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.
1999 – 2000: Postdoctoral Fellow, Samuel Lunenfeld Research Institute, Mt Sinai Hospital, Toronto, Canada.
1996-2001: Residency in Neurology, University of Toronto, Canada
|Virtually all cell surface and secreted proteins are modified by addition of complex carbohydrates in the ER/Golgi secretory pathway, providing information encoding distinct from the genome. Unlike DNA/RNA/protein, production of complex carbohydrates is not template driven, but rather is controlled by the activity of ER/Golgi enzymes and metabolic supply of their substrates. 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 and disease states. The branching and number of Asn (N) linked-glycans per protein molecule cooperate to regulate binding to galectins, forming a molecular lattice at the cell surface that controls the distribution, lateral mobility, clustering and endocytosis of surface glycoproteins in a predictable manner. In the immune system, the N-glycan branching pathway negatively regulates T cell activation via the T cell receptor and growth arrest by CTLA-4. N-glycan branching by the Golgi Mgat1 and Mgat5 enzymes prevents spontaneous autoimmune demyelination and neurodegeneration in mice, the two critical pathologic characteristics of Multiple Sclerosis (MS). Indeed, we have recently observed that multiple MS risk modulators converge to alter N-glycosylation and CTLA-4 surface retention conditional on metabolism and/or Vitamin D3, including genetic variants in interleukin-7 receptor-a, interleukin-2 receptor-a, MGAT1 and CTLA-4. These data suggest a unifying molecular mechanism in MS, whereby multiple environmental and genetic inputs lead to dysregulation of a final common pathway, namely N-glycosylation. Our data also suggest that therapeutic supplementation to N-glycan biosynthesis may provide a personalized medicine approach to suppress disease. Indeed, oral supplementation with the simple sugar N-acetylglucosamine (GlcNAc) or Vitamin D3 rescues N-glycan branching deficiency on mouse T cells in vivo, inhibits mouse models of Multiple Sclerosis and autoimmune diabetes and improved disease in 8 of 12 human children with treatment-resistant inflammatory bowel disease.|
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) Grigorian, A.; Newton, B.L.; Demetriou, M. (2010). Glycoimmunology in ‘Carbohydrate Recognition: Biological problems, methods and applications’ Wily Interscience, New Jersey (In Press).|
|14) Mkhikian, H., Grigorian, A.; Li, C.F.; Chen, H-L; Newton, B.L.; Zhou, W.; Beeton, C; Torossian, 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). Environmental and genetic dysregulation of N-glycosylation is a unifying mechanism in Multiple Sclerosis. Nature Communications (In press).|
|Grants||R01AI082266 NIH/NIAID 6/1/09 – 1/31/14 Title: ‘Human Autoimmunity and Genetic Defects in 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|
|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.|
|F32AI081456 NIH/NIAID 7/1/09 - 6/30/11 Ruth Kirchstein Post-Doctoral Fellowship Title: ‘Vitamin D3, Autoimmunity and N-glycosylation’ Fellow: Ani Grigorian Mentor: 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|
|R01AI053331-S1 NIH/NIAID 08/05/2010 – 08/05/2012 Title: ‘T cell regulation by N-glycosylation’ Principal Investigator: 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|