In collaboration with the radiation Biodosimetry Laboratory and the modeling group at NASA Johnson Space Center and with the International Computer Science Institute (ICSI) at University of California (UC) Berkeley, the investigator team will bring unique interdisciplinary expertise to integrate the large array of cancer data generated over the past 25 years and archived by NASA under the various Human Research Program (HRP) funded projects. The main goal of this study is to identify factors influencing radiation-induced carcinogenesis and integrate them into a multi-scale model already started at the Berkeley Lab that encompasses DNA damage response and intercellular signaling to predict cancer risk for any types of high energy particles (HZE). Because experimental data are dispersed across many different cancer models, radiation qualities, and measurement types, this study will also generate a complete set of experimental data designed to fully inform and validate the model. In this project, the model will impose the types of measurements being made, with a strong emphasis on well-established blood biomarkers.
This study has the following specific aims:
The DNA damage phenotype will be correlated to cancer incidence in collaboration with Dr. Mike Weil, from Colorado State University, who has been exposing a genetically diverse population of mice to high-LET ionizing radiation and monitoring cancer incidence. Primary skin fibroblast from each animal have also been exposed in 96 well plates to high-LET and persistent DNA damage is being quantified by the Costes Lab at NASA Ames Research Center. These data will eventually be shared with Dr. Weil and we will be working with his staff to have these data available via LSDA.
In parallel, the investigators propose to fully characterize the DNA damage response and cell death from ionizing radiation administered ex-vivo to 15 genetically different strains of mice and to 768 human blood donors, with high genetic diversity (18-75 years old, 50/50 Males/Females, Caucasian of Northern European descent). Taken together, an array of ex-vivo phenotypic features of responses to ionizing radiation will be associated to genomic traits across mice and humans, as well as analyzed as a function of demographic variables including age, gender, body mass index, and latent viral infections.
The investigators proposed novel mathematical formalisms to model the generation of radiation-induced foci (RIF) as a function of irradiation doses for both low- and high-LET radiation (X-rays, 350 MeV/n 40Ar and 600 MeV/n 56Fe). This model was validated using skin fibroblast cells from 15 strains of mice, including 5 inbred reference strains and 10 collaborative-cross strains. Different DNA damage responses were observed according to the mouse strain, indicating that the number and sizes of repair domains are modulated by the genetic background of each strain. These data also confirm that the clustering mechanism of double strand breaks into RIF is shared across species, confirming previous observations in a human immortalized cell line.
At the genomic level, investigators identified suggestive genetic loci association with the large differences in repair rates between the 15 studied strains of mice. At the temporal level, investigators observed a good agreement between persistent levels of radiation-induced foci measured in vitro for all 15 strains of mice and survival levels of immune cells collected from irradiated mice in vivo. These results suggest that in vivo radiation toxicity can be anticipated in vitro by using the persistent level of radiation-induced foci at 24hous post-irradiation as a surrogate biomarker. Manuscript in preparation
The investigators analyzed radiation-induced responses for 768 human donors exposed to both low- and high-LET irradiation (gamma rays, 350 MeV/m 28Si, 350 MeV/n 40Ar and 600 MeV/n 56Fe) at 4h and 24h post-irradiation. The responses were quantified in terms of DNA damage, cell death and oxidative stress for each individual, and compared to demographic variables (age, BMI, gender) as well as baseline levels of DNA damage prior to irradiation. In addition, low coverage whole genome sequencing was performed for all 768 donors in order to identify genetic associations with individual levels of radiation sensitivity. Once completed, this study will provide genetic predictors of radiation sensitivity in humans, as well as a set of radiation biomarkers for in vitro assessment of radiation responses.
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