Therapeutic/Toxic Effects of Electron Emitting Nuclides

超出所提供的空间。拟议研究的目的是阐明诊断和治疗放射性核素（俄歇电子和α粒子）发出的密集电离辐射对辐射防护和癌症治疗的影响。我们打算探索在特征明确的简单系统（质粒）和高阶染色质结构（哺乳动物细胞核）中产生DNA损伤的机制，并评估衰变核素的空间定位（通过计算建模方法确定）以及周围环境变化的后果。我们还计划通过(i)将放射性核素衰变诱导的细胞凋亡与这些放射性核素的物理衰变特征、衰变部位、细胞类型和细胞放射敏感性联系起来，确定微观剂量与有害生物效应之间的定量关系；（ii）研究活体肿瘤模型中的旁观者效应；（iii）评估细胞质定位后这些放射性核素衰变的致突变反应，并检查这是直接或间接机制的结果；（iv）确定导致正常哺乳动物细胞基因表达改变和肿瘤转化的剂量。最后，我们将利用动物肿瘤模型作为临床前系统来确定胸腺嘧啶类似物5-[12Sl]碘-2'-脱氧尿苷在癌症治疗中的效用。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. The objective of the proposed research is to elucidate the implications of densely ionizing radiations emitted by diagnostic and therapeutic radionuclides (Auger electrons and alpha particles) for both radiation protection and cancer therapy. We intend to explore mechanisms producing DNA damage in well-characterized simple systems (plasmids) and in higher order chromatin structures (mammalian cell nuclei) and assess the consequence of spatial positioning of the decaying nuclide (ascertained by computational modeling methods) as well as changes in the surrounding environment. We also plan to determine the quantitative relationships between microscopic dose and detrimental biologic effects by (i) associating radionuclide-decay-induced apoptosis with the physical decay characteristics of these radionuclides, their site of decay, cell type, and cell radiosensitivity; (ii) investigating the bystander effect in fn-vivo tumor models; (iii) assessing the mutagenic response to the decay of these radionuclides following cytoplasmic localization and examining whether this is a consequence of direct or indirect mechanisms; and (iv) determining doses that lead to alterations in gene expression and neoplastic transformation in normal mammalian cells. Finally, we will exploit an animal tumor model as a preclinical system for determining the utility of the thymidine analog 5-[12Sl]iodo-2'-deoxyuridine in cancer therapy. PERFORMANCE SITE ========================================Section End===========================================