Michael Demetriou

Director, National Multiple Sclerosis Society Designated Comphrehensive Care Clinic, Neurology
School of Medicine

National Multiple Sclerosis Society desinated Research Center
School of Medicine

Professor, Neurology
School of Medicine

M.D., University of Toronto, 1996

Ph.D., University of Toronto, 1995

FRCP (C), Royal College of Physicians and Surgeons, Canada, 2001

Phone: (949) 824-9775
Email: mdemetri@uci.edu

University of California, Irvine
208 Sprague Hall
Mail Code: 4032
Irvine, CA 92697

picture of Michael  Demetriou

Multiple Sclerosis, autoimmunity, T cells, Human Genetics, N-glycosylation, metabolism, glycobiology
2001: The Royal College of Physicians and Surgeons of Canada Research Award for Specialty Residents, Medicine Division
2002: UCI College of Medicine Committee on Research Award
2002: Health Science Partners Research Award
2002-2005: UCI Academic Senate Distinguished Service Award
2007: Dr S. Van Den Noort Research Award for Junior Faculty
2010: ‘Orange County Physician of Excellence’, selected by the
Orange County Medical Association
2010: National Multiple Sclerosis Society Research Volunteer of the Year.
2011: Member, American Neurological Association
Appointments 1999 – 2000: Postdoctoral Fellow, Samuel Lunenfeld Research Institute, Mt Sinai Hospital, Toronto, Canada.

1996-2001: Residency in Neurology, University of Toronto, Canada
Our work has revealed how genetic and metabolic regulation of protein glycosylation controls the function and activity of cell surface glycoproteins to affect cell growth/differentiation and disease states such as autoimmunity. Virtually all cell surface and secreted proteins in animals are modified by the addition of complex carbohydrates in the ER/Golgi secretory pathway, imparting substantial molecular information not encoded by the genome. We find that genetic, metabolic and environmental regulation of Golgi N-glycosylation controls macromolecular complexes on the cell surface to influence cell growth, differentiation and disease states. The branching and number of N-glycans per protein molecule cooperate to regulate binding to galectins, forming a galectin-glycoprotein lattice that controls the distribution, clustering and endocytosis of surface glycoproteins in a predictable manner. N-glyan branching deficiency induces T cell hyper-activity and spontaneous autoimmune disease in mice by enhancing T cell receptor clustering/signaling, reducing surface retention of the growth inhibitor CTLA-4 and promoting differentiation into pro-inflammatory cells. In humans, multiple genetic and environmental risk factors for Multiple Sclerosis (MS) converge to dysregulate N-glycosylation and CTLA-4 surface retention. These include genetic variants in interleukin-7 receptor-a, interleukin-2 receptor-a, MGAT1, MGAT5 and CTLA-4 as well as Vitamin D3 and metabolic production of UDP-GlcNAc, the substrate for MGAT1 and MGAT5. Rescuing N-glycan branching deficiency in T cells in vitro and in vivo by metabolically increasing UDP-GlcNAc with the dietary supplement N-acetylglucosamine (GlcNAc), suppresses T cell growth, enhances CTLA-4 surface expression, blocks pro-inflammatory T cell differentiation, inhibits MS and autoimmune diabetes models and rescues N-glycan branching deficiency induced by MS genetic risk factors. Therapeutic supplementation to N-glycan biosynthesis may provide a personalized medicine approach to suppress an underlying molecular defect promoting human autoimmunity.
Available Technologies
Publications 1) Demetriou, M., Granovsky, M, Quaggin, S, and Dennis, J.W. (2001). Negative Regulation of T-cell Activation and Autoimmunity by Mgat5 N-Glycosylation. Nature 409, 733-738.

- Minireview: Lowe, J.B. Glycosylation, Immunity and Autoimmunity. Cell 104, 809-812.

