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

本提案旨在研究我们已经确定的不同于高剂量机制的独特的低辐射剂量机制。除了DNA效应外，它们还包括线粒体作为重要的靶点和应答者，受辐射剂量和剂量率的调节。该提案分为两个阶段；最初将选择具有功能性或非功能性线粒体的细胞系。这些将受到一系列低剂量和低剂量率的照射。将评估生存参数。后续工作将使用相同的剂量范围，但将使用特定的化学阻滞剂来测试线粒体功能的哪些方面是重要的。在所有情况下，直接照射和非靶向的旁观者细胞及其后代的存活将是关键的终点，线粒体DNA分析将是绘制已经确定的基因组标记的关键终点。由于我从上次DG中获得了氚（低能β发射器）和Cs-137（中能γ发射器）的初步数据，这些最初将用作辐射源，但当初始数据已知时，将测试更广泛的辐射源。所有的生物检测都将伴随着线粒体数量和形状的定量超结构分析，因为这些参数对于确定辐照细胞中能量捕获和转化过程中的机电和电化学转变非常重要。预测是线粒体将是一个关键的低剂量目标。了解产生低剂量辐射效应的机制将有助于研制旨在保护受照射工人、病人和公众的缓解剂。目前的假设是高剂量会产生某些影响，而低剂量会产生较少的相同影响，这可能会产生误导。它阻碍了开发针对细胞器（如线粒体）或低剂量暴露（如电化学梯度控制）特有的机械过程的放射性减轻剂的新靶标的识别。越来越多地依赖于涉及辐射暴露的医学诊断技术，例如CT扫描或PET成像。核工业在加拿大经济中也是一个重要的利益相关者，生产了加拿大15%的电力（安大略省60%）。卫生和能源部门将受益于旨在减少对健康影响的不确定性和寻求新的缓解目标的研究。进一步的影响是，在拟议的项目期间，学生将在多学科环境中接受新技术的培训，使他们非常适合生物物理学科领域的研究，或者非常适合工业、大学或医院的健康物理学或医学物理学职业。拟议的研究项目还将为政府、非政府组织和工业界制作教育材料，这些材料将阐明暴露在低水平辐射下的影响，为监测影响提供更好的生物技术。

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.