Group: Novartis Institutes for BioMedical Research, Basel, Switzerland

Key members: Juan Zhang (left), Klaus Seuwen (middle), Andreas W. Sailer (right)

Contact: Juan Zhang, juan.zhang@novartis.com

 

Research activities: We and others have identified 7-alpha, 25-dihydroxycholesterol and closely related oxysterols as ligands for a G protein-coupled receptor called EBI2 (aka GPR183) (1). The EBI2 receptor is required for the humoral immune responses and has been linked to autoimmune disease. To characterize the molecular interaction between oxysterols and the EBI2 receptor we have initiated a mutagenesis study to identify critical residues for ligand receptor interaction and developed small molecule antagonists for EBI2 (2). Furthermore we are interested in establishing sensitive methods to measure oxysterols in tissues and biological fluids by mass spectrometry (3). Many of these activities are done in collaboration with academic investigators (4). Overall, we are interested in understanding the roles of metabolism in cellular functions and its relationship to diseases as well as therapeutic interventions. We develop methods for targeted metabolomics using various LC-MS technologies, e.g., RP-LC, ion-exchange chromatography, and HILIC combined with Triple-Q MS or FT-MS. Our methods cover intermediates on the central metabolism pathways, e.g, glycolysis, TCA, PPP, nucleotide metabolism, urea cycle, glutaminolysis, amino acids, and cholesterol metabolism. Our methods have been applied to various drug discovery projects for target identification/validation, biomarker discovery, quantitation, and validation in both pre-clinical and clinical researches.

 

Key papers related to ENOR:

(1) Hannedouche, S. et al. (2011). Oxysterols direct immune cell migration via EBI2. Nature 475, 524.

(2) Gessier, F., et al. Identification and characterization of small molecule modulators of the EBI2 receptor (2014). J. Med. Chem., 57, 3358.

(3) Karuna, R., et al. Detection of dihydroxycholesterols in human plasma using HPLC-ESI-MS/MS (2015). Steroids 99; 131

(4) Rutkowska, A., et al.. EBI2 receptor regulates myelin development and inhibits LPC-induced demyelination (2017). J. of Neuroinflammation, in press.

(5) Wanke, F. et. al., EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells, Cell Reports 2017, 18(5):1270

(6) Vigne S. et.al., IL-27-Induced Type 1 Regulatory T-Cells Produce Oxysterols that Constrain IL-10 Production, Frontiers in Immunology, 2017,

(7) Crick. P, et.al.,  Reduced plasma levels of 25-hydroxycholesterol and increased CSF levels of bile acid precursors in patients suffering from multiple sclerosis,  Molecular Neurobiology, 2016, 54(10),

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