Faculty

At the interface of Chemistry and Biology, a recent revolution has taken place that has uncovered a plethora of small non-coding (nc)RNAs in our bodies, which outnumber protein-coding genes by several-fold, dominate the expression patterns of all genes in all cells, and have inspired entirely new therapeutic intervention approaches.  Our group's goal is to understand the structure-function relationships in these ncRNAs and then utilize them for biomedical, bioanalytical and nanotechnological applications.  The ncRNAs we study range from small RNA catalysts, such as the hammerhead, hairpin and hepatitis delta virus ribozymes with potential use in human gene therapy and relevance to human disease, to large RNA-protein complexes, such as RNA interference machinery involved in gene regulation and virus suppression.  In particular, we employ fluorescence techniques to study in real-time the kinetic mechanisms of these ncRNAs, in bulk solution, in live cells, and at the single-molecule level. Applications include the identification and optimization of ribozymes for gene therapy and as novel biosensors, as well as the characterization of antiviral and antibiotic drugs that target pathogenic RNA function.
Our research by its very nature is highly interdisciplinary, engaging students with a diverse background and providing a broad education. The molecules we study are extremely dynamic over time scales of microseconds to hours. To understand these dynamics we combine state-of-the-art chemical, molecular biological, and biophysical approaches. An outline of several exciting current projects is given below.

1. Developing a model system for understanding gene silencing by directly observing, using flourescence techniques, the action of small interfering (si)RNAs and micro (mi)RNAs on pathogenic mRNAs in cell extracts and live cells.

2. Utilizing single molecule flourescence imaging techniques to follow movement of the ribosome on a secondary structured mRNA.

3. Utilizing single molecule flourescence imaging techniques in nanotechnology to follow autonomously moving engineered "molecular spiders."

4. Generating new biosensors for high-throughput screening of the broncho-dilator drug theophylline, by directly monitoring the cleavage activity of a theophylline controlled hammerhead ribozyme by FRET.

5. Using single-molecule flourescence techniques to observe in unprecedented detail fluctuations of single ribozyme molecules between catalytically active and inactive conformations.

Awards

Visiting Scholar, Harvard University (Sunney Xie group), 2006
Alumnus of the Year Award, Sherbrooke RiboClub, 2006
JILA Distinguished Visitor Fellowship, 2006
Camille Dreyfus Teacher-Scholar Award, 2004
Dow Corning Assistant Professorship - University of Michigan, 2002
Otto-Hahn medal for Outstanding Researchers of the Max-Planck Society
Feodor-Lynen Postdoctoral Research Fellowship from the Alexander von Humboldt Foundation
Kekule Ph.D. Scholarship from the Stiftung Stipendienfonds des Verbandes der Chemischen Industrie
Anton Keller Prize for best Chemistry Diploma of the Year at the Technical University of Darmstadt
Study Scholarship from the Studienstiftung des Deutschen Volkes

Representative Publications

1. Hoerter, J.A.H., Walter, N.G., "Chemical Modification Resolves the Asymmetry of siRNA Strand Degredation in Human Blood Serum", RNA, 2007, 13, 1887.

2. Liu, S., Bokinsky, G., Walter, N.G., "Dissecting the Multi-Step Reaction Pathway of an RNA Enzyme by Single-Molecule Kinetic 'Fingerprinting'", Proc. Natl. Acad. Sci. USA, 2007, 104, 12634.

3. Sefcikova, J., Krasovska, M.V., Sponer, J., Walter, N.G., "The Genomic HDV Ribozyme Utilizes a Previously Unnoticed U-turn Motif to Accomplish Fast Site-Specific Catalysis", Nucleic Acids Res., 2007, 35, 1933.

4. Tinsley, R.A.,Furchak, J.R.W., Walter, N.G., "Trans-Acting glmS Catalytic Roboswitch:Locked and Loaded", RNA, 2007, 13, 468.

5. Walter, N.G., Meiners, J.C., Meyhofer, E., Neubig, R.R., Perkins, N.C., Steel, D.G., Sunahara, R.K., Swanson, J.A., "Meeting Report-- Under the Microscope:Single Molecule Symposium at the University of Michigan 2006", Biopolymers, 2007, 85, 106.

6. Rhodes, M.M., Reblova, K., Sponer, J., Walter, N.G., "Trapped Water Molecules are Essential to Structural Dynamics and Function of a Ribozyme", Proc. Natl. Acad. Sci. USA, 2006, 103, 13381.

7. Rueda., D., Bokinsky, G., Rhodes, M.M., Rust, M.J., Zhuang, X. and Walter, N.G., "Single-molecule Enzymology of RNA: Essential Functional Groups Impact Catalysts from a Distance", Proc. Natl. Acad. Sci. USA, 2004, 101, 10066.