Director, National Multiple Sclerosis Society Designated Comphrehensive Care Clinic, Neurology
National Multiple Sclerosis Society desinated Research Center
|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
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.|
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|
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|