National Laboratories
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.
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:
Low Dose Radiation Effects on Cell, Genetic, and Tissue Physiology - Lawrence Berkeley National Laboratory
Contact: Dr. Joe Gray
The Lawrence Berkeley National Laboratory's (LBNL) Low Dose Radiation Research Program SFA will address the cell and molecular biology, human genetics, and tissue physiology that determine responses to low dose radiation. The proposed program represents an evolution of LBNL's long-standing program in low dose radiation research.
Researchers at LBNL have pioneered studies of the fundamental mechanisms of homeostatic control and epithelial carcinogenesis mediated by the microenvironment and how these are affected by radiation. They have also characterized novel molecular mechanisms for coordinating DNA damage responses to oxidative DNA damage and their inducibility by low dose radiation, identified new mechanisms of epigenetic regulation, and defined transcriptional response networks that are activated in response to low-dose exposures.
The LBNL SFA program focuses on coordinating this multidisciplinary expertise to define the mechanisms and consequences of radiation response in tissues and complex biological systems in terms of endpoints that are relevant to regulatory decision-making. Program researchers will study the impact of low dose radiation on three biological radiation-response processes in relation to cancer, which is the clearest radiation-induced health effect and the endpoint that can be most easily translated into radiation regulatory models. The processes are
- Adaptive responses
- Non-targeted responses
- Epigenetic regulation.
The Adaptive Response Project aims to determine how low dose and adaptive response mechanisms affect risk of breast cancer and lymphoma, two radiation-sensitive cancers. Leader: Andrew Wyrobek; Co-Leader: Priscilla Cooper.
The Non-Targeted Effects Project employs systems genetic analysis of the relative contribution of non-targeted vs. targeted radiation effects on cancer risk. Leader: Mina Bissell; Co-Leader: Jian-Hua Mao.
The Epigenetics Project examines the effects of ionizing radiation on chromatin composition and organization, and determines the impact of these effects on extracellular signaling-dependent phenotypic transitions in human cells. Leader: Terumi Kohwi-Shigematsu; Co-Leader: Gary Karpen.
The LBNL SFA also has two technical cores: imaging and omics & informatics.
The Imaging Core provides a comprehensive set of imaging instruments that are tightly integrated with the bioinformatics core for image data management and analysis. Leader: Damir Sudar; Co-Leader: Bahram Parvin.
The Omics & Informatics Core assists the program personnel in applying existing omics (genomics, proteomics, transcriptomics, metabolomics, etc.) analysis tools to problems of the program's interest, and develops bioinformatics solutions to the program's problems. Leader: Joe Gray
Linear and Nonlinear Tissue Signaling Mechanisms in Response to Low Dose/Low Dose-Rate Ionizing Radiation - Pacific Northwest National Laboratory
Contact: Dr. William Morgan
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.
Major Objectives
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.
Investigators
- 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.
