Effects of nonuniform distributions of radioactivity

描述(由申请人提供)：人们认识到，有许多变量可以决定含有放射性的组织的生物反应。在许多变量中，包括组织的辐射敏感性、宏观和细胞水平的放射性分布、辐射(例如，α、β、俄歇电子)和旁观者效应。我们对这些变量如何与放射性分布不均匀引起的生物效应之间的关系有一个有限的了解。越来越多的证据表明，旁观者效应在决定生物反应方面发挥着重要作用。这些都是当前对人类健康具有重大意义的问题，因为它涉及诊断和治疗性核医学。鉴于涉及放射性材料的放射性恐怖主义的可能性，这些问题已变得越来越迫切需要解决。在过去的几年里，我们一直致力于将含有放射性的组织的生物反应与细胞吸收剂量和与旁观者效应相关的变量联系起来。我们在第一次赠款期间取得了实质性进展，包括揭示了细胞内放射性引起的旁观者效应的现象学和机制的重要见解。我们的进展将对我们预测放射性生物效应的能力产生相当大的影响。事实上，我们的贡献在ICRU关于核医学剂量规格的报告中得到了认可。我们的工作还提出了关于对放射性分布不均匀的反应的预测的重要的新问题，这些问题在本提案中得到了解决。总体而言，我们假设含有被掺入的放射性核素的组织的生物反应可以与细胞吸收剂量和与旁观者效应相关的变量相关。我们将使用逐步增加复杂性的模型来检验这一假设。我们将使用我们独创的三维(3D)多细胞簇模型来解决与存活剂量反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，我们投入了相当大的努力，将我们关于多细胞剂量学和旁观者效应的研究过渡到一种新的体外细胞矩阵模型，该模型模拟了体内正常的人体组织。这一新的3D模型将用于评估肿瘤和正常人类细胞类型中放射性分布不均匀导致的细胞周期变化、DNA损伤和细胞杀伤。对这一新模型的补充将是开发一种理论上的多细胞剂量学模型，该模型融合了3DPCT成像和细胞的程式化分析模型。这将使我们能够测试我们的多细胞剂量学方法是否可以在这个更复杂的系统中预测反应。最后，为了启动我们的多细胞剂量学方法向体内的过渡，我们将在小鼠睾丸中进行旁观者研究。

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.