Mechanisms for Radiation Damage to DNA: LET Effects

DNA 辐射损伤机制：LET 效应

• 批准号: 6908143
• 负责人: MICHAEL Douglas SEVILLA
• 金额: $ 20.59万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908143
• 关键词: DNA damage; DNA repair; autooxidation; bioenergetics; computer simulation; electron transport; free radicals; gamma radiation; intermolecular interaction; linear energy transfer; mathematical model; nuclear magnetic resonance spectroscopy; oxygen; particle accelerators; radiation genetics; radiation protection; radiation sensitivity; radioprotective agents; statistics /biometry; sugar nucleotide

DESCRIPTION (provided by applicant): Our overall research goal is to elucidate fundamental mechanisms of radiation damage to DNA by radiations of varying linear energy transfer (LET). Our comprehensive model for DNA radiation damage that describes events from the formation of the initial DNA ion radicals, to hole and electron transfer, finally to molecular products will be tested at each step to elucidate the fundamental processes for DNA radiation damage. These studies, which are performed under conditions that emphasize the direct effect of radiation, will employ magnetic resonance spectroscopies, density functional theory and product analysis techniques as well as gamma and cyclotron heavy ion beam irradiations. There are five aims: First is the characterization of electron and hole transport in DNA which will concentrate on the role of electron transfer through the stacked bases, to intercalated species of known redox potential. The hypothesis that hole transfer localizes multiple oxidative damage sites to single a guanine base and thereby provides a radioprotective effect will also be tested. In our second aim, we will make use of an experimental breakthrough that allows for scavenging of holes and electrons in irradiated DNA providing for the isolation of the neutral (mainly sugar) radicals and the facile investigation of the nature and identity of these species. For the first time, it may be possible to identify and quantitate a number of immediate strand break processes from the direct effect at the radical stage. Our third aim will test mechanisms of sugar radical formation likely with high LET irradiation by an investigation of cationic radical excited states within DNA and components. Our fourth aim will use magnetic resonance techniques to characterize radicals (ESR, ENDOR) and to ascertain their spatial distribution and clustering (PELDOR) as a function of the LET of the radiation along the radiation track. Our ability to capture both holes and electrons allows us, now, to isolate and compare low and high LET generated neutral radicals. Our final aim will employ theoretical calculations to further test and confirm molecular mechanisms proposed in the above studies. Of prime interest will be a test via density functional theory of the hypotheses that low energy electrons cause immediate strand breaks. We believe this focused, collaborative effort will allow us to establish new understandings of fundamental radiation processes for biomedical research.

描述（由申请人提供）： 我们的总体研究目标是阐明不同线性能量转移 (LET) 辐射对 DNA 造成辐射损伤的基本机制。我们的 DNA 辐射损伤综合模型描述了从最初 DNA 离子自由基的形成到空穴和电子转移，最后到分子产物的事件，我们将在每个步骤中进行测试，以阐明 DNA 辐射损伤的基本过程。这些研究是在强调辐射直接影响的条件下进行的，将采用磁共振波谱、密度泛函理论和产物分析技术以及伽马和回旋加速器重离子束辐照。有五个目标：首先是 DNA 中电子和空穴传输的表征，重点关注电子通过堆叠碱基转移到已知氧化还原电位的插层物质的作用。空穴转移将多个氧化损伤位点定位到单个鸟嘌呤碱基并从而提供辐射防护作用的假设也将得到测试。在我们的第二个目标中，我们将利用一项实验性突破，清除受辐照 DNA 中的空穴和电子，从而分离中性（主要是糖）自由基，并轻松研究这些物种的性质和身份。 首次有可能根据激进阶段的直接影响来识别和定量许多立即链断裂过程。我们的第三个目标是通过研究 DNA 和组分内的阳离子自由基激发态来测试高 LET 照射下糖自由基形成的机制。我们的第四个目标将使用磁共振技术来表征自由基（ESR、ENDOR）并确定它们的空间分布和聚类（PELDOR）作为沿辐射轨迹的辐射 LET 的函数。现在，我们捕获空穴和电子的能力使我们能够分离和比较低和高 LET 产生的中性自由基。我们的最终目标是利用理论计算来进一步测试和确认上述研究中提出的分子机制。最令人感兴趣的是通过密度泛函理论对低能电子导致立即链断裂的假设进行的测试。我们相信，这种集中的协作努力将使我们能够对生物医学研究的基本辐射过程建立新的理解。