2) Morgan, M, Gao, G, Pawling, J, Dennis, JW, Demetriou, M, Li, B (2004). N-acetylglucosaminyltransferase V (Mgat5) N-glycosylation Negatively regulates TH1 cytokine production by T cells. Journal of Immunology 173 7200-7208.

3) Lau, K; Partridge, E.; Grigorian, A.; Silvescu, C; Reinhold, V, Demetriou, M, Dennis, JW (2007). Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129, 123-134 (2007).

- Minireview: Stanley, P. (2007). A method to the madness of N-glycan complexity? Cell 129 27-29.
- News and Views: Taniguchi, N. (2007). A sugar-coated switch for cellular growth and arrest. Nat. Chem. Biol. 3 307-309

4) Grigorian, A; Lee, S-U; Tian, W; Chen, I-J; Gao, G; Mendelsohn, R; Dennis, J.W.; Demetriou, M. (2007). Control of T cell mediated autoimmunity by metabolite flux to N-glycan biosynthesis. J. Biol. Chem. 282, 20027-20035.

5) Lee, S-U; Grigorian, A; Pawling, J; Chen, I-J; Gao, G; Mozaffar, T; McKerlie, C; Demetriou, M. (2007). N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration. J. Biol. Chem. 282, 33725-33734.

6) Chen, I-J; Chen,H-L; Demetriou, M. (2007). Lateral compartmentalization of TCR versus CD45 by galectin – N-glycan binding and microfilaments coordinates basal and activation signaling. J. Biol. Chem. 282, 35361-35372.

7) Grigorian, A.; Torossian, S.; Demetriou, M. (2009). T cell growth, cell surface organization and the Galectin-Glycoprotein lattice. Immunological Reviews 230, 232–246

- featured on the cover.

8) Chen, H-L; Li, C.F.; Grigorian, A.; Tin, W.; Demetriou, M. (2009). T cell receptor signaling co-regulates multiple Golgi processing enzymes to enhance N-glycan branching. J. Biol. Chem. 284, 32454-61 (epub Aug 25, 2009).

- featured as “Paper of the Week”
- featured on the cover.

9) Dennis, J.W; Nabi, I.R.; Demetriou, M. (2009). Metabolism, Cell Surface Organization and Disease. Cell 139, 1229.

10) Dennis, J.W; Lau, K.; Demetriou, M.; Nabi, I.R. (2009). Adaptive regulation at the cell surface by N-glycosylation. Traffic 10, 1569-78 (epub Sep 2, 2009).

11) Kölln, J.; Zhang, Y.; Thai, G.; Demetriou, M.; Hermanowicz, N.; Duquette, P. Van den Noort, S.; Qin, Y. (2010). Inhibition of GAPDH activity by antibodies present in the cerebrospinal fluid of patients with Multiple Sclerosis. Journal of Immunology 185 1968-75. (Epub 2010 Jul 7).

12) Grigorian, A. and Demetriou, M. (2010). Manipulating cell surface glycoproteins by targeting N-glycan – galectin interactions. Methods in Enzymology 480, 245-66.
  13) Mkhikian, H., Grigorian, A.; Li, C.F.; Chen, H-L; Newton, B.L.; Zhou, W.; Beeton, C; Torossian1, S.; Tatarian, G.G.; Lee, S-U; Lau, K; Walker, E.; Siminovitch, K.A.; Chandy, K.G.; Yu, Z.; Dennis, J.W; Demetriou, M. (2011). Genetics and the environment converge to dysregulate N-glycosylation in Multiple Sclerosis. Nature Communications 2 (334) 1-13.
- Faculty of 1000: Exceptional (FFa-10): Stanley P: 2011. F1000.com/12147958
  14) Bahaie, N.S.; Kang, B.N.; Frenzel, E.M.; Hosseinkhani, R.; Ge, X.N.; Greenberg, Y.; Ha, S.G.; Demetriou, M.; Rao, S.P. and Sriramarao, P. (2011) N-glycans differentially regulate eosinophil and neutrophil recruitment during allergic airway inflammation. J. Biol. Chem. 286 38231-41 (Epub Sept 12, 2011).
  15) Grigorian, A.; Araujo L.; Naidu, N.N.; Choudhury, B. and Demetriou, M. (2011). N-acetylglucosamine inhibits T-helper 1/T-helper 17 responses and treats experimental autoimmune encephalomyelitis. J. Biol. Chem. 286 40133-40141 (Epub Sept 29, 2011).

