Michael Demetriou
Director, National Multiple Sclerosis Society Designated Comphrehensive Care Clinic, Neurology
School of Medicine
School of Medicine
Professor, Neurology
School of Medicine
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
Ph.D., University of Toronto, 1995
FRCP (C), Royal College of Physicians and Surgeons, Canada, 2001
University of California, Irvine
208 Sprague Hall
Mail Code: 4032
Irvine, CA 92697
208 Sprague Hall
Mail Code: 4032
Irvine, CA 92697
Research Interests
Multiple Sclerosis, autoimmunity, Cancer immunotherapy, T cells, Car T cells, N-glycosylation, metabolism, glycobiology
Academic Distinctions
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
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
1996-2001: Residency in Neurology, University of Toronto, Canada
Research Abstract
My laboratory focuses on the roles of complex Asn(N)-linked glycans in cell function and disease. Our work has revealed that genetic, metabolic and environmental regulation of Golgi N-glycosylation controls macromolecular complexes on the cell surface to influence cell growth, differentiation and disease states1-4. The branching and number of N-glycans per protein 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 and humans 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. N-glycan branching deficiency also 1) reduces B cell development and central tolerance, 2) drives B cell dependent inflammatory demyelination via promotion of antigen presenting cell activity through enhanced cell surface signaling/retention of multiple Toll Like Receptors (TLRs) and 3) inhibits primary myelination and myelin repair following demyelination to prevent neuro-axonal damage via promotion of oligodendrocyte precursor cell differentiation. In humans, multiple genetic and environmental risk factors for MS converge to dysregulate N-glycan branching. Metabolically increasing N- glycan branching with the dietary supplement N-acetylglucosamine (GlcNAc) suppresses T cell growth, enhances CTLA-4 surface expression, blocks TH1/TH17 differentiation, promotes iTreg differentiation, drives myelin repair by oligodendrocyte precursor cells and inhibits MS and autoimmune diabetes models. In humans, age associated increases in GlcNAc synergizes with IL-7 signaling to trigger immune senescence in the elderly by raising N-glycan branching in naïve T cells. In multiple sclerosis patients, low levels of an endogenous marker of GlcNAc correlate with worse neurological disability and MRI imaging measures of myelin and neuro-axonal damage in MS patients. In a recently completed NIH funded open-label dose-escalation investigator-initiated mechanistic clinical trial of oral GlcNAc for 4-weeks in MS patients on glatiramer acetate and not in relapse, GlcNAc was safe, modulated N-glycan branching in lymphocytes and dose-dependently lowered multiple inflammation/neurodegeneration markers including serum IFNg, IL-17, IL-6 and neurofilament light chain (NfL), the latter a marker of ongoing neuro-axonal damage. GlcNAc treatment was also associated with confirmed improvement in clinical disability (EDSS) in 30% of patients.
In cancer, malignant transformation is near universally accompanied by aberrant changes of N- and/or O- linked glycosylation on the cell surface, driving tumor growth, and metastasis. Although these tumor associated carbohydrate antigens (TACA’s) provide an excellent target for immunotherapies for cancer, antibodies poorly bind pure glycans. In work funded by the Biden Cancer Moonshot initiative of the National Cancer Institute that is currently in revision at Cell, we developed Glycan-dependent T cell Recruiter (GlyTR) pan-cancer immunotherapeutics that utilize high-avidity ‘velcro-like’ lectin binding to target and kill cells with high but not low TACA-expression. GlyTR1 and GlyTR2 bind ß1,6GlcNAc-branched N-glycans or multiple TACA’s (Tn, sialyl- Tn , LacDiNAc, GD2), respectively, and trigger target-density dependent T cell mediated pan-cancer killing with EC50’s as low as 10 femtomolar and effector: tumor (E:T) ratio = 1:140; yet lack toxicity in mice with human-like TACA expression. The GlyTR1 bi-specific protein is undergoing IND enabling studies at the NCI Experimental Therapeutics program for a planned Phase 1 basket trial in refractory solid cancer, and similar translation of the GlyTR2 CAR T cell is pending.
