It is now well established that exposure of human cells to environmental stresses, including ionizing radiation, activates multiple signal transduction pathways, resulting in complex patterns of gene expression change. Expression of specific genes can be both dose- and stress- dependent, making gene expression profiling a potentially informative approach for much-needed radiation biodosimetry. Several issues remain to be resolved, however, including variations in baseline and treated expression levels among the population, potential confounding effects, and identification of an optimally informative gene set. Circulating lymphocytes represent a sensitive target for early radiation injury, highly responsive in terms of induced gene expression changes, and relatively easily biopsied. Peripheral blood cells will therefore be our primary model for development of a gene expression biodosirneter for radiation exposure. This Core will 1) establish and refine gene expression signatures diagnostic of human radiation exposure and dose in support of Project 2, 2) assess gene expression in parallel with micronuclei (Project 1) and patient urinary metabolomics (Project 3) to enable direct comparisons of biodosimetric techniques, and 3) provide a resource for oversight of experimental design pertaining to functional genomics and training of staff in support of Project 3 and the Pilot Projects as needed. By allowing measurement of gene expression changes across virtually the entire genome in a single experiment, the modern long oligonucleotide microarray approach is not only an efficient screen for potentially informative radiation biomarkers, but may also provide insight into the mechanistic basis of the human response to early radiation injury. Such information may suggest refinements of other biodosimetry techniques, and facilitate future collaborations between the Center for High-Throughput Minimally-Invasive Radiation Biodosimetry and the other Centers for Medical Countermeasures against Radiation, for instance by suggesting """"""""druggable targets"""""""" and opportunities for development of chemoprotective intervention strategies.
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