Targets and signalling pathways of radiation hypersensitivity and resistance (ZiSS)

Cellular radiation hypersensitivity and radiation resistance are main issues of applied radiation science for several reasons. On the one hand, radiation hypersensitivity may increase tumour risk for individuals occupationally or medically exposed to radiation, on the other hand radiation hypersensitivity and resistance of tumour and normal tissues are important factors in radiation therapy of tumours. Herefore, the knowledge of individual radiation sensitivity has an increasing impact on both radiation protection and radiation therapy.

All kinds of potential biomarkers have been identified during the past ten years, but none has been successfully validated until now, and none can be used to predict radiation sensitivity or the radio oncological therapy outcome. Strategies aimed at investigating the molecular basics of radiation hypersensitivity and resistance in cell culture models with a defined genetic background and well characterized radiation sensitivity therefore are a promising approach.

The objective of this multidisciplinary project was to identify molecular targets and signalling pathways underlying cellular radiation hypersensitivity and resistance of tumour and normal tissue.

To this purpose, a network of five national partners

• Federal Office for Radiation Protection;
• Helmholtz Center Munich;
• Ludwig-Maximilians-University, Munich;
• Institute of Cell Biology, Essen;
• Charité Berlin

investigated human cell lines with a defined radiation sensitivity and determined radiation modified gene and protein expression.

Integrated analysis of the molecular data from different cellular levels, as

• genome,
• transcriptome,
• epigenome,
• proteome and
• phosphoproteome

were performed to identify deregulated molecular networks and their respective central effector genes/ proteins.

Time-resolved perturbation experiments were carried out and mathematical models developed to detect the radiation modulated signal cascades and potential molecular targets. Cells with controlled regulation of the identified candidate genes/ proteins were generated and the influence on radiation sensitivity was validated by in vitro and in vivo models.

Based on the results the effect of potential radiosensitizing and radioprotective substances (small molecules) were tested.

The project was funded by the German Ministry of Education and Research (grant 02NUK024A) and is terminated.

The BfS is part of the research consortium ZiSStrans which continues the research work in a follow-up project again funded by the German Ministry of Education and Research (grant 02NUK047B).