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.

通过此RUI奖，《生命过程的化学计划》计划支持里士满大学的米歇尔·哈姆教授，以更好地了解决定了8-氧化物-2'-脱氧瓜（ODG）及其5'-三磷酸盐衍生物的生物活性性的空间和/或电子特性，ODGTP。 氧化受损的2'-脱氧藻苷衍生物ODG是最突出的DNA病变之一，与衰老以及包括癌症在内的几种疾病有关。与仅与DNA中仅与2'-脱氧胞苷（DC）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，从而在复制过程中允许突变。 HAMM组在DG/DGTP和ODG/ODGTP之间合成了核苷酸类似物，并将其用于生化实验，重点是重复和修复这些有害核苷酸。通过比较合成类似物与DG/DGTP，ODG/ODGTP以及彼此之间的酶促活性，可以提出相应的假设，其最终目标是确定ODG和ODGTP生物活性的分子基础。 活性氧是由化学致癌物，来自太阳的辐射以及正常代谢过程产生的。它们会损害DNA并改变其携带的信息，可能导致衰老和疾病（例如癌症）。虽然对这种损害的一般效果有充分的理解，但导致观察到的效果的确切化学特性更加难以捉摸。这项工作的目的是更好地了解最突出的氧化DNA损伤类型背后的化学反应。这项追求将涉及主要是本科机构的本科生，并提供有关拟议研究中使用的合成和生化技术的专业培训。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交流。这些活动将使它们在高级水平和学术或工业环境中进行进一步研究做好准备。