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

这项建议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，它们还涉及线粒体作为重要的靶点和响应者，受到辐射剂量和剂量率的调节。该计划分为两个阶段；首先，将选择具有功能或非功能线粒体的细胞系。这些人将暴露在一系列低剂量和剂量率下。将评估生存参数。稍后的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，直接照射和非靶向旁观者细胞及其后代的生存将是关键终点，线粒体DNA分析也将是关键终点，以绘制已确定的基因组标记。由于我有我上一次DG中关于氚(低能贝塔发射体)和Cs-137(中能伽马发射体)的初步数据，这些辐射源最初将被用作辐射源，但当初始数据已知时，将测试更广泛的辐射源。所有的生物分析都将伴随着线粒体数量和形状的定量超微结构分析，因为这些参数对于确定辐射细胞中能量捕获和转换过程中的机械-电子和电化学转变是重要的。据预测，线粒体将成为一个关键的低剂量靶点。对产生低剂量辐射影响的机制的了解将有助于开发旨在保护受照射工人、患者和公众的减压剂。目前的假设是，高剂量产生一定的影响，而低剂量产生的相同影响较少，这可能是误导的。它阻碍了新靶点的确定，以开发以线粒体等细胞器为靶标的放射减少剂，或针对低剂量暴露特有的机械过程，如控制电化学梯度。人们越来越依赖涉及辐射暴露的医疗诊断技术，例如CT扫描或正电子发射计算机断层扫描。核工业也是加拿大经济的重要利益相关者，其发电量占加拿大发电量的15%(安大略省为60%)。卫生和能源部门将受益于旨在减少有关健康影响的不确定性和寻求新的缓解目标的研究。另一个影响是，在拟议的项目期间，学生将在多学科环境中接受新技术培训，使他们非常适合生物物理学科领域的研究，或者完全适合工业、大学或医院的健康物理或医学物理职业。拟议的研究计划还将为政府、非政府组织和工业界制作教育材料，这将澄清暴露在低水平辐射中的影响，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.