The development of small molecule compounds that target discrete protein binding domains can be improved by detailed structural resolution of the protein target, and Dr. Wagner’s lab is considered an authority on applying NMR spectroscopy to the elucidation of protein structure and protein-protein interactions. The lab’s expertise is in NMR spectroscopy, computational biology and small molecule screening.  The Wagner lab is well suited for collaborating with industry to pursue translational studies in a variety of therapeutic areas, including cancer, transplantation and immune rejection, and atherosclerosis.

Recent interests include the study of capped mRNA translation, perturbing the association of calcineurin with NFAT in the interest of making improved immunosuppresants, and exploring the druggability of transcriptional co-activators for a variety of diseases.

Dr. Wagner’s lab is investigating biological mechanisms by studying the detailed structural characteristics of cytoplasmic and membrane proteins in solution. These studies relate to a range of cellular processes, including protein translation, T-cell activation and metabolism. Protein translation is a highly regulated process, and cancer cells have developed mechanisms that lead to enhanced translation of oncogenic proteins as compared to normal cells. A key aspect underlying this ability is translation initiation, which is altered in cancer cells such that mRNAs possessing long 5’ UTRs, a group that includes a disproportionately high number of proto-oncogene transcripts, have a greater likelihood for translation. Dr. Wagner’s lab is capitalizing on structure-function analysis of protein initiation factors such as eIF4E to develop small molecule compounds that preferentially block translation of proto-oncogene mRNAs.

The lab is also exploring avenues for designing more selective therapeutics that target calcineurin, a protein involved in T-cell activation and immune rejection of allogeneic tissues. Their approach is to disrupt a specific protein-protein interaction that is key for calcineurin-depending signaling in T-cells, while leaving the phosphatase activity of calcineurin unobstructed, so that side-effects of this therapy could be minimized.

Other projects in the lab encompass structure-function relationships of transcription factors that modulate cholesterol and lipid metabolism and metabolomic studies in blood cancers that are investigating gene expression signatures and biomarkers as diagnostic tools and indicators of drug response.
 

Dr. Wagner is expert on structural characterization for proteins and multiprotein complexes, employing NMR spectroscopic methodology, mathematical models, and biological techniques. He is particularly expert in NMR spectroscopy-based analysis of larger proteins (> 35 - 40 kDa), and has published several studies for improving and optimizing NMR spectroscopic methods for studying this class of polypeptides. Moreover, he has championed the use of NMR spectroscopy for characterizing the perturbations that occur following protein-protein or protein-nucleic acid associations, as well as in-cell NMR spectroscopy. He has explored structure/function aspects for protein constituents  of eukaryotic protein translation, apoptosis, T-cells, and various other cellular processes.

One of Professor Wagner's recent studies focused on protein phosphorylation. Dr. Wagner employed high-resolution NMR to visualize a sequential protein phosphorylation process in vitro as well as in live cells, and by doing so uncovered new mechanistic aspects. A separate project elucidated the structure of a membrane protein channel by reconstituting the protein in detergent micelles. In addition to uncovering the secondary structure, the NMR data pinpointed the binding sites on the protein for various interacting species. Another study explored the protein translation inhibitor designated as Programmed Cell Death 4 (PDCD4). The lab relied on several lines of evidence, including data obtained from NMR and x-ray crystallography, to determine that two similar domains in the protein cooperate to form a strong complex with eIF4A. This interaction leads to a liberation of eIF4G and RNA from eIF4A, and ultimately a blockage of protein translation. Other work has focused on deciphering protein-protein interactions that regulate the T-cell receptor, such as the association of the Nck adaptor protein and the CD3 subunit of the T-cell receptor. 
 

Biological Mechanisms and Pathways

• Apoptosis •
• Beta-catenin •
• Calcineurin •
• Chemical biology •
• Computational biology •
• Eukaryotic protein translation initiation •
• Immune suppression •
• Macromolecular interaction •
• Membrane proteins •
• Metabolomics •
• Protein structure •
• Protein-Protein interaction •
• T-cell •
• Translational control
•  

Cancer

• Apoptosis
•  

Research Tools and Instrumentation

• NMR spectroscopy
•  

Therapeutics

• Small molecule inhibitors
•