Our overriding theme is ultra high-throughput radiation biodosimetry. It is well established that this is a central and necessary component of any effective response to a large scale radiological event. The RABIT (Rapid Automated Biodosimetry Tool) system developed to date in Project 1 has a current throughput of 6,000 samples / day, and a projected (2010) throughput of 30,000 samples / day. These throughputs were achieved by complete robotically-based automation of standard micronucleus and ?-H2AX assays. One first main renewal theme, "Beyond Simple Exposures", is to assess the significance of various realistic radiation event scenarios, in particular protraction of radiation exposure, partial-body exposure, internal emitters, and neutron exposure. Our goal is to understand the responses of the standard RABIT assays to these types of exposures, and quantify the uncertainties associated with dose reconstruction in these scenarios. The assays will be done both with irradiated mice and with ex-vivo irradiated human blood, with the unique irradiation facilities of the Irradiation Core, allowing sample sharing with the other two Projects. While the micronucleus assay has high throughput and excellent post-irradiation stability, its assay time is ~3 days, due to the need to stimulate cell division in vitro. We have preliminary evidence of the practicality of a micronucleus assay using /T?ononi;c/ear lymphocytes, which have already divided in vivo. Our second theme is to develop and assess this system which, with full automation, would reduce the assay time to ~3 hrs Having developed high-throughput systems using various biomarkers for biodosimetry, we are in a unique position to probe the application of these high-throughput biomarkers for predicting inter-individual sensitivity to acute radiation injury. Thus our final renewal theme is "Beyond Dose: Towards Individual Radiosensitivity". The six high-throughput automated RABIT endpoints that we will use are baseline micronuclei, ex-vivo radiation-induced micronuclei, ex-vivo radiation-induced ?-H2AX, ex-vivo radiation-induced chromosomal deletions, DNA damage repair kinetics (with ?-H2AX, ATM, 53BP1, and Mdcl foci), and residual damage after 24 h. The practical use of this number of assays is made possible by their being fully automated within the RABIT. Studies will be done with inbred mice with differing acute radiosensitivities, and by assessing associations between these endpoints and acute erythema in 500 irradiated breast cancer patients.
A dirty bomb or improvised nuclear device could result in mass casualties from multiple types of radiation exposures, and a need for rapid, high-throughput biodosimetry to identify those who most require treatment. By developing practical radiological triage approaches that are applicable for partial body, low dose-rate, internal emitters, and mixed neutron exposures, and that start to account for individual radiosensitivity, this project will address a critical need of national preparedness.
|Sprung, Carl N; Ivashkevich, Alesia; Forrester, Helen B et al. (2015) Oxidative DNA damage caused by inflammation may link to stress-induced non-targeted effects. Cancer Lett 356:72-81|
|Shuryak, Igor; Lubin, Jay H; Brenner, David J (2014) Potential for adult-based epidemiological studies to characterize overall cancer risks associated with a lifetime of CT scans. Radiat Res 181:584-91|
|Turner, Helen C; Sharma, P; Perrier, J R et al. (2014) The RABiT: high-throughput technology for assessing global DSB repair. Radiat Environ Biophys 53:265-72|
|Repin, Mikhail; Turner, Helen C; Garty, Guy et al. (2014) Next generation platforms for high-throughput biodosimetry. Radiat Prot Dosimetry 159:105-10|
|Laiakis, Evagelia C; Mak, Tytus D; Anizan, Sebastien et al. (2014) Development of a metabolomic radiation signature in urine from patients undergoing total body irradiation. Radiat Res 181:350-61|
|Goudarzi, Maryam; Weber, Waylon; Mak, Tytus D et al. (2014) Development of urinary biomarkers for internal exposure by cesium-137 using a metabolomics approach in mice. Radiat Res 181:54-64|
|Forrester, Helen B; Li, Jason; Leong, Trevor et al. (2014) Identification of a radiation sensitivity gene expression profile in primary fibroblasts derived from patients who developed radiotherapy-induced fibrosis. Radiother Oncol 111:186-93|
|Forrester, Helen B; Sprung, Carl N (2014) Intragenic controls utilizing radiation-induced alternative transcript regions improves gene expression biodosimetry. Radiat Res 181:314-23|
|Luo, Xiuquan; Suzuki, Masatoshi; Ghandhi, Shanaz A et al. (2014) ATM regulates insulin-like growth factor 1-secretory clusterin (IGF-1-sCLU) expression that protects cells against senescence. PLoS One 9:e99983|
|Paul, Sunirmal; Ghandhi, Shanaz A; Weber, Waylon et al. (2014) Gene expression response of mice after a single dose of 137CS as an internal emitter. Radiat Res 182:380-9|
Showing the most recent 10 out of 85 publications