This Program represents a cohesive approach motivated by the practical needs of very high-throughput biodosimetry in a variety of different large-scale exposure scenarios, to predict both individual dose and also individual sensitivity to future injury. A central characteristic remains our focus on 3 different high-throughput approaches: fully automated cytogenetics (Project 1), gene expression (Project 2), and metabolomics (Project 3). These have different balances of capabilities in terms of throughput, time-to-result, dose reconstruction, exposure scenario identification and individual radiosensitivity prediction, and the final goal is to quantify their optimal integrated usage in different large-scale exposure scenarios. The Projects share four common themes: 1: ?Beyond Simple Exposures?: Towards High-Throughput Biodosimetry for Complex Exposures: After an IND there will be a wide variety of exposure scenarios including very high dose rate, neutron exposure, partial-body exposure (all from the initial prompt radiation), and varying dose rate and low dose rate (from external fallout and internal exposure). The goals are to 1) understand how these different exposure scenarios modulate the response of the predictive biomarkers that we have developed, and 2) optimally use these biomarkers to identify / characterize these different exposure scenarios to which individuals may be exposed. 2: ?Beyond Dose?: Towards High-Throughput Individualized Predictors of Photon and Neutron- Induced Radiosensitivity and Late Radiation Injury: Gene expression and metabolomics each have utility for predicting individualized onset of late radiation-induced lung disease, and for predicting which irradiated animals will die from the disease. This work will be extended to neutron-induced late effects, whilst also assessing the significance of senescent cells for late disease development and for our lung disease signatures. 3: ?Beyond Model Systems?: Probing the Applications of Experimentally-Generated Photon and Neutron Biomarkers to In-Vivo Human Exposure Scenarios: The goal is to assess in-vivo human exposures, but biodosimetric assay development is typically performed either with ex-vivo irradiated human blood or in-vivo in animals. For both photons and neutrons, ex-vivo vs. in-vivo generated biomarkers will be compared, and ex-vivo generated biomarkers from different species will be characterized and compared. 4: Optimized Biomarker Integration: The three different biomarker systems reflect different balances of capabilities in terms of, for example, throughput, time-to-result, signal lifetime, dose reconstruction, exposure scenario identification and individual radiosensitivity prediction. The goal here is to identify their optimal integrated usage in each of a variety of very different possible large-scale exposure scenarios. Three scientific cores (Animal, Irradiation & Dosimetry, and Biostatistics) bring together key support technologies, with each Core supporting each of the Research Projects. Because of the integrated nature of the research, this results in major gains in efficiency.
This Program represents a cohesive approach motivated by the practical needs of very high-throughput radiation biodosimetry in a variety of very different large-scale exposure scenarios, to estimate past individual dose and to predict individual sensitivity to future injury. A central characteristic remains focus on three different approaches: fully automated cytogenetics, gene expression, and metabolomics; these have different balances of capabilities in terms of throughput, time-to-result, signal lifetime, dose reconstruction, exposure scenario identification and individual radiosensitivity prediction, and the final goal is to quantify their optimal integrated usage in each of the many different potential exposure scenarios.
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|Eppensteiner, John; Davis, Robert Patrick; Barbas, Andrew S et al. (2018) Immunothrombotic Activity of Damage-Associated Molecular Patterns and Extracellular Vesicles in Secondary Organ Failure Induced by Trauma and Sterile Insults. Front Immunol 9:190|
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|Lacombe, Jerome; Sima, Chao; Amundson, Sally A et al. (2018) Candidate gene biodosimetry markers of exposure to external ionizing radiation in human blood: A systematic review. PLoS One 13:e0198851|
|Lee, Younghyun; Pujol Canadell, Monica; Shuryak, Igor et al. (2018) Candidate protein markers for radiation biodosimetry in the hematopoietically humanized mouse model. Sci Rep 8:13557|
|Rudqvist, Nils; Laiakis, Evagelia C; Ghandhi, Shanaz A et al. (2018) Global Gene Expression Response in Mouse Models of DNA Repair Deficiency after Gamma Irradiation. Radiat Res 189:337-344|
|Suresh Kumar, M A; Laiakis, Evagelia C; Ghandhi, Shanaz A et al. (2018) Gene Expression in Parp1 Deficient Mice Exposed to a Median Lethal Dose of Gamma Rays. Radiat Res 190:53-62|
|Zheng, Zhihong; Fan, Shengjun; Zheng, Jing et al. (2018) Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma. J Hematol Oncol 11:29|
|Beach, Tyler A; Groves, Angela M; Johnston, Carl J et al. (2018) Recurrent DNA damage is associated with persistent injury in progressive radiation-induced pulmonary fibrosis. Int J Radiat Biol 94:1104-1115|
|Ghandhi, Shanaz A; Turner, Helen C; Shuryak, Igor et al. (2018) Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells. PLoS One 13:e0191402|
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