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

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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.