基于模式生物线虫的重离子细胞损伤效应和径迹过程的关联研究

Heavy ion radiation has been widely used in tumor therapy due to its special dose-depth distribution and higher relative biological effects. The heavy ion-induced biological effects are determined by multiple physical parameters along heavy ion tracks, such as the absorbed doses and track structure, which might sometimes lead to the difference between the biological and physical Bragg curves. Therefore, it is significant and valuable to investigate the arrangement of biological effects along tracks, the molecular mechanisms and relationship with original physical process for the application of heavy ion radiation in tumor therapy. However, the related experiments were all performed with single-cell models, there is not yet the evidence regarding the biological effects in vivo along the tracks. In the present proposal, using two tissue models in model animal Caenorhabditis Elegans (C. elegans) in vivo, germ cell apoptosis and reproductive cell death, the heavy ion –induced cell damage effects and the genomic instability will be demonstrated. The roles of DNA damage repair machineries in the cell damage effects will also be investigated with the loss-function strains in these pathways. Finally, a theoretical model will be established by correlating the biological effects with physical parameters along the tracks.

重离子具有独特的深度剂量分布和高相对生物学效应，被认为是理想的放疗手段。重离子的生物学效应在径迹形成过程中由多个物理参量（能量沉积、径迹结构等）共同决定，导致其生物效应曲线和物理Bragg曲线会出现一定程度的歧离。因此，研究辐射损伤相关的生物学终点沿重离子径迹的分布特征、分子机制以及与物理过程的关联性，对重离子肿瘤放疗方案的设计和优化有着重要的理论和应用价值。目前相关的研究主要是在细胞体系上进行的，尚缺少活体上的实验数据。本项目使用线虫活体组织模型—生殖细胞凋亡和增殖性细胞死亡，研究重离子细胞损伤效应和损伤传代效应（基因组不稳定性）的径迹分布；引入DNA损伤修复功能缺失线虫品系，进一步明确DNA损伤修复激活的径迹分布及其与细胞损伤效应的关系；最后模拟计算重离子径迹形成过程中的物理参量，关联相应的生物学效应，建立活体水平重离子细胞损伤效应的理论模型，为重离子更好的应用于肿瘤放疗提供理论基础。

重离子独有的深度剂量分布“Bragg”曲线使其在癌症放疗应用中能够在有效杀伤癌细胞的同时，又减少对路径上正常细胞组织的损伤。本项目以线虫生殖细胞凋亡和阴门细胞增殖性细胞死亡这两个癌症放疗最相关的细胞死亡方式作为研究对象，演示碳离子辐射生物学效应沿入射路径的分布，以及DNA损伤反应通路上游基因的功能缺失对碳离子生物学效应空间分布的改变。同时，鉴于碳离子径向径迹中丰富的低LET辐射成分，低LET的伽玛射线也被用来研究线虫增殖性细胞死亡的辐射适应性反应。本项目首次在活体水平演示了辐射适应性反应和辐射旁效应之间的关联性，以及DNA损伤检验点在这种关联中的远程介导作用。我们也发现一种挥发性的辐射损伤信号可以跨个体诱导线虫的辐射适应性反应。这些研究结果对提升重离子肿瘤放疗效果，改进肿瘤治疗策略有一定的理论和实际价值。