RUI: Chemical Investigations into the Bioactivity of the DNA Lesion 8-Oxo-2'-deoxyguanosine

RUI：DNA 损伤 8-Oxo-2-脱氧鸟苷生物活性的化学研究

• 批准号: 1305548
• 负责人: Michelle Hamm
• 金额: $ 25.5万
• 依托单位: University of Richmond
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1305548&HistoricalAwards=false
• 关键词: RUI; Chemical; Investigations; into; Bioactivity

With this RUI Award, the Chemistry of Life Processes Program is supporting Professor Michelle Hamm of the University of Richmond to better understand the steric and/or electronic properties that dictate the bioactivity of 8-oxo-2'-deoxyguanosine (OdG) and its 5'-triphosphate derivative, OdGTP. The oxidatively damaged 2'-deoxyguanosine derivative OdG is one of the most prominent DNA lesions and has been linked to aging as well as several diseases including cancer. Unlike 2'-deoxyguanosine (dG) which base pairs only with 2'-deoxycytidine (dC) in DNA, OdG can pair with both dC and 2'-deoxyadenosine (dA), thus allowing for mutations during replication. The Hamm group synthesizes nucleotide analogues on the spectrum between dG/dGTP and OdG/OdGTP, and uses these in biochemical experiments focused on the replication and repair of these harmful nucleotides. By comparing the enzymatic activities of the synthesized analogues to dG/dGTP, OdG/OdGTP, and each other,one can put forth commensurate hypotheses with the ultimate goal of establishing the molecular basis for the bioactivity of OdG and OdGTP. Reactive oxygen species are created by chemical carcinogens, radiation from the sun, and normal metabolic processes. They can damage DNA and alter the information it carries, possibly leading to aging and diseases such as cancer. While the general effects of this damage are well understood, the exact chemical properties that lead to the observed effects have been more elusive. It is the goal of this work to better understand the chemistry behind one of the most prominent types of oxidative DNA damage. This pursuit will involve undergraduate students at a primarily undergraduate institution and provide specialized training in the synthetic and biochemical techniques used in the proposed studies. The researchers will also learn important skills including time management, critical thinking, experimental design, and verbal and written communication. These activities will prepare them for further study at an advanced level and for research in an academic or industrial setting.

凭借该 RUI 奖，生命过程化学项目正在支持里士满大学的 Michelle Hamm 教授更好地了解决定 8-oxo-2'-deoxyguanosine (OdG) 及其 5 生物活性的空间和/或电子特性。 '-三磷酸衍生物，OdGTP。 氧化损伤的 2'-脱氧鸟苷衍生物 OdG 是最显着的 DNA 损伤之一，与衰老以及包括癌症在内的多种疾病有关。与仅与 DNA 中的 2'-脱氧胞苷 (dC) 碱基配对的 2'-脱氧鸟苷 (dG) 不同，OdG 可以与 dC 和 2'-脱氧腺苷 (dA) 配对，从而允许复制过程中发生突变。 Hamm 小组合成了 dG/dGTP 和 OdG/OdGTP 之间的核苷酸类似物，并将其用于生化实验，重点关注这些有害核苷酸的复制和修复。通过比较合成的dG/dGTP、OdG/OdGTP类似物的酶活性，可以提出相应的假设，最终为OdG和OdGTP的生物活性奠定分子基础。 活性氧是由化学致癌物、太阳辐射和正常代谢过程产生的。它们会损害 DNA 并改变其携带的信息，可能导致衰老和癌症等疾病。虽然这种损害的一般影响已广为人知，但导致观察到的影响的确切化学性质却更加难以捉摸。这项工作的目标是更好地了解最常见的氧化 DNA 损伤类型之一背后的化学原理。这项研究将涉及主要本科院校的本科生，并提供拟议研究中使用的合成和生化技术的专门培训。研究人员还将学习重要的技能，包括时间管理、批判性思维、实验设计以及口头和书面沟通。这些活动将为他们进一步进行高级学习以及在学术或工业环境中进行研究做好准备。