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

内部放射性核素污染后毒性的多尺度评估和减轻

• 批准号: 10327393
• 负责人: GAYLE E. WOLOSCHAK
• 金额: $ 224.67万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327393
• 关键词: Address; Age; Animal Model; Architecture; Biological; Biological Markers; Biological Models; Cells; Chemicals; Chemistry; Communities; DNA; Daughter; Development; Devices; Evaluation; Excision; Exposure to; External Beam Radiation Therapy; Fluorescence Microscopy; General Population; Goals; Half-Life; Health; Histology; Immune system; Immunohistochemistry; Industrialization; Information Distribution; Intake; Knowledge; Literature; Measurement; Medical; Metabolism; Modeling; Morphology; Nuclear; Nuclear Accidents; Organ; Particle Size; Physiology; Process; Radiation; Radiation Accidents; Radiation Physics; Radiobiology; Radiochemistry; Radioisotopes; Reaction; Recording of previous events; Research; Roentgen Rays; Route; Science; Signal Transduction; Solubility; Specificity; Structure; Technology; Time; Tissues; Toxic effect; base; data modeling; dosimetry; genetic makeup; human model; improved; in silico; internal radiation; migration; model development; molecular marker; nanoscale; novel; particle; phantom model; pharmacokinetics and pharmacodynamics; programs; sex; tissue repair; tool; uptake; virtual; Address; Age; Animal Model; Architecture; Biological; Biological Markers; Biological Models; Cells; Chemicals; Chemistry; Communities; DNA; Daughter; Development; Devices; Evaluation; Excision; Exposure to; External Beam Radiation Therapy; Fluorescence Microscopy; General Population; Goals; Half-Life; Health; Histology; Immune system; Immunohistochemistry; Industrialization; Information Distribution; Intake; Knowledge; Literature; Measurement; Medical; Metabolism; Modeling; Morphology; Nuclear; Nuclear Accidents; Organ; Particle Size; Physiology; Process; Radiation; Radiation Accidents; Radiation Physics; Radiobiology; Radiochemistry; Radioisotopes; Reaction; Recording of previous events; Research; Roentgen Rays; Route; Science; Signal Transduction; Solubility; Specificity; Structure; Technology; Time; Tissues; Toxic effect; base; data modeling; dosimetry; genetic makeup; human model; improved; in silico; internal radiation; migration; model development; molecular marker; nanoscale; novel; particle; phantom model; pharmacokinetics and pharmacodynamics; programs; sex; tissue repair; tool; uptake; virtual

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.

总体：摘要 历史告诉我们，几乎在美国任何地方的任何一天都会发生暴露于放射性核素的情况， 在其他地方，我们几乎没有做好准备。我们为此执行剂量模型的能力 对生物标志物和缓解发现的方案和努力是古老的，我们倾向于依靠外部 梁辐射以建模这些完全放错了位置。我们应该，我们可以做得更好。 该计划的重点是以下假设：内部发射器的辐射在 身体，器官，甚至器官，组织和细胞内。半衰期和衰减模式 放射性核素，其活性和浓度，粒度和形态以及其化学形式和溶解度为 所有关键的摄取途径，组织结构，遗传构成，生理学，危险信号和 与免疫系统串扰。从概念上讲，这表明放射性核素分布的分析 需要在MESO，微观和纳米水平上进行测量，以进行准确的剂量模型和生物动力学 分析，这将更好地与生物端点保持一致，因此与有意义的对策 发展。在许多方面，我们的计划整合了辐射科学的三个主要支柱，即辐射 考虑到药代动力学和药效学，物理，辐射化学和辐射生物学 亚细胞，细胞和组织水平上颗粒分布的各个方面。 换句话说，了解内部发射器的生物学效应并找到最佳的缓解措施 策略是一个系统的研究，其中包括但不限于：a）放射性核素的物理和 化学形式和内内迁移，b）持久暴露时间，c）辐射质量参数，d）新颖 虚拟幻影建模超出了少数宏参考模型； e）性别和年龄的新型生物动力学 - 特异性； f）中核素的MESO，微尺度和纳米量表组织学和免疫组织化学 分销信息； g）探索放射性核素摄入和污染的分子生物标志物以及H） 调节放射性核素分布并可能改善DNA，细胞和组织修复的对策。 我们已经组建了一个具有多种科学专业知识的团队，可以在综合的情况下应对这些挑战 程序。我们可以使用一个令人印象深刻的技术工具箱，我们的目标是产生一个 有意义的蓝图，用于理解和预测暴露于放射性核素的生物学后果。 该计划对辐射研究界和一般人群的可能好处是 巨大。