The Low Dose Radiation Program funding encompasses several Scientific Focus Areas (SFAs). The SFAs fund merit-reviewed research at DOE national laboratories. This management approach was created in 2008 by the Office of Biological and Environmental Research (BER) within the U.S. Department of Energy's (DOE's) Office of Science.
PNNL's Low Dose Radiation Research Program Scientific Focus Area
Linear and Nonlinear Tissue-Signaling Mechanisms in Response to Low Dose and Low Dose-Rate Radiation
This program is funded as a U.S. Department of Energy Scientific Focus Area (SFA), and is an integrated cooperative program to understand low dose radiation effects in a complex model system.
Coordinating Multidisciplinary Expertise
The SFAs are designed to take advantage of the multidisciplinary, team-oriented research that is a strength of National Laboratories. The SFA structure makes it easier to communicate a holistic view of science within BER, and it enables DOE to identify areas for future solicitations.
The Low Dose Radiation Program SFAs encompass the following areas:
A Systems Biology Approach to Assessment of Responses to Low Dose/Dose-Rate Ionizing Radiation—Lawrence Berkeley National Laboratory
Contact: Dr. Gary Karpen
This program, led by Gary Karpen, has been developed to address the similarly named Scientific Focus Area (SFA) identified by the U.S. Department of Energy (DOE). The program uses a strategy that integrates systems genetics and discovery approaches with mechanistic information from all levels of biological organization - molecules, cells, tissues, and animal models—to address key questions concerning the effects on human health of low dose, low dose-rate exposure to ionizing radiation.
The emphasis is on biological mechanisms that contribute to carcinogenic risk, especially for breast cancer. The approach considers effects both on the epithelial cells that are at risk of malignancy and on stromal cells that do not become malignant but which impact radiation-induced carcinogenesis through changes in the tissue microenvironment. The central issues being addressed are to what extent responses to low doses differ from high dose responses and can alter the response to subsequent exposures, the mechanisms and genetic determinants responsible for such effects, and their consequences with respect to deviation from a linear dose response for carcinogenesis.
Four inter-connected SFA research components coordinately investigate low dose responses through complementary studies using both in vivo mouse models of differing radiosensitivity and comparative culture systems for mammary-derived mouse and human cells: component one focuses on non-linear and adaptive response mechanisms in mammary cell culture models; component two investigates mammary tissue radiation response phenotypes predicted by transcriptome responses; component three uses systems genetics and organotypic culture to understand differences in susceptibility to low-dose radiation-induced mammary tumors; the fourth component, the Integration Hub, provides support for advanced technologies and integrative data analysis applied across all components.
Blakely , EA, Lauriston S. Taylor Lecture: What makes particle radiation so effective? Health Phys. 103(5):508-528; 2012
Lowe X. R., Wyrobek A. J. (2012), Characterization of the Early CNS Stress Biomarkers and Profiles Associated with Neuropsychiatric Diseases. Current Genomics, 2012, Vol. 13, No. 6
Lee DY, Bowen B, Nguyen DH, Parsa S, Huang Y, Mao JH, Northen TR. (2012) Low-Dose Ionizing Radiation-Induced Blood Plasma Metabolic Response in a Diverse Genetic Mouse Population. Radiation Research, IN PRESS.
Snijders AM, Marchetti F, Bhatnagar S, Duru N, Han J, Hu Z, Mao J-H, Gray JW, Wyrobek AJ. Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility. PLoS One, IN PRESS
Neumaier T, Swenson J, Pham C, Polyzos A, Lo AT, Yang P, Dyball J, Asaithamby A, Chen DJ, Bissell MJ, Thalhammer S, Costes SV. (2012) Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells. Proc Natl Acad Sci U S A. Jan 10; 109(2):443-8.
Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH, Ravani SA, Zavadil J, Borowsky AD, Jerry DJ, Dunphy KA, Seo JH, Haslam S, Medina D, and Barcellos-Hoff MH. Radiation acts on the microenvironment to affect Breast carcinogenesis by distinct mechanisms that decrease breast cancer latency and affect tumor type. Cancer Cell, 19: 640-651 (2011).
Wyrobek AJ, Manohar CF, Krishnan VV, Nelson DO, Furtado MR, Bhattacharya MS, Marchetti F, Coleman M. Radiation response networks and pathways in human lymphoblastoid cells exposed from 1 to 10 cGy of acute gamma radiation. Mutation Res. 722(2):119-30 (2011).
Chiolo, I., Minoda, A., Colmenares, S. U., Polyzos, A., Costes, S. V., Karpen, G. H. Double-strand breaks in heterochromatin move outside of a dynamic HP1a domain to complete recombinational repair. Cell 144(5): 732-44. (2011).
Full thickness human skin model composed of keratinocytes and fibroblasts (and cell-derived matrix) grown in 3D culture.
The goal of Pacific Northwest National Laboratory's (PNNL's) Low Dose Radiation research program is to use an integrated, systems-level approach to understand the fundamental signaling events mediated by low dose (LD) and low dose rate (LDR) radiation, focusing on the tissue response rather than individual cells.
