A functional genomics approach using radiation-induced changes in gene expression to study low dose radiation effects in vitro and in vivo

Abstract

for final report for project entitled A functional genomics approach using radiation-induced changes in gene expression to study low dose radiation effects in vitro and in vivo which has been supported by the DOE Low Dose Radiation Research Program for approximately 7 years. This project has encompassed two sequential awards, ER62683 and then ER63308, in the Gene Response Section in the Center for Cancer Research at the National Cancer Institute. The project was temporarily suspended during the relocation of the Principal Investigators laboratory to the Dept. of Genetics and Complex Diseases at Harvard School of Public Health at the end of 2004. Remaining support for the final year was transferred to this new site later in 2005 and was assigned the DOE Award Number ER64065. The major aims of this project have been 1) to characterize changes in gene expression in response to low-dose radiation responses; this includes responses in human cells lines, peripheral blood lymphocytes (PBL), and in vivo after human or murine exposures, as well as the effect of dose-rate on gene responses; 2) to characterize changes in gene expression that may be involved in bystander effects, such as may be mediated by cytokines and other intercellular signaling proteins; and 3) to characterize responses in transgenic mouse models with relevance to genomic stability. A variety of approaches have been used to study transcriptional events including microarray hybridization, quantitative single-probe hybridization which was developed in this laboratory, quantitative RT-PCR, and promoter microarray analysis using genomic regulatory motifs. Considering the frequent responsiveness of genes encoding cytokines and related signaling proteins that can affect cellular metabolism, initial efforts were initiated to study radiation responses at the metabolomic level and to correlate with radiation-responsive gene expression. Productivity includes twenty-four published and in press manuscripts, as well as a U.S. patent. There are several additional publications that will be submitted in 2007 that were supported in part by this program. These future publications include one manuscript on in vivo expression profiling analysis in mouse models, one manuscript on radiation responses in human cell lines, at least one on development of stress signatures in human cells, and three manuscripts on radiation metabolomics.