10/24/19 - 9:45 AM to 11:00 AM
Department Seminar: Professor Catherine L. Grimes
Breaking down walls and building new materials to understand inflammation
The bacterial cell wall, a polymer of carbohydrate and peptides, makes an excellent antibiotic target for two reasons: (1) it is essential for bacteria and (2) humans do not have bacterial cell walls – thus the drugs do not harm human cells. In addition to serving as a target for antibiotics, the human innate immune system uses the bacterial cell wall as a molecular calling card to recognize their presence and subsequently generate the appropriate immune response. We are interested in understanding how the bacterial cell wall is processed both by bacteria and the human host and propose new methods and tools for the characterization of this important polymer. Both commensal and pathogenic bacteria are believed to produce peptidoglycan fragments and misrecognition can lead to the development of inflammatory bowel disease (IBD) such as Crohn’s disease (CD), asthma, and gastrointestinal (GI) cancers. Importantly, a long-standing debate around the biological relevance of the immunoactive synthetic fragment muramyl dipeptide (MDP) remains unclear due to a lack of NAM-based probes. We hypothesize that there are unidentified enzymatic targets and bacterial cell wall fragments that will be useful in the design of novel antibiotics and anti-inflammatory therapies.
We have taken a two-pronged approach towards testing this hypothesis. From the small molecule side, we have established an in vitro assay, which allows us to assess the affinity of Nod2, an innate immune receptor that binds to bacterial cell wall fragments. This assay has allowed us to tease apart binding from activation and we have begun to derive rules for molecular recognition by intracellular innate immune receptors. From the larger polymer side, we have embedded carbohydrates with small modifiable tags into the bacterial cell wall. We developed a method to label the NAM glycan backbone of E. coli, P. putida, and B. subtillis in whole cells The results reveal fundamental architectural details of the glycan chains of the peptidoglycan, and further enable us to track the engulfment and breakdown of bacteria by macrophages, ultimately revealing a peptidoglycan digestion mechanism for invasive bacteria. Finally, we have combined the approached to produce peptidoglycan arrays to probe the involvement of the adaptive immune system in sensing these bacterial walls.
Professor Catherine Grimes’ research program focuses on the development and chemical synthesis of small molecule carbohydrate probes that mimic intermediates of bacterial cell wall biosynthesis and bacterial-host immune recognition.
She is nationally recognized as a young leader in the field of chemical biology, as has received numerous awards, including a Pew Biomedical Scholars Award, a Cottrell Scholar, and an Alfred P. Sloan Research Fellowship. She received the American Chemical Society’s Infectious Disease Young Investigator Award and the Dreyfus Teacher Scholar Award. She is the co-director of a National Institutes of Health funded graduate program at the interface of chemistry and biology, and the faculty mentor to a dynamic group of undergraduate STEM majors, “The Scientistas.”
Professor Grimes obtained a bachelor’s degree from Villanova University, a master’s from Princeton University, and a doctorate from Harvard University. She was a post-doctoral fellow at Harvard University and Massachusetts General Hospital. She joined the University of Delaware’s Chemistry and Biochemistry Department in 2011, and is a joint faculty member in the Department of Biological Sciences.