In order to prepare for the possible detonation of a radiological dispersal device (RDD or so-called "dirty bomb"), an improvised nuclear device (IND), or radiological accidents, the development of rapid, minimally invasive, and field-deployable biodosimetry is a high priority. Our project addresses this priority with the powerful global profiling capabilities of metabolomics, a biomarker discovery platform uniquely suited for the analysis of easily accessible biofluids, such as blood and urine, that require minimally- or non-invasive procedures to acquire. We have established the field of radiation metabolomics, and have published a series of seminal papers on responses at the small molecule level after radiation. Metabolomics has been used to define signatures of metabolites in urine from mice, rats, non-human primates, and humans.
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What is radiation metabolomics?
The study and quantification of small molecules (<1kDa) in biofluids and tissues following exposure to ionizing radiation.
The use of global profiling technologies has contributed substantially to the understanding of the radiation cellular stress response and has contributed to the elucidation of many of the complex biological networks associated with gene expression and signal transduction. On a similar level, global understanding of how ionizing radiation exposure affects small molecule concentrations (such as metabolites) would be expected to lead to the identification of metabolites that can be used to monitor for exposure and extent of the injury. Metabolomics is a rapidly advancing field that aims to identify and quantify the concentration changes of all metabolites (i.e., the metabolome) in a given biofluid or model system.
In order to assess the metabolic changes associated with ionizing radiation exposure, our approach employs ultra-pressure liquid chromatography (UPLC) coupled with highly sensitive time-of-flight (TOF) mass spectrometry (MS) to profile small molecules (<1kDa) from cultured cells, mice, and patient samples. We are utilizing the Waters ACQUITY UPLC-TOFMS system and the Waters Xevo G2 QTOF for metabolomic profiling of various easily accessible biofluids (i.e. urine, blood), cells, and tissues. Quantification of the validated metabolites is performed with the Waters Xevo TQ-S. Putative biomarkers are picked utilizing statistical approaches through chemometric software (SIMCA-P+ from Umetrics), Random Forests through R, and in-house developed statistical software (MetaboLyzer).
The overall strategy is to develop metabolomic signatures of radiation exposure using mouse models and to integrate these results with those from patients undergoing total body irradiation.