Physical mechanisms involved in the generation of radiation-induced signalling events

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This proposal aims to investigate the unique low radiation dose mechanisms we have identified that are different to high dose mechanisms. In addition to DNA effects they involve mitochondria as important targets and responders, modulated by both radiation dose and dose rate. The proposal has two phases; initially cell lines with functional or non-functional mitochondria will be selected. These will be exposed to a range of low doses and dose rates. Survival parameters will be assessed. Later work will use the same dose ranges but will use specific chemical blockers to test which aspects of mitochondrial function are important. In all cases survival of directly irradiated and non-targeted bystander cells and their progeny will be key endpoints as will mitochondrial DNA analysis to map the already identified genomic markers. As I have preliminary data from my last DG for tritium (low energy beta emitter) and Cs-137 (mid-energy gamma emitter) these will initially be used as radiation sources but when the initial data are known, a wider range of radiation sources will be tested. All bio-assays will be accompanied by quantitative ultra-structural analysis of the number and shape of the mitochondria since these parameters are known to be important in determining the mechano-electrical and electro-chemical transitions during energy trapping and conversion in irradiated cells. The prediction is that mitochondria will be a key low dose target. Knowledge of the mechanisms involved in producing low dose effects of radiation will help in development of mitigating agents aimed at protection of exposed workers, patients and the public. The current assumption that high doses produce certain effects and low doses produce less of the same effects may be misleading. It hinders identification of novel targets for development of radio-mitigating agents targeting organelles such as mitochondria, or mechanistic processes unique to low dose exposures such as control of electrochemical gradients. There is increasing reliance on medical diagnostic techniques involving radiation exposure e.g. CT scans or PET imaging. The nuclear industry is also an important stakeholder in the Canadian economy producing 15% of Canada's electricity (60% in Ontario). The Health and Energy sectors will benefit from research aimed at reducing uncertainty concerning health effects and seeking new mitigation targets. A further impact is that during the proposed project students will be trained in novel techniques in a multidisciplinary environment making them well suited to research in biophysical subject areas or a perfect fit in Health Physics or Medical Physics careers in industry, university or hospitals. The proposed research program will also enable production of educational material for government, NGOs and Industry, which will clarify the effects of exposure to low levels of radiation providing better biological techniques for monitoring impacts.