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.

有了这个RUI奖，生命过程计划的化学是支持里士满大学的米歇尔哈姆教授，以更好地了解空间和/或电子性质，决定了8-氧代-2 '-脱氧鸟苷（OdG）及其5'-三磷酸衍生物，OdGTP的生物活性。 氧化损伤的2 '-脱氧鸟苷衍生物OdG是最突出的DNA损伤之一，并且与衰老以及包括癌症在内的几种疾病有关。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，从而允许在复制期间发生突变。 哈姆小组合成了dG/dGTP和OdG/OdGTP之间的核苷酸类似物，并将其用于生物化学实验，重点研究这些有害核苷酸的复制和修复。通过比较合成的类似物与dG/dGTP、OdG/OdGTP以及彼此的酶活性，可以提出相应的假设，最终目标是建立OdG和OdGTP生物活性的分子基础。 活性氧是由化学致癌物、太阳辐射和正常代谢过程产生的。它们会破坏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经很好地理解，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突出的氧化DNA损伤类型之一背后的化学。这一追求将涉及本科生在一个主要的本科院校，并提供在拟议的研究中使用的合成和生物化学技术的专门培训。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。这些活动将使他们为在高级水平上进一步学习和在学术或工业环境中进行研究做好准备。