Using a human skin tissue model system, PNNL researchers are addressing the hypothesis that the normal tissue response to LD/LDR radiation supports homeostasis, and that this is achieved through intercellular signaling best understood through an integrated experimental and pathway modeling approach.
The research program will leverage PNNL's strengths in systems biology, global proteomics, genomics, imaging, computational biology, and radiation biology to achieve the following major objectives:
- Identify functional signaling modules induced by LD radiation and quantitatively compare these to modules affected by high dose exposures linked to chronic health effects.
- Develop iterative computational/experimental strategies for functional and scalable module-based modeling of low dose radiation-induced signaling in multi-cellular systems.
- Understand the spatial organization of information flow and signaling between cell types and how this influences tissue response to low dose radiation.
- Determine the effects of radiation dose rate on key signaling intermediates of response identified in Objectives 1 and 2 to more realistically model real-life exposures.
The results will provide a fundamental understanding of how LD/LDR-induced signaling is coordinated through intercellular communication, and determine how these mechanisms impact the linearity of dose-response behavior at low doses.
PNNL scientists will use this information to usher in the next generation of radiation risk models built on mechanistic information across relevant special and temporal scales in radiobiology.
- William F. Morgan, PhD, DSc. PNNL Low Dose SFA program manager.
- David L. Stenoien, PhD. Principal investigator: analysis of protein phosphorylation events and follow-on molecular analysis of their role in radiation-induced signaling.
- Marianne B. Sowa, PhD. Principal investigator: targeted microbeam irradiation and image analysis using the high-speed microscopy capabilities at PNNL.
- Thomas J. Weber, PhD. Principal investigator: analysis of gene expression changes by microarray and follow-on analysis of their role in radiation-induced signaling.
- David L. Springer, PhD. Principal investigator: analysis of protein abundance changes induced by radiation using proteomics in whole cell and cell organelle fractions and extracellular medium.
- Colette A. Sacksteder, PhD. Principal investigator: analysis of primary proteomic (MS) data and analysis of radiation-induced protein complex changes using proteomics technologies.
- John H. Miller, PhD. Principal investigator, Washington State University Tri-Cities: conduct bioinformatics related to the large genomic and proteomic dataset collected at PNNL and perform computational biology related to experiments performed at PNNL on a model skin system exposed to ionizing radiation.
- Harish Shankaran, PhD. Computational biology and network modeling of cell signaling pathways induced by low dose radiation. Experimental design and data analysis and interpretation of experimental results.
- Susan M. Varnum, PhD. Protein microarrays and their use in identifying biomarkers of biological response.
- Katrina M. Waters, PhD. Data analysis and integration.
- Adam J. Lewis, Master's student, WSU-Tri-Cities: working with Dr. Sowa on the generation of reactive oxygen species as a result of low dose radiation exposures and the subsequent effects on the cells in the 3D human skin model.
- Nila Reitz, Master's student, WSU-Tri-Cities: working with Dr. Miller on computational pathway analysis of phosphoproteomic data generated by Drs. Stenoien and Varnum with the goal of generating molecular interaction maps.
- Ryan L. Sontag, Master's student, WSU-Tri-Cities: working with Dr. Weber studying the similarities between wound healing and low dose radiation-induced carcinogenesis.
A Systems Genetics Approach to Low-Dose Radiation - Oak Ridge National Laboratory
Contact: Dr. Brynn H. Voy
The Low Dose Radiation Research Program SFA at ORNL addresses the response to radiation as a complex trait through the use of a systems genetics framework. This approach is made possible by the integration of genetic reference populations, genome sequence, and analytical tools that have emerged in recent years.
Systems genetics is a discovery-based, forward genetics paradigm that provides the potential for a new set of discoveries about low dose effects that are not readily attainable through other strategies. Specifically, it allows for simultaneous relation of radiation-response phenotypes to the underlying molecular networks while highlighting regions of the genome that confer altered sensitivity to radiation exposure. Because the approach is executed in the context of a population-based model, it provides a robust picture of radiation effects that occur in the context of natural genetic variation.
We are using two powerful genetic reference populations of mice for these studies:
- BXD (C57BL/6J X DBA/2J) RI strain panel, which we have been using with previous DOE funding
- The Collaborative Cross, an emerging population of mice that contains a level of genetic and phenotypic diversity on par with the human population.
Our tasks integrate biological emphasis on the immunological effects of low dose radiation with development and enhancement of computational and bioinformatic tools that will accelerate low dose discoveries from multiple data types, including large-scale 'omics datasets. We include a pilot study to begin new exploration into neurobiological impacts of low dose exposure.
Finally we will create a tissue bank that can be mined by other investigators in the low dose community that will enable us to realize the full, integrative power of systems genetics. Collectively, this project will advance the field of low dose radiobiology by uncovering multilevel networks that link genetic variants to radiation response outcomes in a population-based model system.