Biological risks associated with space radiation and microgravity are major concerns for long-term space travel. Through a Systems Biology approach our previous NASA work has shown both TGF xce xb2 signaling pathways and miRNAs have a critical impact on defining health risks with and without space irradiation. We hypothesize that circulating microRNA (miRNA) signatures are driving microvascular disease and muscle degeneration associated with accelerating aging and will be enhanced by exposure to the space environment (radiation and microgravity). We investigated this hypothesis both in vivo and in vitro and test novel antagonist therapies to these miRNA signatures as countermeasures to reduce space radiation-induced health risks. A comprehensive Systems Biology approach was used to examine the influence by high atomic number by high (H) atomic number (Z) and energy (E) (HZE) irradiation. To simulate low-dose exposure due to galactic cosmic rays (GCR) we used the ions energy and doses determined by a NASA consensus formula of 7 different ions to represent GCR (referred to as GCR sim model). To simulate high-dose radiation exposure due to solar particle events (SPE) we used an acute dose of SPE simulated beam at 1Gy which has energies ranging from 50MeV to 150MeV. C57BL/6 wild-type mice were utilized for irradiation with our established simulated microgravity model (hindlimb suspension model) and an in vitro 3D microvasculature tissue model under simulated microgravity (clinostat) conditions will also be irradiated. To expand on the circulating miRNA signature determined from our preliminary data we determined a group of conserved miRNAs which are commonly being regulated in the majority of the organs and tissues throughout the host using our established techniques. MiRNA-sequencing on serum (before IR and at time of sacrifice) liver heart and muscle tissue for all radiation groups revealed the key circulating miRNA signature (consisting of multiple miRNAs) impacting disease risk. Collectively understanding of how whole body space radiation impacts microvascular and tissue degeneration through circulating miRNAs will greatly enhance health risk prognostication and provide possible new mechanisms for protection against space radiation.

Biological risks associated with space radiation and microgravity are major concerns for long-term space travel. Through a Systems Biology approach our previous NASA work has shown both TGF xce xb2 signaling pathways and miRNAs have a critical impact on defining health risks with and without space irradiation. We hypothesize that circulating microRNA (miRNA) signatures are driving microvascular disease and muscle degeneration associated with accelerating aging and will be enhanced by exposure to the space environment (radiation and microgravity). We investigated this hypothesis both in vivo and in vitro and test novel antagonist therapies to these miRNA signatures as countermeasures to reduce space radiation-induced health risks. A comprehensive Systems Biology approach was used to examine the influence by high atomic number by high (H) atomic number (Z) and energy (E) (HZE) irradiation. To simulate low-dose exposure due to galactic cosmic rays (GCR) we used the ions energy and doses determined by a NASA consensus formula of 7 different ions to represent GCR (referred to as GCR sim model). To simulate high-dose radiation exposure due to solar particle events (SPE) we used an acute dose of SPE simulated beam at 1Gy which has energies ranging from 50MeV to 150MeV. C57BL/6 wild-type mice were utilized for irradiation with our established simulated microgravity model (hindlimb suspension model) and an in vitro 3D microvasculature tissue model under simulated microgravity (clinostat) conditions will also be irradiated. To expand on the circulating miRNA signature determined from our preliminary data we determined a group of conserved miRNAs which are commonly being regulated in the majority of the organs and tissues throughout the host using our established techniques. MiRNA-sequencing on serum (before IR and at time of sacrifice) liver heart and muscle tissue for all radiation groups revealed the key circulating miRNA signature (consisting of multiple miRNAs) impacting disease risk. Collectively understanding of how whole body space radiation impacts microvascular and tissue degeneration through circulating miRNAs will greatly enhance health risk prognostication and provide possible new mechanisms for protection against space radiation.