In the immune system, N-glycan branching deficiency controls differentiation of thymocytes, induces T cell hyper-activity and promotes autoimmune disease in mice and humans 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. N-glycan branching deficiency also 1) reduces B cell development and central tolerance, 2) drives B cell dependent inflammatory demyelination via promotion of antigen presenting cell activity through enhanced cell surface signaling/retention of multiple Toll Like Receptors (TLRs) and 3) inhibits primary myelination and myelin repair following demyelination to prevent neuro-axonal damage via promotion of oligodendrocyte precursor cell differentiation. In humans, multiple genetic and environmental risk factors for MS converge to dysregulate N-glycan branching. Metabolically increasing N- glycan branching with the dietary supplement N-acetylglucosamine (GlcNAc) suppresses T cell growth, enhances CTLA-4 surface expression, blocks TH1/TH17 differentiation, promotes iTreg differentiation, drives myelin repair by oligodendrocyte precursor cells and inhibits MS and autoimmune diabetes models. In humans, age associated increases in GlcNAc synergizes with IL-7 signaling to trigger immune senescence in the elderly by raising N-glycan branching in naïve T cells. In multiple sclerosis patients, low levels of an endogenous marker of GlcNAc correlate with worse neurological disability and MRI imaging measures of myelin and neuro-axonal damage in MS patients. In a recently completed NIH funded open-label dose-escalation investigator-initiated mechanistic clinical trial of oral GlcNAc for 4-weeks in MS patients on glatiramer acetate and not in relapse, GlcNAc was safe, modulated N-glycan branching in lymphocytes and dose-dependently lowered multiple inflammation/neurodegeneration markers including serum IFNg, IL-17, IL-6 and neurofilament light chain (NfL), the latter a marker of ongoing neuro-axonal damage. GlcNAc treatment was also associated with confirmed improvement in clinical disability (EDSS) in 30% of patients.
In cancer, malignant transformation is near universally accompanied by aberrant changes of N- and/or O- linked glycosylation on the cell surface, driving tumor growth, and metastasis. Although these tumor associated carbohydrate antigens (TACA’s) provide an excellent target for immunotherapies for cancer, antibodies poorly bind pure glycans. In work funded by the Biden Cancer Moonshot initiative of the National Cancer Institute that is currently in revision at Cell, we developed Glycan-dependent T cell Recruiter (GlyTR) pan-cancer immunotherapeutics that utilize high-avidity ‘velcro-like’ lectin binding to target and kill cells with high but not low TACA-expression. GlyTR1 and GlyTR2 bind ß1,6GlcNAc-branched N-glycans or multiple TACA’s (Tn, sialyl- Tn , LacDiNAc, GD2), respectively, and trigger target-density dependent T cell mediated pan-cancer killing with EC50’s as low as 10 femtomolar and effector: tumor (E:T) ratio = 1:140; yet lack toxicity in mice with human-like TACA expression. The GlyTR1 bi-specific protein is undergoing IND enabling studies at the NCI Experimental Therapeutics program for a planned Phase 1 basket trial in refractory solid cancer, and similar translation of the GlyTR2 CAR T cell is pending.
Available Technologies
Publications
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.
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.
39) Annapragada A, Sikora A, Bollard C, Conejo-Garcia J, Cruz CR, Demehri S, Demetriou M, Demirdjian L, Fong L, Horowitz M, Hutson A, Kadash-Edmondson K, Kufe D, Lipkin S, Liu S, McCarthy C, Morgan M, Morris Z, Pan Y, Pasquini M, Schoenberger S, Van Allen E, Vilar E, Xing Y, Zha W; IOTN Consortium and Odunsi A.J. (2020). Cancer Moonshot Immuno-Oncology Translational Network (IOTN): accelerating the clinical translation of basic discoveries for improving immunotherapy and immunoprevention of cancer. Journal for ImmunoTherapy of Cancer 8(1), 1-9.
40) Mortales, C.L., Lee SU, and Demetriou, M. (2020). N-glycan branching is required for B cell development. Journal of Immunology 205(3):630-636. Senior and Corresponding Author.
41) Mortales CL, Lee SU, Manousadjian A, Hayama KL, Demetriou M. (2020). N-Glycan Branching Decouples B Cell Innate and Adaptive Immunity to Control Inflammatory Demyelination. iScience. 23(8):101380.
42) Bäcker-Koduah P, Infante-Duarte, C., Ivaldi, F., Uccelli, A., Bellmann-Strobl, J., Wernecke, K-D., Sy, M., Demetriou, M., Dörr, J., Paul, F., Brandt, A.U. (2020). Effect of vitamin D supplementation on N-glycan branching and cellular immunophenotypes in MS. Annals of Clinical and Translational Neurology. (ePub Aug 23, 2020).
43) Sy, M; Brandt, A.U.; Lee, S-U; Newton, B; Pawling, Golzar, A.; Rahman, A.; Yu, Z.; Cooper, G.; Scheel, M.; Paul, F.; Dennis, J.W. and Demetriou, M. (Dec 18, 2020). N-Acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation. Journal of Biological Chemistry.
#1 most read research paper in the J. Biol. Chem. Fall 2020.
44) Brandt AU, Sy M, Bellmann-Strobl J, Newton BL, Pawling J, Zimmermann HG, Yu Z, Chien C, Dörr J, Wuerfel JT, Dennis JW, Paul F, Demetriou M. (2021). Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration. JAMA Neurology 2021;78(7):842-852.
Altmetric score 166: In the top 2% of tracked articles of a similar age.
45) Mkhikian, H.; Sy, M; Dennis, J.W. and Demetriou, M. (2021). The galectin-lattice: a decoder of bio-equivalent glycans. Glycoforum Vol.24 (4), A10.
