Jeffrey Agar

Associate Professor,
College of Science and Department of Pharmaceutical Sciences,
Northeastern University

Multiplexed MS Quantitation of Any Biomolecule, in Any Feed, and in Every Organism Using Arbitrary Changes in Isotopomer Distribution (ACID)

Current metabolic labeling mass spectrometry (MS) techniques work for a limited number of organisms. Our inexpensive, multiplex technique is conceivably applicable to any organism, and both top-down and bottom-up MS. An arbitrary amount of labeled metabolite, in one case sugar, can be added to any growth medium or feed. Labeled carbon is then incorporated into proteins – in fact, all biomolecules- through glycolytic intermediates. The resulting arbitrary change in isotopomer distribution (ACID), produces a distinguishable (heavy) intact protein peak for isotope dilution MS. With the goals of labeling animals (in particular humans) and additional multiplexing (including neutron encoding), the ACID concept has been extended to other clinically relevant metabolic pathways and heavy element labels. This resulted in techniques for incorporating heavy isotopes of carbon, hydrogen, and nitrogen, thereby enabling quantitative MS of biomolecules that contain these elements.

Biosketch

I am a formally trained spectrometrist and spectroscopist, having performed magnetic-optical techniques (magnetic circular dichroism, electron paramagnetic resonance, Resonance Raman, etc.) with Michael Johnson and in FT-ICR mass spectrometry (MS) with Jon Amster. I teach well-reviewed fundamentals and advanced (e.g. to practicing industry mass spectrometrists) MS courses and a number of my former Ph.D., MS, and even undergraduate students are now MS practitioners. My principal research interest has always been characterizing novel protein modifications and their biological roles, and we specialize in developing tools for this purpose. One arm of our group currently develops ultra-high resolving power MS tools, including imaging MS, for characterizing metabolites, lipids, and proteins. The second arm of our group applies these tools to the study of ALS, having discovered disease-related post-translational modifications of SOD1 and defined some of their biological consequences. We also characterized structural aberrations common to dissimilar ALS-causing SOD1 variants, and are developing small molecules that stabilizing SOD1 in cell culture. Our preclinical drug discovery studies in ALS models will benefit from Nathalie Agar’s matrix deposition, microscopy, and MS instrumentation, as well as her group’s substantial expertise in CNS drug delivery. The four publications listed below demonstrate: a subset of the tools we can offer for FT-ICR MS data analysis (Li 2010); that we require the delivery of pharmacological chaperones to the CNS (Auclair 2010 and Granted and Provisional Patents on stabilizing SOD1); proof of a productive collaboration with N. Agar (Liu, one of many such publications); and our ability to incorporate RNAseq data and characterize thousands of proteins by proteomics (Salisbury 2015).

Date
Date(s) - September 10, 2015
7:00 pm - 10:00 pm

Emplacement / Location
Morris and Rosalind Goodman Agora