BIO 300 attenuates whole blood transcriptome changes in mice exposed to total-body radiation
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ABSTRACT:
PROVIDER: PRJNA1115786 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR29151800_1.fastq.gz | Fastqsanger.gz | |||
| SRR29151800_2.fastq.gz | Fastqsanger.gz | |||
| SRR29151900_1.fastq.gz | Fastqsanger.gz | |||
| SRR29151900_2.fastq.gz | Fastqsanger.gz | |||
| SRR29151801_1.fastq.gz | Fastqsanger.gz |
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Project description:Development of radiation medical countermeasures under the U.S. Food and Drug Administration Animal Rule requires the capability to translate an effective animal to human drug dose. One method of human dose translation is using a biomarker and determining drug doses that modulate the biomarker to the desired level. BIO 300 Oral Powder (BIO 300) is a prophylactic radiation medical countermeasure that is currently being developed following the Animal Rule. The present study aimed to identify biomarkers that can be used for human dose conversion by conducting transcriptomics of whole blood collected from BIO 300-treated CD2F1 mice in the presence and absence of total-body irradiation (TBI). Mice were treated with vehicle or 50, 100 or 200 mg/kg BIO 300, twice daily, for 6 days. Whole blood samples were collected 24 and 48 h after the last dose of the drug. Animals were also treated with vehicle or 200 mg/kg BIO 300 for 6 days prior to 9.2 Gy TBI 24 h after the last dose, with blood collection 24 h after irradiation. RNA sequencing demonstrated 100 – 200 mg/kg doses caused significantly more differential gene expression at 48 h post-drug dose compared to 50 mg/kg. Pathway analysis of the transcriptome profile from vehicle-treated/radiation-exposed mice revealed that many inflammatory signaling pathways were activated in these animals. Signaling pathways enriched in BIO 300-treated/TBI mice were involved in cellular stress and immune response and were predicted to be inhibited. We also identified pathways that were in inverse states (activation/inhibition) in vehicle and BIO 300-treated mice with TBI. There were two pathways specifically activated in vehicle-treated animals with TBI and inhibited in BIO 300-treated animals (with or without TBI), pathogen-induced cytokine storm signaling and S100 family signaling. In comparison to previously published human data, pulmonary fibrosis idiopathic signaling and wound healing signaling were enriched in healthy volunteers treated with BIO 300 and BIO 300-treated mice with TBI. In all, four signaling pathways were identified that were activated in vehicle-treated animals exposed to total body radiation but inhibited in irradiated animals or healthy humans treated with BIO 300. These pathways should be explored to identify potential biomarkers of BIO 300 that can be used for human dose translation.
2024-08-14 | GSE268247 | GEO
Project description:Development of radiation medical countermeasures under the U.S. Food and Drug Administration Animal Rule requires the capability to translate an effective animal-to-human drug dose. One method of human dose translation is using a biomarker and determining drug doses that modulate the biomarker to the desired level. BIO 300 Oral Powder (BIO 300) is a prophylactic radiation medical countermeasure that is currently being developed following the Animal Rule. The present study aimed to identify biomarkers that can be used for human dose conversion by conducting transcriptomics of whole blood collected from BIO 300-treated CD2F1 mice in the presence and absence of total-body irradiation (TBI). Unirradiated mice were treated with vehicle or 50, 100, or 200 mg/kg BIO 300, and irradiated mice were treated with 200 mg/kg or BIO 300 or vehicle prior to TBI. Whole-blood samples were collected after the last dose of the drug and after irradiation. RNA sequencing demonstrated 100 and 200 mg/kg of BIO 300 doses caused significantly more differential gene expression at 48 h after drug dose compared to 50 mg/kg of BIO 300 (7648, 7680, and 55 significantly differently expressed genes, respectively). Interestingly, following TBI, there were no significantly differentially expressed genes between vehicle- and BIO 300-treated mice. Despite the lack of significant changes in gene expression, the transcriptomic profiles in both groups indicated differential changes in signaling pathways. Pathway analysis of the transcriptome profile from vehicle-treated/TBI mice revealed that many inflammatory signaling pathways were activated in these animals. Signaling pathways enriched in BIO 300-treated/TBI mice were involved in cellular stress and immune response and were predicted to be inhibited. In all, four signaling pathways of interest were identified that were differentially enriched in irradiated animals treated with BIO 300: pathogen-induced cytokine storm signaling, S100 family signaling, pulmonary fibrosis idiopathic signaling, and wound-healing signaling. These pathways should be explored to identify potential biomarkers of BIO 300 that can be used for human dose translation.
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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.
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Project description:BackgroundThe mammalian gut harbors very complex and diverse microbiota that play an important role in intestinal homeostasis and host health. Exposure to radiation results in dysbiosis of the gut microbiota leading to detrimental pathophysiological changes to the host. To alleviate the effects of irradiation, several candidate countermeasures are under investigation. BIO 300, containing synthetic genistein formulated as an amorphous solid dispersion or as an aqueous suspension of nanoparticles, is a promising candidate under advanced development. The aim of this study was to investigate the effects of BIO 300 on the gut microbiome and metabolome of mice exposed to 60Co gamma-radiation. The gut microbiota and metabolome of control and drug-treated mice exposed to radiation was characterized by bacterial 16S rRNA amplicon sequencing and untargeted metabolomics.ResultsWe found that irradiation altered the Firmicutes/Bacteroidetes ratio and significantly decreased the relative abundance of Lactobacillus, both in BIO 300-treated and control mice; however, the ratio returned to near normal levels in BIO 300-treated mice by day 14 post-irradiation. Concomitantly, we also observed corrective shifts in metabolic pathways that were perturbed after irradiation.ConclusionsOverall, the data presented show that radiation exposure led to a relative depletion of commensals like Lactobacillus leading to an inflammatory metabolic phenotype while the majority of the drug-treated mice showed alleviation of this condition primarily by restoration of normal gut microbiota. These results indicate that the radioprotective effects of BIO 300, at least in part, may involve correction of the host-microbiome metabolic axis.
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Project description:Cognitive impairments are an important side effect after radiation exposure. Yet, it comes more and more into scientific focus that ionising radiation can resemble pathologies of neurodegenerative diseases such as Alzheimer´s. Here, we used a multidisciplinary approach to elucidate the effect of chronic low-dose irradiation exposure (1 mGy/day and 20 mGy/day) over 300 days (cumulative dose of 0.3 Gy and 6.0 Gy) on the murine ApoE-/- hippocampus as an Alzheimer´s model. By using mass spectrometry to quantify global expression levels of unmodified proteins, phospho-proteins and N-linked sialylated glycoproteins, we found nearly exclusive changes on the phospho-proteome at both doses. These proteins regulate signalling of synaptic plasticity and calcium-dependent signalling. We used synaptic plasticity-targeted transcriptomics, immunoblotting and ELISA to validate our findings and could identify that memory-related CREB signalling is reduced at both doses whereas Rac1-Cofilin signalling is only altered at 1 mGy/day. Interestingly, we noted a reduction in the number of activated microglia in the molecular layer of the hippocampus only at 1 mGy/day paralleled with reduced levels of TNFα mRNA and lipid peroxidation at this dose. Adult neurogenesis (Ki67, GFAP and NeuN as markers) and cell death (activated caspase-3) were not changed / initiated at both doses. Our analysis showed that several molecular targets induced by chronic low-dose radiation overlap with molecular targets of Alzheimer´s pathology. We suggest that chronic low-dose ionising radiation can be a potential confounder in Alzheimer´s disease.
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