other body fluids represent potential valuable candidates as biomarkers. Early prediction of possible acute, intermediate, and delayed effects of radiation exposure will enable timely therapeutic interventions. To address whether lncRNAs could serve as biomarkers for radiation bio-dosimetry, we performed whole genome transcriptome analysis in a mouse model after whole body irradiation. Differential lncRNA expression patterns were evaluated at 16-, 24-, and 48-hour time points post irradiation in total RNA isolated from whole blood of mice exposed to 1, 2, 4, 8, and 12 Gy of gamma-rays. Sham irradiated animals served as controls. Significant alterations in the expression patterns of lncRNAs were observed after different radiation doses at the various timepoints. We identified several lncRNAs known for DNA damage response as well as immune response as radiation induced biomarkers. Long non-coding RNA targets of tumor protein 53 (P53), Trp53cor1, Dino, Pvt1 and Tug1 and an upstream regulator of p53, Meg3 were altered in response to radiation. Gm14005 (Morrbid) and Tmevpg1 were regulated by radiation across all time points and doses. These two lncRNAs have important potential as blood based radiation biomarkers; Gm14005 (Morrbid) has recently been shown to play a key role in inflammatory response while Tmevpg1 has been implicated in the regulation of interferon-gamma. Precise molecular biomarkers will not only enable the development and effective use of medical countermeasures but also may be used to detect and circumvent or mitigate normal tissue injury in cancer radiotherapy treatments.
2018-05-31 | GSE104121 | GEO
Project description:Multiple accidents in nuclear power plants and growing concerns in misuse of radiation exposure in warfare have called for rapid determination of radiation exposure and the chances to survive. Latest findings about circulating microRNA (miRNAs) using several animal models revealed considerable promises, although translating this knowledge to clinics remains a major challenge. To address this issue, we randomly divided 36 non-human primates (NHPs) into six equal groups and each group was exposed to six radiation doses from 6 Gy to 8.5 Gy with 0.5 Gy incremental order. Serum samples were collected pre-total body irradiation (TBI) and three timepoints afterwards namely, day 1, 2 and 6 post-TBI. Global microRNA (miRNA) reads were generated from deep sequencing platform and to increase the translational potential, we diligently aligned the miRNA sequences and functional responses of NHPs to human following an in silico routine. Those miRNAs, which were sequentially and functionally conserved between human and NHPs were curated to meet two primary objectives. First to find the molecular dynamics correlated to radiation dosimetry and second to find putative markers to predict the risk to radiation-induced fatality (RRiF). Multi-variate differential analysis identified dosimetry-miRNA markers that consistently regulated with increasing dose but independent of the time since irradiation (TSI). Likewise, a set of potential TSI-markers were identified that consistently shifted their regulations with increasing TSI, but independent of dosimetry. Functional analysis found a considerable gender bias in low range of dosimetry, but at high dose, when the RRiF increased, the bionetworks across the sexes operated in sync. Bionetworks linked to cell quantity and cell invasion significantly altered between the survived and decedent cohort. Proprietary algorithm identified candidate models with a few miRNAs that can predict RRiF with >80% AUC. An assay could be conceptualized from this putative RRiF panel supplemented with the dose-/TSI-markers to predict RRiF with high confidence.
2024-11-27 | GSE247225 | GEO
Project description:We sought to determine the long-term effects of radiation (IR) on gene expression in the whole heart as a function of IR type and dose. We hypothesize that compared to low doses of gamma-IR, high charge and energy (HZE) particle-IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be IR type- and dose-dependent. We provide for the first time the transcriptome analysis of mouse hearts exposed to low and very low doses of gamma- (137Cs), silicon- (14Si), and titanium- (22Ti) irradiation. Our results show that 16 months after low and very low dose IR exposure, the gene expression in the heart tissue is significantly differentially regulated, suggesting there are long-term effects on dysregulation of varying molecular pathways that are associ-ated with various degrees of cardiovascular, pulmonary and metabolic diseases, as well as biological processes, including abnormal circadian rhythm, cancer, Hutchinson-Gilford progeria syndrome, etc.
