Gary D. Glick, Ph.D.
Werner E. Bachmann Collegiate Professor,
Department of Chemistry
Professor of Biological Chemistry

gglick@umich.edu

In one research area, my laboratory is developing methods to study the structure and folding of both DNA and RNA oligonucleotides. Such studies are important because characterization of oligonucleotides shapes much of our understanding of native, higher-molecular weight DNA and RNA molecules. As one example of our research, we have developed synthetic chemistry to stabilize nucleic acids with disulfide cross-links. These cross-links have been used in a variety of ways including, to trap non-ground-state DNA structures, which in the absence of the cross-link would not be stable. Characterization of non-ground-state DNA conformations is important because some are believed to exist during biological processes like transcription. In recent research, we have engineered disulfide cross-links into RNAs to probe folding. By comparing both the energetics of the modified RNAs to their parent sequences, we can uncover where along the folding pathway various units of secondary structure associate.

In a second area, we are conducting studies aimed at defining the binding properties of anti-DNA autoantibodies that arise in the autoimmune disorder systemic lupus erythematosus. Anti-DNA play a key role in the kidney disease associated with lupus (the major cause of death in lupus patients) through the localization of anti-DNA-DNA complexes within the kidney tissue. Since not all anti-DNA cause kidney damage, one goal in lupus research is to establish a relationship between the binding properties and pathogenicity of anti-DNA. Establishing this correlation will aid in the development both of new diagnostics to detect pathogenic anti-DNA and novel therapeutics. Students working on lupus-related research can be involved in a variety of sub-projects ranging from cloning, expression and mutagenesis of anti-DNA autoantibodies, to experiments aimed at elucidating the structural and thermodynamic basis of anti-DNA-DNA interactions, to cell/molecular biology and animal experiments to evaluate new agents to treat lupus.

Representative Publications

P.C. Swanson and G.D. Glick, Ligand Recognition by Anti-DNA
Autoantibodies. Affinity, Specificity and Mode of Binding. Biochemistry
1996, 35, 1624-1633.

P.C. Swanson, R. Yung, M. Eagan, J. Norris, N. Blatt, K. Johnson,
B.C. Richardson, and G.D. Glick, Ligand Recognition by Murine Anti-DNA Autoantibodies. II. Genetic Analysis and Pathogenicity. J. Clin. Invest.
1996, 97, 1748.

S.Y. Stevens and G.D. Glick, Evidence for Sequence Specific
Recognition of DNA by Anti-ssDNA Autoantibodies. Biochemistry 1999, 38, 560.

Blatt, N.B. and Glick, G.D. Anti-DNA Autoantibodies and Systemic Lupus Erythematosus. Pharmacology and Therapeutics 1999, 83, 125.

N.B. Blatt, R.E. Warner, J.J. Bednarski, R. Yung, B.C. Richardson,
K.J. Johnson, J.A. Ellman, A.A. Opipari, Jr, and G.D. Glick,
Pharmacological Modulation of Autoimmune Nephritis in NZB/W mice with a Novel Pro-Apoptotic Benzodiazepine, manuscript in press.