COBRE for the Center for Molecular Medicine- Organic Synthesis Core

This COBRE Phase III proposal is aimed at sustaining and transitioning to independence the research infrastructure developed during the Phases I and II of COBRE funding. Our COBRE on the Molecular Basis of Human Disease and the Center for Molecular Medicine has had a number of successes. During the previous funding period 30 junior faculty from 12 different departments and centers were mentored. The mentored junior faculty received 30 NIH RO1 grants, 5 other NIH grants, and 30 peer-reviewed extramural grants. The members of the Center published more than 370 research papers. The Department of Molecular and Cellular Biochemistry, in which the COBRE is housed, rose from 28th to its current position of 14th in NIH rankings in terms of Public Medical School Biochemistry Departments, and 28th overall during the tenure of the COBRE. Research funding more than doubled over this period excluding monies from the COBRE grant. These and other successes can in large part be attributed to the availability of the scientific cores associated with the COBRE. For this application, we propose to transition three scientific cores to independence of NIH/NIGMS support and to enhance and upgrade core technologies. It is worth noting that two of our original cores have or soon will transition to independence; the Proteomics core developed by this COBRE is now a University run fee-for-service core, and the COBRE supported Microscopy core is soon to become a department supported core. During the proposed five-year transition period we will increase the competitiveness of our cores so as to attract greater usage and cost recovery. Through the use of vouchers we will promote core usage. Through pilot grants we will develop new research collaborations and competitive grant submissions and broaden our outreach. The Administrative Core will serve as the focal point of the grant and in conjunction with the Program Coordinator and the Oversight Committee will serve as the operational arm of the Center. An External Advisory Committee, consisting of world-renown scientists will provide ongoing assessment and evaluation of the Center. Continuing Institutional commitments will ensure programmatic growth, and long-term sustainability The University of Kentucky (UK) COBRE Organic Synthesis Core serves investigators in the Center for Molecular Medicine who are conducting research utilizing "small molecules" for the study of important biological problems, and also serves other investigators at the University of Kentucky as well as at other institutions. In particular, the Core provides COBRE and other investigators with access to small molecules and small molecule libraries (mw < 2 kDa) that are not available through commercial sources, thus supporting cutting edge research in human disease. The Core essentially removes the ad hoc nature of past efforts and provides consistent and timely access to organic compounds. In addition, the Director and/or Co-Director consult with investigators to understand their particular needs, design appropriate "small-molecule" probes, and arrange for the core staff to synthesize and characterize these novel compounds. In recent years, the Core has furnished structurally modified heterocyclic drugs, small peptides, lipids, and natural products. In many cases, the Core tailors these small molecules to include suitable functional groups for linkage to proteins, peptide-nucleic-acid (PNA) mimics, and polymers, or the core links these small molecules to suitable markers for the detection and monitoring of a particular drug or natural product. Tailoring includes the incorporation of fluorescent tags, photoactive groups, non-radiogenic labels (e.g., deuterium) or radiolabels, as needed. The Core has all the necessary equipment to prepare and purify organic compounds with molecular masses of 2 kDa or less, and has access to advanced analytical techniques, including NMR spectroscopy, mass spectrometry and X-ray crystallography, to confirm structural assignments. Prior to the creation of the Core, investigators needing small-molecule probes used commercial sources or ad hoc collaborations, but the expense, time and variability of outcomes made these approaches costly and inefficient, particularly for new investigators. Thus, the Core has become a unique local and increasingly valuable regional and national resource and underpins an essential translational feature of the Center for Molecular Medicine. .