Multi-Scale Evaluation and Mitigation of Toxicities Following Internal Radionuclide Contamination

总体：摘要 历史告诉我们，暴露于放射性核素在美国几乎任何地方都可能发生，而且 在其他地方，我们几乎没有做好准备。我们对这种情况进行剂量建模的能力 在生物标志物和缓解措施发现方面的情景和努力是陈旧的，我们倾向于依赖外部 用光束辐射来模拟这些是完全错误的。我们应该做得更好，也可以做得更好。 该计划的中心假设是，来自内部发射器的辐射在 在身体、器官之间，甚至在器官、组织和细胞内。原子的半衰期和衰变模式 放射性核素，其活度和浓度，颗粒大小和形态，其化学形态和溶解度 所有这些都是至关重要的，摄取途径、组织结构、基因组成、生理、危险信号和 与免疫系统的串扰。从概念上讲，放射性核素分布的分析 需要在介观、微米和纳米水平进行测量，以进行准确的剂量建模和生物动力学 分析，这将更好地与生物终点保持一致，从而与有意义的对策相一致 发展。在许多方面，我们的计划整合了辐射科学的三大支柱，即辐射 物理学、辐射化学和辐射生物学，考虑到药代动力学和药效学 在亚细胞、细胞和组织水平上的颗粒分布方面。 换句话说，为了了解内部发射器的生物效应，并找到可能的最佳缓解措施 需要进行系统研究的战略，包括但不限于：a)放射性核素物理和 化学形态和活体内迁移，b)延长暴露时间，c)辐射质量参数，d)新奇 超越几个宏观参考模型的虚拟体模建模；e)具有性别和年龄的新生物动力学- 特异性；f)中、微和纳米尺度的组织学和免疫组织化学综合放射性核素 分布信息；g)探索放射性核素摄取和污染的分子生物标志物和h) 调整放射性核素分布并可能改善DNA、细胞和组织修复的对策。 我们已经组建了一支拥有不同科学专业知识的团队，可以在一个综合的 程序。我们有一个令人难以置信的令人印象深刻的技术工具箱，我们的目标是生成一个 了解和预测暴露于放射性核素的生物后果的有意义的蓝图。 这项计划对辐射研究界和普通民众可能带来的好处是 非常大。

OVERALL: ABSTRACT History has taught us that exposures to radionuclides can happen any day almost anywhere in the US and elsewhere and we have done little to prepare ourselves. Our ability to perform dosimetry modeling for such scenarios and efforts into biomarker and mitigation discovery are archaic and our tendency to rely on external beam radiation to model these is utterly misplaced. We should and we can do much better. This program centers on the hypothesis that radiation from internal emitters is very unevenly distributed within a body, amongst organs, and even within organs, tissues and cells. The half-life and decay schema of the radionuclide, its activity and concentration, particle size and morphology, and its chemical form and solubility are all critical, as are the route of uptake, tissue structure, genetic makeup, physiology, danger signaling and the crosstalk with the immune system. Conceptually this suggests that the analysis of radionuclide distribution requires measurements at the MESO, MICRO and NANO level for accurate dosimetry modeling and biokinetics analyses, that will much better align with biological endpoints, and therefore with meaningful countermeasure development. In many ways our program integrates the three main pillars of radiation science, namely radiation physics, radiation chemistry and radiation biology, taking into account pharmacokinetics and pharmacodynamics aspects of particle distribution at subcellular, cellular, and tissue levels. In other words, to understand the biological effects of internal emitters and find the best possible mitigation strategies a systematic study is called for, one that includes but is not limited to: a) radionuclide physical and chemical form and intravital migration, b) protracted exposure times, c) radiation quality parameters, d) novel virtual phantom modeling beyond few MACRO reference models ; e) novel biokinetics with sex- and age- specificity; f) MESO, MICRO and NANO scale histology and immunohistochemistry with integrated radionuclide distribution information; g) exploration of molecular biomarkers of radionuclide intake and contamination and h) countermeasures that modulate radionuclide distribution and possibly also improve DNA, cell and tissue repair. We have assembled a team with diverse scientific expertise that can tackle these challenges within an integrated program. There is an incredibly impressive technological toolbox at our disposal and our goal is to generate a meaningful blueprint for understanding and predicting biological consequences of exposure to radionuclides. The possible benefits of this program to the radiation research community and the general population are immense.