Areas of Interest
In one research area, my laboratory is developing methods to study the structure and folding of DNA and RNA molecules. A key aspect of this work involves the use of chemically-modified nucleotides as probes of structure, function, and folding. For example, we have engineered disulfide cross-links into medium-sized RNAs to probe folding pathways, much in the way disulfide bonds have been used to explore aspects of protein folding. These cross-links have allowed the first structural assessment of an RNA folding transition state which is important for developing mechanistic model of folding.
A second research area is aimed at defining the binding properties of anti-DNA autoantibodies. Anti-DNA autoantibodies are a hallmark of the autoimmune disorder systemic lupus erythematosus. In a process involving antigen recognition, these antibodies mediate the kidney inflammation that results in much of the morbidity and mortality associated with lupus. However, the specific DNA antigens recognized by anti-DNA and the way in which anti-DNA interact with these molecules remains poorly understood. Using in vitro selection experiments we have identified high affinity consensus sequences for several monoclonal anti-DNA autoantibodies and we are now correlating their binding properties and pathogenicity. Not only do these experiments provide knowledge about the pathology of lupus, but they also provide fundamental insight about protein-DNA interactions in general.
The third avenue of research in my laboratory is aimed at developing small molecule agents to treat lupus and other autoimmune disorders. At present, broad-acting immunosuppressive agents are typically employed as therapeutics for lupus and related disorders. However, these drugs produce serious side effects that limit treatment. We have identified a class of pro-apoptotic benzodiazepines that in several animal models, effectively treats autoimmune disease by selectively killing disease-determining lymphocytes. Unlike current therapies, our compounds are not adversely immunosuppressive. Current efforts on this project focus on delineating the signaling pathways that mediate the benzodiazepine-induced death of lymphocytes and how this process leads to disease improvement.
Honors & Awards
1992-95 Nat Arthritis Foundation Arthritis Investigator Award
1993-96 American Cancer Soc. Junior Faculty Research Award
1993-98 National Science Foundation Young Investigator Award
1995-98 Camille Dreyfus Teacher-Scholar Award
1995-97 Research Fellow of the Alfred P. Sloan Foundation
1998 & 2001 Excellence in Research Award, UM, LS&A
1999 Werner E. Bachmann Collegiate Professorship
2007 AAAS Fellow
Cain, R.J. and Glick, G.D. (1998) The Use of Cross-Links to Study the Conformational Dynamics of Triplex DNA. Biochemistry 37, 1456. PMID: 9477975
Maglott, E.J., Deo, S. and Glick, G.D. (1998) Conformational Transitions of an Unmodified tRNA Transcript: Implications for RNA Folding. Biochemistry 37, 16349.
Stevens, S.Y. and Glick, G.D. (1999) Evidence for Sequence Specific Recognition of DNA by Anti-ssDNA Autoantibodies, Biochemistry 38, 560.
Maglott, E.J., Goodwin, J.T. and Glick, G.D. (1999) Probing an RNA Tertiary Structure Unfolding Transition State, J. Am. Chem. Soc. 121, 7461.
Jhaveri, S., Kirby, R., Conrad, R., Maglott, E., Bowser, M., Kennedy, R., Glick, G., Ellington, A., Designed Signaling Aptamers that Transduce Molecular Recognition to Changes in Fluorescence Intensity, J. Am. Chem. Soc., 2000;122, 2467.
Blatt, N.B., Warner, R., Bedarski, J.J., Leonetii, F., Johnson, K.J., Yung, R., Richardson, B.C., Ellman, J.A., Opipari, A. and Glick, G.D. Modulation of Autoimmune Nephritis in NZB/W mice with a Pro-Apoptotic Benzodiazepine, manuscript submitted.