2021-01-05 | GSE164234 | GEO
Project description:Radiation therapy is commonly used to treat glioblastoma multiforme (GBM) brain tumor. Ionizing radiation (IR) induces dose- specific variations in transcriptional programs, implicating they are tightly regulated and critical components in the tumor response and survival. Yet, our understanding of the downstream molecular events triggered by lethal vs sublethal IR doses is limited. Herein, we report that variations in the genetic programs are positively and functionally correlated with the exposure to lethal or sublethal IR doses. Genome architecture analysis revealed that gene regulation is spatially and temporally coordinated with DNA repair kinetics. Radiation-activated genes were pre-positioned in active sub-nuclear compartments and were up-regulated following DNA damage response, while the DNA repair activity shifted to the inactive heterochromatic spatial compartments. The IR dose affected the levels of DNA damage repair and transcription modulation, but not the order of events, which was linked to their spatial nuclear positioning. Thus, distinct coordinated temporal dynamics of DNA damage repair and transcription reprogramming in the active and inactive sub-nuclear compartments highlight the importance of high-order genome organization in synchronizing the molecular events following IR.
2024-01-29 | GSE244868 | GEO
Project description:Radiation therapy is commonly used to treat glioblastoma multiforme (GBM) brain tumor. Ionizing radiation (IR) induces dose- specific variations in transcriptional programs, implicating they are tightly regulated and critical components in the tumor response and survival. Yet, our understanding of the downstream molecular events triggered by lethal vs sublethal IR doses is limited. Herein, we report that variations in the genetic programs are positively and functionally correlated with the exposure to lethal or sublethal IR doses. Genome architecture analysis revealed that gene regulation is spatially and temporally coordinated with DNA repair kinetics. Radiation-activated genes were pre-positioned in active sub-nuclear compartments and were up-regulated following DNA damage response, while the DNA repair activity shifted to the inactive heterochromatic spatial compartments. The IR dose affected the levels of DNA damage repair and transcription modulation, but not the order of events, which was linked to their spatial nuclear positioning. Thus, distinct coordinated temporal dynamics of DNA damage repair and transcription reprogramming in the active and inactive sub-nuclear compartments highlight the importance of high-order genome organization in synchronizing the molecular events following IR.
2024-01-29 | GSE244666 | GEO
Project description:Objective:Biomarkers of radiation injury are needed in planning therapeutic measures for cancer patients receiving radiation therapy and civilians exposed to nuclear events. Previous research has highlighted the impact of radiation damage, with cancer patients developing acute disorders including radiation induced pneumonitis or chronic disorders including pulmonary fibrosis months after radiation therapy ends. Discovery of biomarkers that predict these injuries will offer the potential to treat people proactively to mitigate this damage and improve quality of life. Recent research has highlighted the potential for messenger RNA (mRNA), microRNA (miRNA), and long non-coding RNA (lncRNA) to be used as radiation biomarkers. Our study focused on the changes in these RNAs at 48h after radiation exposure of mouse lung tissue to define biological pathway changes and determine potential biomarkers. Result: We observed sustained dysregulation of specific mRNAs, lncRNAs, and miRNAs across all doses. We observed gene dysregulation which can be used to develop both markers to identify no-exposure vs radiation exposure including Hba and Hbb mRNA which were dysregulated even at 1 Gy. We also observed genes which can indicate high dose exposure including Cpt1c and Pdk4. Gdf15, and Eda2r, mRNA markers of senescence and fibrosis, were the most significantly upregulated. Only three miRNAs were significantly dysregulated across all radiation doses, with miRNA-142-3p and miRNA-142-5p downregulated and miRNA-34a-5p upregulated. IPA analysis indicated that numerous pathways relevant to immune function, cell proliferation and survival decreased with increasing doses of radiation. This data highlighted early pathways of dysregulation depending on dose of exposure. This data will help with development of treatments and in medical decision-making. Further experiments are planned to develop medical countermeasures based on this early dysregulation.
2022-06-06 | GSE202586 | GEO