Radiation effects are not confined to directly irradiated tissues. The contribution of systemic “out-of-target” effects to the risks of a long-term health detriment following exposure to radiation is largely unknown. Indeed, both protective and damaging effects have been described, and no information on a dose response relationship exists. From the radiation protection standpoint this level of uncertainty of the risk is problematic, as workplace, environmental and medical exposures frequently involve partial body exposures to low dose irradiation.

Our work has shown that brain and skin cancer development is increased by an exposure of distant tissues in genetically sensitive mice, indicating that there is a level of communication between irradiated and non-irradiated tissues and organs. We have also described changes in the levels of non-coding RNA molecules released from irradiated tissues in patients undergoing radiation therapy limited to the head. The nature of the molecule(s) and pathways responsible for this signalling is unknown, although numerous candidates have been proposed, ranging from calcium, NO, RNA, cytokines and growth factors. Understanding how the signal(s) are transmitted to nonirradiated cells/tissues and how it/they provoke a systemic response is crucial, but far from being complete.

In SEPARATE we will extend these studies to the analysis of the effects on brain, heart, and liver, following exposures of the lower third of the body, whilst the target organs are shielded. We will examine changes in these important organs at the transcriptome, non-coding RNAs, protein, and metabolic levels. Where possible, we will carry out partial-organ irradiation, and we will look at molecular and cellular damage in non-irradiated organ portions. We will also investigate exosomes from exposed tissues, and their specific bioactive cargo - particularly RNA content – for their role in mediating out-of-target effects in vitro and in vivo. By combining this cellular, molecular and bioinformatic data we will be able to identify the response pathways in the different tissues, and by inference, suggest the candidate signalling molecules involved. A second major outcome of this project will be the discovery of candidate biomarker molecules of both whole body and partial body irradiation responses.