EXCEED THE SPACEPROVIDED,Research design and methods will be pursued to accomplish three specific aims, which are centeredon peptides, proteins, lipids, and nucleic acids. Mass spectrometric instrumentation, method, andcomputer software will be developed to facilitate proteomics and to expedite the determination of thestructure and properties of peptides and proteins. An important goal is the muscle proteome.Resident at Washington University is the necessary personnel and equipment infrastructure todetermine this proteome and make unique contributions to understanding metabolic andneuromuscular diseases. The means to achieving this specific aim are to implement computer andchemical means to enhance information content of mass spectrometric methods in proteomics, toidevelop hydrogen/deuterium amide exchange to probe protein structure and interactions, and todevelop Fourier transform mass spectrometric instrumentation for iimproving mass resolving powerand mass-measurement accuracy for peptides and proteins. The second analyte focus is complexlipids, an area of long-standing and productive interest at Washington University. Structuredetermination of this class of analytes will be pursued by developing new methods and comparingcutting-edge instruments for analysis of lipids in complex mixtures. To facilitate interpretation ofstructural information, a major experimental and theoretical effort will be continued to understand themechanisms of lipid fragmentation in mass spectrometry. Better means of determining lipidstructure will have major impact in understanding diabetes mellitus, atherosclerotic cardiovasculardisease, and lipotoxicity. The third analyte is nucleic acids, and the goal is to use massspectrometry to determine the structures of normal and damaged oligonucleotides and themechanisms of the fragmentations that underpin structure determination. The research hasimportant implications in understanding the origins of a wide variety of cancers. Building on thefoundation of the efforts in research and methods will be a large number of collaborations inbiophysics and in various human diseases. The core and collaborative research will also becomplemented by active programs in service, training, and dissemination.
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