MECHANISTIC STUDIES OF NUCLEIC ACID DAMAGE

描述：拟议研究的总体目标是探索 自由基介导的核酸损伤的基本反应机制。 所处理的许多问题都来自使用 电离辐射作为对核酸造成损害的媒介。 一 我们的努力的一个重要部分是集中在阐明反应性 核碱基自由基，因为它们的产生是唯一的电离 辐射，它们参与链损伤是不确定的。 总 该方法涉及独立产生活性中间体， 与合成前体造成的核酸损伤有关。 具体 目标包括： 1. 通过以下方式研究核酸损伤扩增： a.核碱基自由基到糖的自旋换位 相邻的核苷酸。 B.超氧化物的损失（及其随后转化为 羟基自由基）从核苷衍生的过氧自由基 根的 C.研究双链损伤的产生， 链间氢原子转移和/或生成 来自原发性核酸病变的扩散反应性物质。 2. 5-溴脱氧尿苷 使核酸对链损伤敏感。 3. 确定通过提取形成的糖基的作用 核酸中核苷的C1'的氢原子 损害 4. 检查放射增敏剂对放射性核素化学的影响 核碱基自由基中间体。 增加对这些分子过程的了解有助于 了解核酸损伤与病原学之间的关系 疾病。 此外，新核酸的潜在发现 损伤机制可以为设计新的治疗方法提供动力， 剂.

DESCRIPTION: The overall goal of the proposed research is to probe the fundamental reaction mechanisms of radical mediated nucleic acid damage. Many of the issues addressed are derived from observations made using ionizing radiation as an agent for inflicting damage on nucleic acids. A significant portion of our effort is focused on elucidating the reactivity of nucleobase radicals, because their generation is unique to ionizing radiation, and their involvement in strand damage is uncertain. The general approach involves the independent generation of reactive intermediates that are involved in nucleic acid damage from synthetic precursors. Specific aims include: 1. Investigation of nucleic acid damage amplification via: a. The transposition of spin from nucleobase radicals to the sugar of adjacent nucleotides. b. The loss of superoxide (and its subsequent transformation into hydroxyl radical) from peroxyl radicals derived from nucleoside radicals. c. Investigation of the production of bistranded lesions via interchain hydrogen atom transfer and/or the generation of diffusible reactive species from primary nucleic acid lesions. 2. Elucidation of the mechanism by which 5-bromodeoxyuridine sensitizes nucleic acids to strand damage. 3. Determination of the role of sugar radicals formed via abstraction of hydrogen atoms from C1' of nucleosides in nucleic acid damage. 4. Examination of the effects of radiosensitizers on the chemistry of a nucleobase radical intermediate. Increased understanding of these molecular processes is useful to understanding the association between nucleic acid damage and the etiology of diseases. Furthermore, the potential discovery of novel nucleic acid damage mechanisms can provide the impetus for the design of new therapeutic agents.