- Faculty of 1000: Must Read (FFa-8): Freeze H: 2011. F1000.com/13336042
- #3 most read paper in the J. Biol. Chem. Sept. through Nov., 2011
  16) Yu, Z; Gillen, D; Li, CF; Demetriou, M (2013). Incorporating parental information into family-based association tests. Biostatistics 14 556-72 (epub Dec 23 2012).
  17) Li, C.F.; Zhou, R.W.; Mkhikian H; Newton B.L.; Yu, Z. and Demetriou, M. (2013). Hypomorphic MGAT5 Polymorphisms Promote Multiple Sclerosis Cooperatively with MGAT1 and Interleukin-2 and 7 Receptor Variants. Journal of Neuroimmunology 256 71-6 (epub Jan 22 2013).

18) Nourse, J.L.; Prieto, J.L.; Dickson, A.R.; Lu, J.; Pathak, M.M.; Tombola, F.; Demetriou, M.; Lee, A.P. and Flanagan, L.A. (2014). Membrane biophysics define neuron and astrocyte progenitors in the neural lineage. Stem Cells 32 706-16.

19) Williams, R.; Ma, X.; Schott R.K.; Mohammad, N.; Ho, C.Y.; Li, C.F.; Chang, B. S.W.; Demetriou, M.; Dennis, J.W. (2014). Encoding asymmetry of the N-glycosylation motif facilitates glycoprotein evolution. Plos One 9(1):e86088.

20) Yu, Z.; Li, C.F.; Mkhikian, H.; Zhou, R.W.; Newton, B.L. and Demetriou, M. (2014). Family studies of type 1 diabetes reveal additive and epistatic effects between MGAT1 and three other polymorphisms. Genes and Immunity. (Epub Feb 27).
Grants R01AI108917 NIH/NIAID 12/15/13 – 11/30/18 Title: ‘Impaired T cell immunity in the Elderly via enhanced N-glycosylation’ Principal Investigator: Michael Demetriou
R01AI053331 NIH/NIAID 05/01/10 – 04/30/15 Title: ‘T cell regulation by N-glycosylation’ Principal Investigator: Michael Demetriou
R01AI082266 NIH/NIAID 6/1/09 – 1/31/14 (in NCE) Title: ‘Human Autoimmunity and Genetic Defects in N-glycosylation’ Principal Investigator: Michael Demetriou
R01AT007452-01* NIH/NCCAM 5/01/14 – 4/30/19 Title: ‘Mechanisms of human immune modulation by oral N-acetylglucosamine’ Principal Investigator: Michael Demetriou (*funding expected based on perfect score of ‘10’ by the study section)
National Multiple Sclerosis Society 11/1/09 – 10/31/14 Collaborative Multiple Sclerosis Research Center. Principal Investigator: Tom Lane Project 2, Principal investigator: Michael Demetriou.
F30 HL108451-01 NIH/NHLBI 4/1/11 - 6/30/14 Ruth Kirchstein Individual Predoctoral MD/PhD Fellowship Title: ‘N-glycosylation as a downstream effector of Interleukin-7’ Fellow: Haik Mkhikian Mentor: Michael Demetriou
Graduate Programs Cellular and Molecular Biosciences


Research Centers Institute for Immunology
Cancer Research Institute
Multiple Sclerosis Research Center
Link to this profile http://www.faculty.uci.edu/profile.cfm?faculty_id=5788
Last updated 04/03/2014