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
My laboratory focuses on the roles of complex Asn(N)-linked glycans in cell function and diseases such as autoimmunity, Multiple Sclerosis (MS) and cancer. Our work has revealed how genetic and metabolic regulation of N-glycosylation controls the function and activity of cell surface glycoproteins to affect cell growth/differentiation and diseases such as MS. 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.
In the immune system, N-glycan branching deficiency controls differentiation of thymocytes, induces T cell hyper-activity and promotes 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 TH1/TH17 cells while inhibiting anti-inflammatory Treg and TH2 cells. In humans, multiple genetic and environmental risk factors for Multiple Sclerosis (MS) converge to dysregulate N-glycan branching. 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 TH1/TH17 differentiation, promotes iTreg differentiation and inhibits MS and autoimmune diabetes models. An NIH funded and FDA approved (IND 122235) Phase 1 trial of GlcNAc in MS revealed that oral GlcNAc was safe, well tolerated by MS patients and raised N-glycan branching in T cells.
The emergence of targeted anti-cancer drug therapies called Immunotherapies, which stimulate the body’s own immune system to fight cancer, hold great promise for cancer treatment over the traditional modalities of surgery, chemotherapy and radiation. Malignant transformation is near universally accompanied by aberrant changes of N- and/or O-linked glycosylation on the cell surface. Moreover, aberrant glycan expression in carcinomas drives tumor growth, motility, invasion, and metastasis. As both a marker and driver of many diverse cancers, glycans provide an excellent target for development of targeted immunotherapies for cancer. As such, we have developed a novel class of immunotherapeutic bi-specific proteins that target abnormal N- or )-glycans expressed by many di=verse cancer types. We have termed these “Glycan-dependent T cell Recruiter” or GlyTR. GlyTR1 bi-specific protein 1) specifically binds to both human CD3 and targeted glycans, 2) robustly activate T cells only in the presence of cancer cells, 3) induce T cell dependent killing of many diverse cancer cells with an EC50 as low as 5pM, and 4) markedly inhibit in vivo growth of cancer xenografts in humanized NSG mice.
1) Fernandes, B., Sagman, U., Auger, M., Demetriou, M., and Dennis, J.W. (1991). Beta 1-6 branched oligosaccharides as a marker of tumour progression in human breast and colon neoplasia. Cancer Research. 51. 718-23.
2) Simon, H.U., Higgins, E.A., Demetriou, M., Datti, A., Siminovitch, K.A., and Dennis, J.W. (1993). Defective expression of CD23 and autocrine growth-stimulation in Epstein-Barr Virus (EBV) transformed B cells from patients with Wiskott-Aldrich syndrome. Clinical and Experimental Immunology. 91(1), 43-49.
3) Demetriou, M., Nabi, I.R., Coppolino, M., Dedhar, S., and Dennis, J.W. (1995). Reduced contact-inhibition and substratum adhesion in epithelial cells expressing GlcNAc-transferase V. Journal of Cell Biology. 130(2), 383-92.
4) Demetriou, M., Binkert, C., Sukhu, B., Tenenbaum, H.C., and Dennis, J.W. (1996). Fetuin/alpha2-HS glycoprotein is a transforming growth factor-beta type II receptor mimic and cytokine antagonist. Journal of Biological Chemistry. 271 (22), 12755-61.
5) Binkert, C., Demetriou, M, Sukhu, B., Szweras, M, Tenenbaum, H.C., and Dennis, J.W. (1999). Regulation of Osteogenesis by Fetuin. Journal of Biological Chemistry. 274 (40), 28514-20.
6) 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.
7) Dennis, J.W., Warren, C.E., Granovsky, M, Demetriou, M. (2001). Genetic defects in N-glycosylation and cellular diversity in mammals. Current Opinion in Structural Biology 11(5), 601-607.
8) Dennis, J.W., Pawling, J, Cheung, P, Partridge, E, Demetriou, M. (2002). UDP-N-acetylglucosamine:alpha-6-D-mannoside beta1,6 N-acetylglucosaminyltransferase V (Mgat5) deficient mice. Biochim Biophys Acta 1573(3), 414-22.
9) 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.
10) 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.
Minireview: Stanley, P. Cell 129, 27-29 (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
Faculty of 1000: Must Read (FFa-8): Mahal L: 2007. F1000.com/1081826
Faculty of 1000: Must Read (FFa-8): Irvine K: 2007. F1000.com/1081826
11) 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.
12) 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.
13) 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.
14) 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.
15) 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.
16) 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).
17) Dennis, J.W; Nabi, I.R.; Demetriou, M. (2009). Metabolism, Cell Surface Organization and Disease. Cell 139, 1229.
18) 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).
19) Grigorian, A. and Demetriou, M. (2010). Manipulating cell surface glycoproteins by targeting N-glycan – galectin interactions. Methods in Enzymology 480 245-266.
20) 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
21) Grigorian, A. and Demetriou, M. (2011). Mgat5 deficiency in T cells and Experimental Autoimmune Encephalomyelitis ISRN Neurology 374314, 1-6 doi:10.5402/2011/374314
22) 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).
23) 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
24) Grigorian, A.; Mkhikian, H. and Demetriou, M. (2012). Interleukin-2, Interleukin-7, T cell mediated autoimmunity and N-glycosylation. New York Academy of Sciences 1253 49-57 (epub Jan 30, 2012).
