Creation of Tools for the Study of Reactive Intermediates in DNA and RNA

在国家科学基金会化学部有机动力学计划的支持下，俄亥俄州托莱多大学化学系的Amanda Bryant-Friedrich教授将开发高效和新颖的方法来产生修饰的核酸低聚物。提案中所述工作的成功完成将为使用亚磷酰胺和H-膦酸自动核酸制备技术合成糖衍生物DNA和RNA寡核苷酸提供高效的方案。这些化学方法已被广泛应用于合成大量修饰的寡核苷酸。这项提议旨在使这项技术多样化，并使其适用于更广泛的衬底。作为提案目标的修饰低聚物将用于在DNA和RNA低聚物中产生核酸糖基，以确定氧化损伤对核酸结构的影响。DNA和RNA的氧化损伤产物已被证明与几种重大疾病有关。这些底物将用于开发疾病发生和发展的生物标记物。这些研究中设计的系统将被用来开发新的、灵敏的分析方法，以识别和量化核酸损害产物。这些技术和实验结果与癌症、糖尿病和阿尔茨海默氏症等疾病的理解高度相关。在化学系有机动力学项目的支持下，Bryant-Friedrich教授将培训学生在药物、药物和生物化学方面操纵合成核酸，这些学生将熟练掌握许多不同类型的层析、电泳和质谱学技术。由于拟议调查的性质，参与这些项目的学生将成为高度协作研究项目的一部分，在该项目中，他们将与不同学科、文化和机构的科学家互动。这是培养成功的未来一代科学家的重要组成部分。该实验室在研究生(10名妇女)和本科生(过去四年中有12名妇女和4名少数族裔)招聘少数群体和妇女方面有着良好的记录。这一趋势在实验室的文化中根深蒂固，在招聘和留住合格人员方面一直是一个重要的重点。

With the support of the Organic Dynamics Program in the Chemistry Division at the National Science Foundation, Professor Amanda Bryant-Friedrich of the Chemistry Department at the University of Toledo in Toledo OH will develop highly efficient and novel methods for the generation of modified nucleic acid oligomers. The successful completion of the work described in the proposal will provide highly efficient protocols for the synthesis of sugar derivatized DNA and RNA oligonucleotides using phosphoramidite and H-phosphonate automated nucleic acid preparation techniques. These chemistries are well established and have been applied to the synthesis of a large number of modified olignucleotides. This proposal seeks to diversify this technology and make it useful for application to an even broader number of substrates. The modified oligomers that are the target of the proposal will be used for the generation of nucleic acid sugar radicals in DNA and RNA oligomers to determine the impact of oxidative damage on nucleic acid structure. The products of oxidative damage to DNA and RNA have been shown to contribute to several significant diseases. These substrates will be used for the development of biomarkers for disease initiation and progression. The systems designed in these studies will be used to develop new and sensitive analytical methods for the identification and quantification of nucleic acid damage products. These techniques and experimental outcomes are highly relevant to the understanding of diseases such as cancer, diabetes and Alzheimer's. With the support of the Organic Dynamics Program in the Chemistry Division, Professor Bryant-Friedrich will train students in pharmaceutical, medicinal, and biological chemistry in the manipulation of synthetic nucleic acids, and these students will become skilled in many different types of chromatography, electrophoresis and mass spectrometry techniques. Due to the nature of the proposed investigations, students involved in these projects will be a part of a highly collaborative research program in which they will interact with scientists across disciplines, cultures and institutions. This is a vital part of the training of successful future generations of scientists. This laboratory has an excellent track record in the recruitment of minorities and women both at the graduate (10 women) and undergraduate (12 women and 4 minorities in the past four years) levels. This trend is ingrained in the culture of the laboratory and is always a significant focus in the recruitment and retention of qualified individuals.