Effects of nonuniform distributions of radioactivity

描述（由申请人提供）：众所周知，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辐射敏感性，宏观和细胞水平上的放射性分布，发射的辐射（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不均匀分布造成的生物效应相关联的理解有限。越来越多的证据表明，旁观者效应在决定生物反应方面起着重要作用。这些都是当前对人类健康至关重要的问题，因为它涉及诊断和治疗核医学。鉴于涉及放射性物质的放射性恐怖主义的可能性，解决这些问题变得越来越紧迫。在过去的几年里，我们一直致力于将含放射性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。我们在第一个资助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合成物的生物效应的能力产生重大影响。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。我们的工作也提出了一些重要的新问题，关于预测对放射性非均匀分布的反应，这些问题在本提案中得到了解决。总的来说，我们假设含有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。我们将使用我们原始的三维（3D）多细胞集群模型来解决与生存剂量反应曲线形状相关的基本和重要问题。认识到我们的原始模型的局限性，我们已经投入了相当大的努力，将我们的多细胞剂量学和旁观者效应的研究过渡到一个新的体外细胞基质模型，模拟体内正常的人体组织。这种新的3D模型将用于评估肿瘤和正常人类细胞类型中放射性不均匀分布引起的细胞周期改变、DNA损伤和细胞杀伤。补充这个新模型将是一个理论多细胞剂量学模型的发展，它混合了3D pCT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预测这种更复杂系统的反应。最后，为了将我们的多细胞剂量学方法过渡到体内，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.