Biological risks associated with space radiation and microgravity are major concerns for long-term space travel. Through a Systems Biology approach our previous NASA work has shown both TGF xce xb2 signaling pathways and miRNAs have a critical impact on defining health risks with and without space irradiation. We hypothesize that circulating microRNA (miRNA) signatures are driving microvascular disease and muscle degeneration associated with accelerating aging and will be enhanced by exposure to the space environment (radiation and microgravity). We investigated this hypothesis both in vivo and in vitro and test novel antagonist therapies to these miRNA signatures as countermeasures to reduce space radiation-induced health risks. A comprehensive Systems Biology approach was used to examine the influence by high atomic number by high (H) atomic number (Z) and energy (E) (HZE) irradiation. To simulate low-dose exposure due to galactic cosmic rays (GCR) we used the ions energy and doses determined by a NASA consensus formula of 7 different ions to represent GCR (referred to as GCR sim model). To simulate high-dose radiation exposure due to solar particle events (SPE) we used an acute dose of SPE simulated beam at 1Gy which has energies ranging from 50MeV to 150MeV. C57BL/6 wild-type mice were utilized for irradiation with our established simulated microgravity model (hindlimb suspension model) and an in vitro 3D microvasculature tissue model under simulated microgravity (clinostat) conditions will also be irradiated. To expand on the circulating miRNA signature determined from our preliminary data we determined a group of conserved miRNAs which are commonly being regulated in the majority of the organs and tissues throughout the host using our established techniques. MiRNA-sequencing on serum (before IR and at time of sacrifice) liver heart and muscle tissue for all radiation groups revealed the key circulating miRNA signature (consisting of multiple miRNAs) impacting disease risk. Collectively understanding of how whole body space radiation impacts microvascular and tissue degeneration through circulating miRNAs will greatly enhance health risk prognostication and provide possible new mechanisms for protection against space radiation.

BACKGROUND: Ionizing radiation (IR) can be extremely harmful for human cells since an improper DNA-damage response (DDR) to IR can contribute to carcinogenesis initiation. Perturbations in DDR pathway can originate from alteration in the functionality of the microRNA-mediated gene regulation being microRNAs (miRNAs) small noncoding RNA that act as post-transcriptional regulators of gene expression. In this study we gained insight into the role of miRNAs in the regulation of DDR to IR under microgravity a condition of weightlessness experienced by astronauts during space missions which could have a synergistic action on cells increasing the risk of radiation exposure. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed miRNA expression profile of human peripheral blood lymphocytes (PBL) incubated for 4 and 24 h in normal gravity (1 g) and in modeled microgravity (MMG) during the repair time after irradiation with 0.2 and 2Gy of gamma-rays. Our results show that MMG alters miRNA expression signature of irradiated PBL by decreasing the number of radio-responsive miRNAs. Moreover let-7i* miR-7 miR-7-1* miR-27a miR-144 miR-200a miR-598 miR-650 are deregulated by the combined action of radiation and MMG. Integrated analyses of miRNA and mRNA expression profiles carried out on PBL of the same donors identified significant miRNA-mRNA anti-correlations of DDR pathway. Gene Ontology analysis reports that the biological category of Response to DNA damage is enriched when PBL are incubated in 1 g but not in MMG. Moreover some anti-correlated genes of p53-pathway show a different expression level between 1 g and MMG. Functional validation assays using luciferase reporter constructs confirmed miRNA-mRNA interactions derived from target prediction analyses. CONCLUSIONS/SIGNIFICANCE: On the whole by integrating the transcriptome and microRNome we provide evidence that modeled microgravity can affects the DNA-damage response to IR in human PBL.

Space radiations and microgravity both could cause DNA damage in cells but the effects of microgravity on DNA damage response to space radiations are still controversial. A mRNA microarray and microRNA microarray in dauer larvae of Caenorhabditis elegans (C. elegans) that endured spaceflight environment and space radiations environment during 16.5-day Shenzhou-8 space mission were performed. In our study wild type and ced-1 mutant strains of C.elegans endured three conditions during shenzhou-8 spaceflight mission including spaceflight static condition(ss) spaceflight 1-g centrifugal condition(sc) and ground control condition(gc). Limited to the quantity of worm samples we performed technical-repeat test but not sample-repeat test.Accordingly xef xbc x8csix miRNA microarrays were performed.

Space radiations and microgravity both could cause DNA damage in cells but the effects of microgravity on DNA damage response to space radiations are still controversial. A mRNA microarray and microRNA microarray in dauer larvae of Caenorhabditis elegans (C. elegans) that endured spaceflight environment and space radiations environment during 16.5-day Shenzhou-8 space mission were performed. In our study wild type and dys-1 mutant strains of C.elegans endured four conditions during shenzhou-8 spaceflight mission including spaceflight static condition(ss) spaceflight 1-g centrifugal condition(sc) ground control condition(gc) and no-transport control. Limited to the quantity of worm samples we performed technical-repeat test but not sample-repeat test. Accordingly eight miRNA microarrays were performed.

