Areas of Interest
At the interface of Biology and Chemistry, a revolution has recently 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 disease intervention approaches. Our group's goal is to understand the mechanistic structure-function relationships in these ncRNAs using single molecule tools and then utilize them for biomedical, bioanalytical and nanotechnological applications. The ncRNAs we study range from small RNA enzymes, 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 ncRNAs for gene therapy and as novel biosensors and biomarkers, 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 biochemical, molecular biological, and biophysical approaches. An outline of several exciting current projects is given below.
1. Dissecting pre-mRNA splicing by fluorophore labeling individual RNA or protein components and following their fluorescence fluctuations during splicing in cell extracts by single molecule fluorescence microscopy.
2. Using single molecule fluorescence techniques to observe in unprecedented detail fluctuations of single ncRNA molecules between functionally active and inactive conformations.
3. Utilizing single molecule fluorescence imaging to follow movement of the ribosome on a secondary structured mRNA, including riboswitch motifs that utilize an aptamer domain to recognize a specific ligand and effect downstream gene expression.
4. Developing a model system for understanding gene silencing by directly observing, using fluorescence techniques, the action of small interfering (si)RNAs and micro (mi)RNAs on pathogenic mRNAs in cell extracts and live cells.
5. Utilizing super-resolution fluorescence imaging techniques in nanotechnology to follow and optimize autonomously moving engineered "molecular spiders" and the functionality of other RNA and DNA nanodevices.
Analytical Chemistry • Bioanalytical Chemistry • Bioinorganic Chemistry • Biophysical Chemistry • Chemical Biology • Energy Science • Nano Chemistry • Optics and Imaging • Organic Chemistry • Physical Chemistry • RNA Biochemistry • Sensor Science • Surface Chemistry • Sustainable Chemistry • Ultrafast Dynamics
Other Research Interests
- Single Molecule Fluorescence Spectroscopy and Microscopy
- Folding and Function of Non-Coding RNA
- Live-Cell Imaging
- Biophysical Chemistry of Nucleic Acids
Honors & Awards
Visiting Sabbatical Scholar, Chan-Zuckerberg Biohub, San Francisco (hosted by Stephen Quake), 2018
Prasanta Datta Memorial Travel Award, Department of Biological Chemistry, University of Michigan, 2018
Francis S. Collins Collegiate Professor, University of Michigan, 2017
Mid-Career Award, RNA Society, 2017
Jean Dreyfus Boissevain Lecturer, Trinity University, San Antonio, TX, 2015
Harold R. Johnson Diversity Service Award, University of Michigan, 2015
Faculty Recognition Award, University of Michigan, 2013
Imes and Moore Faculty Award, University of Michigan, 2013
Alexander von Humboldt Foundation Visiting Scholar, Johann Wolfgang Goethe University Frankfurt (Harald Schwalbe group), 2012
Elected Fellow, American Association for the Advancement of Science, 2011
Buchanan Lecturer, Bowling Green State University, 2011
ADVANCE Program for Executive Leadership, University of Michigan, 2011
MSFB Study Section Member, National Institutes of Health, 2009–2013
Visiting Sabbatical Scholar, Harvard University (Sunney Xie group), 2006
JILA Distinguished Visitor Fellowship (David Nesbitt group), 2006
Alumnus of the Year Award, Sherbrooke RiboClub, 2006
Camille Dreyfus Teacher-Scholar Award, 2004
Dow Corning Assistant Professorship, University of Michigan, 2002
Otto-Hahn Award for Outstanding Researchers of the Max-Planck Society, 1995
Feodor-Lynen Postdoctoral Research Fellowship, Alexander von Humboldt Foundation, 1995–1998
Kekulé Predoctoral Scholarship, Fund of the German Chemical Industry Association, 1992–1994
Automatic classification and segmentation of single-molecule fluorescence time traces with deep learning.
Li J, Zhang L, Johnson-Buck A, Walter NG.
Nat Commun. 2020; 11: 5833
Hyperosmotic phase separation: Condensates beyond inclusions, granules and organelles.
Jalihal AP, Schmidt A, Gao G, Little S, Pitchiaya S, Walter NG.
J Biol Chem. 2020, in press.
Direct kinetic fingerprinting and digital counting of single protein molecules.
Chatterjee T, Knappik A, Sandford E, Tewari M, Choi SW, Strong WB, Thrush EP, Oh KJ, Liu N, Walter NG, Johnson-Buck A.
Proc Natl Acad Sci U S A. 2020; 117: 22815–22.
Multivalent Proteins Rapidly and Reversibly Phase-Separate upon Osmotic Cell Volume Change.
Jalihal AP, Pitchiaya S, Xiao L, Bawa P, Jiang X, Bedi K, Parolia A, Cieslik M, Ljungman M, Chinnaiyan AM, Walter NG.
Mol Cell. 2020; 79: 978–990.
Cytoplasmic TDP43 Binds microRNAs: New Disease Targets in Amyotrophic Lateral Sclerosis.
Paez-Colasante X, Figueroa-Romero C, Rumora AE, Hur J, Mendelson FE, Hayes JM, Backus C, Taubman GF, Heinicke L, Walter NG, Barmada SJ, Sakowski SA, Feldman EL.
Front Cell Neurosci. 2020; 14: 117.
Following the messenger: Recent innovations in live cell single molecule fluorescence imaging.
Schmidt A, Gao G, Little SR, Jalihal AP, Walter NG.
Wiley Interdiscip Rev RNA. 2020; 11: e1587.
Protein unties the pseudoknot: S1-mediated unfolding of RNA higher order structure.
Lund PE, Chatterjee S, Daher M, Walter NG.
Nucleic Acids Res. 2020; 48: 2107–25.
For a list of publications from PubMed, click HERE