Collaborative application within the framework of the Competence Network Radiation Research (KVSF).

Funded by: BMBF

Duration: 2008 to 2014

Responsible project manager: Dr. R. Kriehuber

Collaborative partners:

Prof. Dr. Georg Iliakis - University of Duisburg-Essen Medical School Institute of Medical Radiation Biology, Hufelandstr. 55, 45122 Essen

Prof. Dr. Martin Stuschke - University of Duisburg Essen Medical School, Department for Radiotherapy, Hufelandstr. 55, 45122 Essen

Prof. Dr. Ekkehard Dikomey - Universität Hamburg, Labor für Strahlenbiologie & Experimentelle Radioonkologie, Klinik für Strahlentherapie und Radioonkologie; Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D 20246 Hamburg

Prof. Dr. Olaf Wolkenhauer - Universität Rostock, Lehrstuhl für Systembiologie und Bioinformatik, Fakultät für Informatik und Elektrotechnik, 18051 Rostock

Scientific & Structural Goals

The major scientific goal of this project is to identify suitable sub-sets of genes which correspond to the protein expression/activation patterns and correlate this information with radiation dose and radiation quality. In addition, it will investigate the effects of single nucleotide polymorphisms on the individual radiation susceptibility and their influence on the proposed biodosimetry system. The specified scientific goals of the project are:

• Identification and verification of genes and proteins showing an altered expression status in a dose dependent manner after radiation exposure
• Identification of gene and protein activation pattern which are specific for different radiation qualities and radiation doses
• Characterization of gene and protein activation pattern after targeted subcellular localisation of Auger electron emitter
• Characterization and modelling of dynamic gene activation pattern after exposure to ionizing radiation
• To clarify whether known specific SNPs influence the gene expression profile in response to radiation exposure
• To elucidate whether SNPs in cell-cycle regulating genes and genes involved in DSB repair are associated with individual radiosensitivity and whether they could serve as a predictive tool for acute and late side-effects after radiotherapy.

Strengthening of interactions between Institutions still active in the field of Radiation Research is a central goal of the present project and a key strategic aim of the BMBF Initiative to support radiation sciences in the country. The complementarity of expertise and resources between the participating Institutions generates an excellent foundation for fruitful synergistic interactions. The preservation of still existing knowledge and simultaneous encouragement of young researcher into the field of radiation biology is a further structural goal of the project. The embedded PhD student programme shall recruit young researcher into the field and allow visits of the PhD students in the participating labs to give insight in the different aspects of current radiation biology. The present project will maintain close interactions with other Projects within this initiative in an effort to coordinate efforts and foster synergisms. We have identified the project  "Individuelle Strahlenempfindlichkeit und genomische Instabilität", coordinated by Prof. Atkinson at the GSF, Neuherberg, as a potential partner in this regard due to its thematic relevance with our project. We have agreed to maintain an active dialogue with the leader of this project, and upon funding to initiate annual joint meetings including all participating groups.

Background

Protection of humans from the adverse effects of ionizing radiation is a major goal of the Radiation Protection field. In the case of accidental exposures to radiation the development of effective counter measures requires information on the actual exposure dose as well as knowledge on the individual radiosensitivity of the exposed group of individuals. Therefore, advances in the field will require: a. Methods allowing dose determination particularly when precise measurements of physical dose are not available b. Parameters allowing the evaluation of the individual radiosensitivity to radiation in order to identify subpopulations with increased risk c. Application of bioinformatics to describe the dynamics and complexity of signalling pathways interactions in order to understand the molecular mechanisms determining cellular radiation response and individual radiosensitivity These central questions are addressed in an integrated project coordinated by the Forschungszentrum Jülich and integrating academic Institutions active in the field. Central in this strategy is the intensification and coordination of efforts in the field of radiation sciences between Jülich and the University of Essen in order to generate a solid foundation for the operations of the present consortium and to facilitate future expansions. The proposed structure ensures rapid revitalization and invigoration of the activities of the Forschungszentrum Jülich in the field of radiation sciences, and through its university outreach contributes significantly to the strengthening of competence in the country. Biodosimetry and Radiation systems biology The assessment of the radiation dose of large populations based on protein activation and expression pattern in single individuals is one of the major topics of current radiation biology research. It is presently carried out with particular emphasis in the USA where a sizable sum of funds has been dedicated to this goal. Therefore, it is essential to strengthen such expertise in Germany as well. The approach promises to provide essential information for the development of appropriate counter measures following radiation accidents or acts of terrorism. A biodosimetry system based on well defined and validated gene and protein activation patterns will have several advantages to already existing methods. The quick assessment due to DNA-array techniques and qRT-PCR will allow screening large populations in a rather short time and will be cost saving due to a high state of automation. The possibility to include different sub-sets of genes will allow screening different dose ranges, radiation qualities and exposure pathways at the same time. Furthermore, the method is not generally restricted to certain cell types and might be adapted easily to different tissues. Biodosimetry based on gene and protein expression pattern analysis is therefore a promising approach to overcome the known limitations of the established methods and will give additional insights in the complexity of the systemic and cellular radiation response in mammalian cells. Radiation systems biology offers a unique method to investigate the activation and suppression patterns of large sets of genes and gives in parallel the possibility to correlate this information with actual protein expression patterns. The complex cellular and systemic response to ionizing radiation can be monitored by this approach and will allow identifying sub-sets of genes which are suitable to quantify radiation doses in a large group of exposed individuals. Individual Radiosensitivity Evaluation of the individual radiosensitivity is a topic of particular interest not only in Radiation Therapy but also in Radiation Protection. Central goal in these efforts is to identify the relatively small subgroup of radiation sensitive individuals in order to subject them to specialized treatment protocols or radiation protection guide lines, while optimizing radiation protection standards or treatment protocols for the remaining population, in the latter case on the basis of optimal tumour response. The genotype determines the radiation impact at the cellular level. Gene polymorphisms are the molecular base of the observed different geno- and phenotypes and even single nucleotide polymorphisms (SNPs) were shown to alter the protein status and hence the cellular response to radiation exposure. To understand and explain the different radiation response in dependence on the genotype will help to identify suitable genes for the purpose of biological dosimetry. Additionally, the planned investigations will help to explain the different radiation susceptibility of the respective genotype which is of great interest in the optimization of radiation therapy.