Space radiations and microgravity both could cause DNA damage in cells but the effects of microgravity on DNA damage response to space radiations are still controversial. A mRNA microarray and microRNA microarray in dauer larvae of Caenorhabditis elegans (C. elegans) that endured space xef xac x82ight environment and space radiations environment during 16.5-day Shenzhou-8 space mission were performed. In our study wild type and dys-1 mutant strains of C.elegans endured four conditions during shenzhou-8 spaceflight mission including spaceflight static condition(ss) spaceflight 1-g centrifugal condition(sc) ground control condition(gc) and no-transport control. Limited to the quantity of worm samples we performed technical-repeat test but not sample-repeat test. Accordingly eight miRNA microarrays were performed.

Space radiations and microgravity both could cause DNA damage in cells but the effects of microgravity on DNA damage response to space radiations are still controversial. A mRNA microarray and microRNA microarray in dauer larvae of Caenorhabditis elegans (C. elegans) that endured space xef xac x82ight environment and space radiations environment during 16.5-day Shenzhou-8 space mission were performed. In our study wild type dys-1 mutant and ced-1 mutant strains of C.elegans endured four conditions during shenzhou-8 spaceflight mission including spaceflight static condition(ss) spaceflight 1-g centrifugal condition(sc) ground control condition(gc) and no-transport control. Limited to the quantity of worm samples we performed technical-repeat test but not sample-repeat test.Accordingly 12 mRNA microarrays were performed.

Space radiations and microgravity both could cause DNA damage in cells but the effects of microgravity on DNA damage response to space radiations are still controversial. A mRNA microarray and microRNA microarray in dauer larvae of Caenorhabditis elegans (C. elegans) that endured spaceflight environment and space radiations environment during 16.5-day Shenzhou-8 space mission were performed. In our study wild type dys-1 mutant and ced-1 mutant strains of C.elegans endured four conditions during shenzhou-8 spaceflight mission including spaceflight static condition(ss) spaceflight 1-g centrifugal condition(sc) ground control condition(gc) and no-transport control. Limited to the quantity of worm samples we performed technical-repeat test but not sample-repeat test.Accordingly 12 mRNA microarrays were performed.

Human deep space and planetary travel is limited by uncertainties regarding the health risks associated with exposure to galactic cosmic radiation (GCR) and in particular the high linear energy transfer (LET) heavy ion component. Here we assessed the impact of two high-LET ions 56Fe and 28Si and low-LET X rays on genome-wide methylation patterns in human bronchial epithelial cells. We found that all three radiation types induced rapid and stable changes in DNA methylation but at distinct subsets of CpG sites affecting different chromatin compartments. The 56Fe ions induced mostly hypermethylation and primarily affected sites in open chromatin regions including enhancers promoters and edges ( shores ) of CpG islands. The 28Si ion-exposure had mixed effects inducing both hyper and hypomethylation and affecting sites in more repressed heterochromatic environments whereas X rays induced mostly hypomethylation primarily at sites in gene bodies and intergenic regions. Significantly the methylation status of 56Fe ion irradiation sensitive sites but not those affected by X ray or 28Si ions could discriminate tumor from normal tissue for human lung adenocarcinomas and squamous cell carcinomas. Thus high LET radiation exposure leaves a lasting imprint on the epigenome and affects sites relevant to human lung cancer. The 56Fe ion signature may prove useful in monitoring the cumulative biological impact and associated cancer risks encountered by astronauts in deep space. Genome wide DNA methylation profiling of normal human bronchial epithelial cells irradiated with varying doses of 28Si-ion radiation ( 300 MeV/u at 0 0.3 1.0 Gy) 56Fe-ion radiation (600 MeV/u at 0 0.1 0.3 1.0 Gy) or X rays (320 kV at 0 1.0 Gy). Triplicate control and irradiated samples were incubated and sampled at 4 timepoints between 2 and 62 days. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across >485,000 CpGs from collected samples. Samples include: 56Fe ions 4 doses x 4 time points x 3 replicates (4 removed in QC) = 44 samples; 28Si ions = 3 doses x 4 time points x 3 replicates = 36 samples; X ray 2 doses x 4 time points x 3 replicates (2 removed in QC)= 22 samples. Overall design: Bisulphite converted DNA from the 102 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip.