Effects of nonuniform distributions of radioactivity

放射性不均匀分布的影响

• 批准号: 7146187
• 负责人: Roger W. Howell
• 金额: $ 25.82万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146187
• 关键词: cell line; radiation sensitivity; radiation therapy dosage; radiobiology; radionuclide therapy; radiopharmacology; tissue /cell culture

DESCRIPTION (provided by applicant): It is recognized that there are many variables that can dictate biological response of tissues that contain radioactivity. Among the many variables are tissue radiosensitivity, distribution of radioactivity at the macroscopic and cellular levels, radiations emitted (e.g. alpha, beta, Auger electrons), and bystander effects. We have a limited understanding of how these variables correlate with biological effects that result from nonuniform distribution of radioactivity. There is mounting evidence that bystander effects play an important role in determining biological response. These are current issues of major importance to human health as it relates to diagnostic and therapeutic nuclear medicine. They have become increasingly urgent to resolve in light of the likelihood of radiological terrorism involving radioactive materials. Over the last several years we have been working toward correlating biological response of tissues containing radioactivity with cellular absorbed dose and variables relating to the bystander effect. We have made substantial progress during our first grant period, including the revelation of important insights into the phenomenology and mechanisms of bystander effects caused by intracellular radioactivity. Our progress will have considerable impact on our capacity to predict the biological effects of incorporated radioactivity. Indeed, our contributions are recognized in the ICRU report on dose specification in nuclear medicine. Our work has also raised important new questions regarding the prediction of response to nonuniform distributions of radioactivity that are addressed in the present proposal. Overall, we hypothesize that the biological response of tissues containing incorporated radionuclides can be correlated with cellular absorbed dose and variables relating to the bystander effect. We will test this hypothesis using a step-wise approach with models of increasing complexity. We will use our original three dimensional (3D) multicellular cluster model to resolve fundamental and significant questions related to the shape of survival dose response curves. Recognizing the limitations of our original model, we have devoted considerable effort toward transitioning our studies on multicellular dosimetry and bystander effects to a new in vitro Cytomatrix model that mimics normal human tissue in vivo. This new 3D model will be used to assess cell cycle alterations, DNA damage, and cell killing caused by nonuniform distributions of radioactivity in both tumor and normal human cell types. Complementing this new model will be development of a theoretical multicellular dosimetry model that blends 3D pCT imaging and stylized analytical models of the cell. This will enable us to test whether our multicellular dosimetry approaches can predict responses in this more complex system. Finally, to initiate transition of our multicellular dosimetry approach to in vivo, we will carry out bystander studies in mouse testis.

描述（由申请人提供）：认识到有许多变量可以决定包含放射性的组织的生物学反应。在许多变量中，有组织放射敏感性，放射性在宏观和细胞水平上的分布，发射的辐射（例如alpha，beta，螺旋钻，螺旋钻）以及旁观者的效果。我们对这些变量与放射性分布不均匀产生的生物学效应的相关性有限。有越来越多的证据表明旁观者效应在确定生物学反应中起着重要作用。这些是与诊断和治疗性核医学有关的目前对人类健康至关重要的问题。鉴于涉及放射性材料的放射恐怖主义的可能性，他们变得越来越紧迫。在过去的几年中，我们一直在努力将含有放射性的组织的生物学反应与与旁观者效应有关的细胞吸收剂量和变量相关联。在第一个赠款期间，我们取得了长足的进步，包括对旁观者的现象学和旁观者效应的机制的重要见解的启示。我们的进步将对我们预测纳入放射性的生物学作用的能力产生相当大的影响。确实，我们的贡献在ICRU关于核医学剂量规范的报告中得到了认可。我们的工作还提出了有关预测本提案中解决的对放射性不均匀分布的反应的重要新问题。总体而言，我们假设含有掺入放射性核素的组织的生物学反应可以与与旁观者效应有关的细胞吸收剂量和变量相关。我们将使用逐步的方法来检验这一假设，并具有增加复杂性的模型。我们将使用原始的三维（3D）多细胞群集模型来解决与生存剂量响应曲线形状相关的基本和重要问题。认识到我们原始模型的局限性，我们致力于将多细胞剂量测定法和旁观者效应转变为一种新的体外细胞瘤模型，以模仿体内正常的人体组织。这种新的3D模型将用于评估细胞周期的改变，DNA损伤以及由肿瘤和正常人类细胞类型中放射性分布不均匀引起的细胞杀死。补充这一新模型将开发理论多细胞剂量测定模型，该模型将3D PCT成像和样式化的分析模型融合在一起。这将使我们能够测试我们的多细胞剂量测定方法是否可以预测这个更复杂的系统中的响应。最后，为了启动我们的多细胞剂量法对体内的过渡，我们将在小鼠睾丸中进行旁观者研究。