Scintillating Emerging Solutions for Discovery Metabolomics

Leveraging Advancements in Ion Mobility Technology for Lipid Applications

Lipids play a critical role in many biological processes as well as acting as biomarkers of many metabolic disorders. The analysis of lipids is complicated by the presence of numerous structural isomers, which are challenging to fully characterize using traditional liquid chromatography-mass spectrometry (LC-MS) workflows. To aid in the resolution of these complex isomeric profiles, ion mobility has become an increasingly important separation technique in lipid-based workflows. However, conventional ion mobility platforms often lack the necessary resolving power to resolve biologically relevant lipid isomers with differences in collision cross section (CCS) of less than ~2%, which includes structural features such as double bond position isomers, cis/trans isomers, and some SN1/SN2 positional isomers. More recently, the introduction of high-resolution ion mobility (HRIM) analytical techniques such as those based on structures for lossless manipulations (SLIM) enables rapid, gas-phase separation of lipids with resolving powers over 250, potentially facilitating the separation and identification of biologically relevant lipid isomers never detected in prior analyses. Here, we provide an overview of capabilities of HRIM technology for lipid analysis, including resolution of challenging isomeric species, cases in which high throughput separations can be achieved without the use of LC, and example application spaces, such as the relative quantitation of ganglioside profiles in a GBA mouse model for Parkinson’s disease. Finally, future applications of highly resolved lipid CCS measurements will be discussed, including the development of predictive informatics and the potential impact for discovery lipidomics.

Presenter: Rachel A. Harris (Application Scientist , MOBILion Systems, Chadds Ford, PA, USA)

Rachel Harris is an applications scientist at MOBILion Systems. She first began her research in the field of ion mobility-mass spectrometry as an undergraduate at UNC Chapel Hill, in the lab of Dr. Gary Glish, where she worked on a prototype FAIMS device. She later received her PhD in Analytical Chemistry from the lab of Dr. John McLean at Vanderbilt University. Her dissertation research focused on the combination of multiple analytical techniques for lipid structural characterization, including ion mobility, ozonolysis, and surface induced dissociation. At MOBILion Systems, she generates applications-specific content to show off the MOBIE platform’s capabilities and serves as the in-house lipids expert, providing actionable feedback for product improvements.

Dose-Response Metabolomics for High-Throughput Screening of Off-Target Effects

Metabolomics is widely applied to understand drug mode of action. The basic premise is that small-molecule drugs inhibit a protein's activity, and this leads to changes in its substrate and product metabolites. A complication, however, is that most small-molecule drugs do not interact with a single protein. As a consequence, the metabolic profiles obtained are often a convolution of multiple inhibited proteins. While complex, these data have the potential to provide important insights into drug activity. By modeling dose-response curves for hundreds to thousands of metabolites, it is possible to identify which specific biochemical pathways are targeted by small-molecule drugs at a comprehensive level. In this presentation, the approach will be applied to well-characterized drugs. The data will reveal surprising drug-protein interactions that lead to unintended off-target effects. A workflow will be reviewed for high-throughput screening of off-target drug effects, which could potentially be applied to lead compounds early in the drug-development process. 

Learning objectives:

• Understand the insight that dose-response metabolomics can provide for characterizing drug activity
• Develop a basic understanding of the steps required to process data from dose-response metabolomics 
• Learn about success stories where dose-response metabolomics revealed unexpected off-target effects

For Research Use Only. Not for use in diagnostic procedures.

Presenter: Gary Patti (Professor of Chemistry and of Genetics and Medicine (School of Medicine), Michael and Tana Powell Professor of Chemistry, Washington University)

Gary Patti is the Michael and Tana Powell Professor at Washington University in St. Louis, where he holds appointments in the department of chemistry and the department of medicine. Dr. Patti is the Senior Director of the Center for Metabolomics and Isotope Tracing, Co-Director of the Metabolic Kinetics Core in the Nutrition Obesity Research Center, Director of Graduate Admissions for the Chemistry Department, and a member of the Siteman Cancer Center. Professor Patti’s research focuses on developing and applying both mass spectrometry- and NMR-based metabolomics technologies to enhance our understanding of human metabolism. Applications of his work range from studies of molecular processes in cell culture to physiological regulation at the organ level in animal models and human patients. Professor Patti has been recognized with numerous awards including the Pew Biomedical Scholars Award, the Alfred P. Sloan Award, the Camille Dreyfus Teacher-Scholar Award, the Mallinckrodt Scholar Award, and the inaugural NIEHS award for revolutionizing, innovative, and visionary research.