Molecular Mechanisms Underlying Cellular Adaptive Response to Low Dose Radiation
Funding Agency: U.S. Department of Energy, Low Dose Radiation Research Program
Low dose radiation triggers cellular effects that protect cells given a subsequent radiation challenge. This phenomenon is termed the radioadaptive response. The Molecular Mechanisms Underlying Cellular Adaptive Response to Low Dose Radiation project team at the Pacific Northwest National Laboratory (PNNL) is studying the radioadaptive response using macrophage and myocyte model systems with an emphasis on the calcium-binding protein and central point in calcium signaling, calmodulin (CaM).
In response to changing concentrations of calcium, CaM regulates energy metabolism on the immediate time scale and regulates gene transcription in the long term. We have generated results in our laboratory, which indicate a central role for CaM in mediating radiation- and other stress-induced cellular responses. These results are consistent with published evidence that suggests calcium-dependent pathways are involved in the radioadaptive response. Given the known regulatory role of CaM and evidence that supports a role for CaM and calcium in the cellular radiation response, we hypothesize that CaM and its associated signaling complexes are sensors of low dose radiation, which initiate changes in energy metabolism and gene expression upon radiation exposure. To understand better the regulatory elements of the radioadaptive response, we are working to:
- identify CaM-associated protein complexes as a function of radiation dose using high-throughput proteomic and mass spectrometry technologies
- understand the role of protein degradation in mediating the low dose adaptive response
- determine dose-dependent changes in biochemical pathways and associated oxidative modifications of proteins using global proteomics combined with 16O/ 18O quantitation techniques.
Our efforts will provide functional links between calcium-regulated CaM activity and the diverse pathways that underlie the adaptive response to low dose radiation, supporting our long-term goal of identifying the molecular basis of the radioadaptive response.