25) Grigorian, A.; Mkhikian, H.; Li, C.F.; Chen, H-L; Newton, B.L.; and Demetriou, M. (2012). Pathogenesis of Multiple Sclerosis via environmental and genetic dysregulation of N-glycosylation. Seminars in Immunopathology 34 415-24. (epub April 11, 2012).
26) 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).
27) 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).
28) 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. (2013). Membrane biophysics define neuron and astrocyte progenitors in the neural lineage. Stem Cells 32 706-16.
29) 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.
30) 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. 15 218-23 (epub Feb 27 2014).
31) Zhou, R.W.; Mkhikian H; Grigorian, A.; Hong, A.; Chen, D.; Arakelyan, A. and Demetriou, M. (2014). N-glycosylation bi-directionally extends the boundaries of thymocyte positive selection by decoupling Lck from Ca2+ signaling. Nature Immunology 15 1038-45.
- #2 Trending Online paper in Nature Immunology (Oct, 2014)
- listed in ‘Most Read’ papers in Nature Immunology (Oct, 2014)
- Altmetric score: 1) ranked in the 95 percentile (ranked 6,094th) of the 123,035 tracked articles of a similar age in all journals and 2) ranked in the 88 percentile (ranked 6th) of the 51 tracked articles of a similar age in Nature Immunology.
32) Yu, Z; Demetriou, M. and Gillen, D.L. (2015). Genome-Wide Analysis of Gene-Gene and Gene-Environment Interactions Using Closed-Form Wald Tests. Genet Epidemiol. 39 446-55..
33) Mkhikian, H.; Mortales, C-L, Zhou, R; Khachikyan, K; Wu, G; Haslam, S.M.; Kavarian, P.; Dell, A. and Demetriou, M (2016). Golgi self-correction generates bioequivalent glycans to preserve cellular homeostasis. eLife 5 e14814.
34) Araujo L.; Khim, P.; Mkhikian, H.; Mortales, C-L and Demetriou, M. (2017). Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. eLife 6 e21330.
35) Tran MH; Mkhikian H; Sy M; Perez-Alvarez I; Demetriou M. (2018). Long-term plasma exchange as maintenance therapy for cerebellar-type Hashimoto's encephalopathy, a case report. 57(3) 418-420
36) Demetriou, M.; Nabi, I.R.; Dennis, J.W (2018). Galectins as Adaptors: Linking Glycosylation and Metabolism with Extracellular Cues. Trends in Glycoscience and Glycotechnology Vol. 30 (172), SE1-SE226
37) Yale AR, Nourse JL, Lee KR, Ahmed SN, Arulmoli J, Jiang AYL, McDonnell LP, Botten GA, Lee AP, Monuki ES, Demetriou M, Flanagan LA. (2018). Cell Surface N-Glycans Influence Electrophysiological Properties and Fate Potential of Neural Stem Cells. Stem Cell Reports 11, 1–14.
38) Lee, S.U., Li, C.F., Mortales, C.L., Pawling, J., Dennis, J.W., Grigorian, A., and Demetriou, M. (2019). Increasing cell permeability of N-acetylglucosamine via 6-acetylation enhances capacity to suppress T-helper 1 (TH1)/TH17 responses and autoimmunity. PLoS One 14, e0214253.
U01CA233078 NIH/NCI 9/21/18 – 8/31/23
Title: ‘N-glycosylation and immunotherapy for cancer’
Principal Investigator: Michael Demetriou
Aim: This grant aims to develop a novel class of immunotherapeutic proteins for cancer that target an N-linked carbohydrate antigen common to the vast majority of solid and hematopoietic cancers.
R01AI144403-01 NIH/NIAID 1/14/19 – 12/31/23
Title: ‘Regulation of B cell function in demyelinating disease by N-glycan branching’
Principal Investigator: Michael Demetriou
Aim: This grant examines the hypothesis that N-glycan branching serves as a critical negative regulator of pro-inflammatory innate immune activity in B cells to suppress inflammatory demyelination.
R01AT007452-01 NIH/NCCAM 6/01/14 – 5/31/20
Title: ‘Mechanisms of human immune modulation by oral N-acetylglucosamine’
Principal Investigator: Michael Demetriou
Aim: This grant examines the molecular mechanisms by which the dietary supplement N-acetylgluocosamine modulates human immune function in vitro and in vivo.
*received a perfect score of ‘10’ from the study section
R41CA233111 NIH/NCI 9/1/18 – 8/31/20
Title: ‘O-Glycan-dependent Immunotherapy for Cancer’
Principal Investigator: Michael Demetriou
Aim: This grant aims to develop a novel class of immunotherapeutic proteins for cancer that target an O-linked carbohydrate antigen common to many solid and hematopoietic cancers.
KL2 TR001416 NIH 06/30/2024-1/17/24
Title: ‘Institutional Career Development Core’
Principal Investigator (contact): Vincent Caiozzo
Co-Principal Investigator: Michael Demetriou
Aim: This grant aims to train young investigators in clinical-translational sciences.
Cellular and Molecular Biosciences
Institute for Immunology
Cancer Research Institute
Multiple Sclerosis Research Center