This overall CMCR program represents a cohesive multidisciplinary approach to highly focused goals: High-throughput biodosimetry and its application to individualized early prediction of radiation-induced injury. A central characteristi of the Columbia CMCR program remains a focus on three different high-throughput approaches: fully-automated cytogenetics (Project 1), functional genomics (Project 2), and metabolomics (Project 3). These different approaches represent a range of risk-benefit balances, and pursuing all three is of synergetic benefit to each, not only in terms of common experimental design and sample sharing, but also in terms of intercomparing and interpreting the results and their practical significance. The three Projects, supported by four integrated scientific Cores, each share the same common themes: 1. Towards High-Throughput Biodosimetry for Complex Exposures: The goal is to assess how different exposure scenarios, in particular different dose rates, internal emitters, and neutron exposure, modulate biomarker response, as well as investigating biomarkers that uniquely reflect the presence of different exposure scenarios. 2. Towards High-Throughput Individualized Predictors of Radiosensitivity / Late Injury: Transcriptomics and metabolomics approaches have been shown here to have utility for predicting individualized radiation-induced acute effects, and this concept will be extended toward late effects. The Project 1 focus is on potential correlations between pneumonitis in radiotherapy patients and high-throughput DNA damage endpoints after ex-vivo blood irradiation. The Project 2 and 3 focus is on transcriptomic and metabolomic biomarkers for individualized early prediction of pulmonary lethality in mice. In keeping with the theme of individual sensitivity, studies are planned of the significance of inflammatory diseases, as well as of predictive assays as an adjunct to radiation mitigator development, as early indicators of mitigator effectiveness. 3. Technology Development: The goal is to take advantage of commercial high-throughput screening technologies, for cell-based screening, transcriptomics, and mass spectrometry, which are increasingly available in university and industry settings. New assay protocols and front-end sample acquisition systems will take advantage of these common devices. A further technology development is an inexpensive continuously-decreasing-dose-rate 137Cs irradiator, simulating any time-decreasing dose rate caused by internal 137Cs exposure; the device can provide a major stimulus to CMCR 137Cs internal-emitter studies. A highly unified organizational structure will be maintained. Overseeing the scientific program at the highest level is the External Scientific Advisory Group (ESAG), whose members meet in person annually. The Internal Advisory Committee (IAC) has responsibility for local coordination of the entire CMCR Program. The interactions between the ESAG and the IAC have been central to the Program's scientific direction.
An improvised nuclear device or dirty bomb could result in mass casualties from multiple types of radiation exposures, and there is thus a need for rapid, high-throughput methods to identify those individuals who received significant radiation exposures. We will extend the high-throughput approaches that we have developed to scenarios involving exposures over very different time frames, to internal radiation exposures and to neutron exposures. We are also developing high-throughput approaches to identify those exposed individuals who are most likely to be especially sensitive to radiation and develop serious long term radiation- induced disease.
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