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

涉及辐射诱导信号事件产生的物理机制

• 批准号: RGPIN-2021-03854
• 负责人: Seymour, Colin
• 金额: $ 1.75万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742753
• 关键词: Physical; mechanisms; involved; generation; radiation

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.

该建议旨在研究我们已经确定的与高剂量机制不同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应答者，受辐射剂量和剂量率的调节。该提案有两个阶段;最初将选择具有功能性或非功能性线粒体的细胞系。这些将暴露于一系列低剂量和剂量率。将评估生存参数。以后的工作将使用相同的剂量范围，但将使用特定的化学阻断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存活率将是关键终点，线粒体DNA分析也将是关键终点，以绘制已经鉴定的基因组标记。由于我从我的最后一个DG的氚（低能量β发射器）和Cs-137（中能量γ发射器）的初步数据，这些最初将被用作辐射源，但当初始数据是已知的，更广泛的辐射源将被测试。所有生物测定将伴随着线粒体的数量和形状的定量超微结构分析，因为已知这些参数在确定辐照细胞中能量捕获和转换期间的机械-电气和电化学转变中是重要的。预测线粒体将成为关键的低剂量靶点。了解产生低剂量辐射效应的机制将有助于开发旨在保护受辐射工人、病人和公众的减缓剂。目前关于高剂量产生某些效应而低剂量产生较少相同效应的假设可能具有误导性。它阻碍了识别新的目标，以开发针对细胞器（如线粒体）或低剂量暴露特有的机械过程（如电化学梯度控制）的放射性缓解剂。人们越来越依赖涉及辐射照射的医疗诊断技术，例如CT扫描或PET成像。核工业也是加拿大经济的重要利益相关者，生产加拿大15%的电力（安大略为60%）。卫生和能源部门将受益于旨在减少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或医学物理职业。拟议的研究方案还将为政府、非政府组织和工业界制作教育材料，阐明低水平辐射照射的影响，为监测影响提供更好的生物技术。