46) McKitrick TR, Ackerman ME, Anthony RM, Bennett CS, Demetriou M, Hudalla GA, Ribbeck K, Ruhl S, Woo CM, Yang L, Zost SJ, Schnaar RL, Doering TL. (2021). The Crossroads of Glycoscience, Infection and Immunology. Frontiers in Microbiology. 12:731008.
47) Mkhikian, H.; Hayam, K.; Khachikyan, K; Li, C-F.; Zhou, R; Pawling, J; Klaus, S.; Tran, PQN; Ly, KM; Gong,A.; Saryan, H.; Hai, JL; Grigoryan, D.; Lee, PL; Newton, BL; Raffatellu, BL; Dennis, JW and Demetriou, M (March 2022). Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching. Nature Aging 2, 231–242.
- News and Views: McGill, C.J.; Benayoun, B.A. (2022). Time isn’t kind to female T cells. Nature Aging 2 189-191
- Altmetric score 127: In the top 3% of tracked articles of a similar age.
48) Mkhikian, H. and Demetriou, M (2022). T cell senescence by N-glycan branching. Aging 14(15): 5964-5965 (epub Aug 13, 2022).
49) Annapragada, A.; Sikora, A.; Marathe, H.; Liu, S.; Demetriou, M; Fong, L.; Gao, J., Kufe, D.; Morris, Z.; Vilar-Sanchez, E.; Sei, S.; Sharon, E.; Hutson, A.; Odunsi, K. (2023). The Cancer Moonshot Immuno-Oncology Translational Network (IOTN) at age 5: accelerating cancer immunotherapies. Journal of the National Cancer Institute 115(11) 1262-1270 (epub Aug 12, 2023).
50) Sy, M; Newton, B; Pawling, J; Hayama, K.L.; Cordon, A.; Yu, Z.; Kuhle, J.; Dennis, J.W.; Brandt, A.U. and Demetriou, M. (2023). N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic study. Journal of Neuroinflammation 20, 209 1-14.
- Altmetric score 118: In the top 2% of tracked articles of a similar age.
51) Mkhikian, H.; Hayam, K.; Zhou, R; Saryan, H.; Dang, J.; Li, C-F.; and Demetriou, M (2024). Journal of Immunology (in press).
40) Mortales, C.L., Lee SU, and Demetriou, M. (2020). N-glycan branching is required for B cell development. Journal of Immunology 205(3):630-636. Senior and Corresponding Author.
41) Mortales CL, Lee SU, Manousadjian A, Hayama KL, Demetriou M. (2020). N-Glycan Branching Decouples B Cell Innate and Adaptive Immunity to Control Inflammatory Demyelination. iScience. 23(8):101380.
42) Bäcker-Koduah P, Infante-Duarte, C., Ivaldi, F., Uccelli, A., Bellmann-Strobl, J., Wernecke, K-D., Sy, M., Demetriou, M., Dörr, J., Paul, F., Brandt, A.U. (2020). Effect of vitamin D supplementation on N-glycan branching and cellular immunophenotypes in MS. Annals of Clinical and Translational Neurology. (ePub Aug 23, 2020).
43) Sy, M; Brandt, A.U.; Lee, S-U; Newton, B; Pawling, Golzar, A.; Rahman, A.; Yu, Z.; Cooper, G.; Scheel, M.; Paul, F.; Dennis, J.W. and Demetriou, M. (Dec 18, 2020). N-Acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation. Journal of Biological Chemistry.
#1 most read research paper in the J. Biol. Chem. Fall 2020.
44) Brandt AU, Sy M, Bellmann-Strobl J, Newton BL, Pawling J, Zimmermann HG, Yu Z, Chien C, Dörr J, Wuerfel JT, Dennis JW, Paul F, Demetriou M. (2021). Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration. JAMA Neurology 2021;78(7):842-852.
Altmetric score 166: In the top 2% of tracked articles of a similar age.
45) Mkhikian, H.; Sy, M; Dennis, J.W. and Demetriou, M. (2021). The galectin-lattice: a decoder of bio-equivalent glycans. Glycoforum Vol.24 (4), A10.
46) McKitrick TR, Ackerman ME, Anthony RM, Bennett CS, Demetriou M, Hudalla GA, Ribbeck K, Ruhl S, Woo CM, Yang L, Zost SJ, Schnaar RL, Doering TL. (2021). The Crossroads of Glycoscience, Infection and Immunology. Frontiers in Microbiology. 12:731008.
47) Mkhikian, H.; Hayam, K.; Khachikyan, K; Li, C-F.; Zhou, R; Pawling, J; Klaus, S.; Tran, PQN; Ly, KM; Gong,A.; Saryan, H.; Hai, JL; Grigoryan, D.; Lee, PL; Newton, BL; Raffatellu, BL; Dennis, JW and Demetriou, M (March 2022). Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching. Nature Aging 2, 231–242.
- News and Views: McGill, C.J.; Benayoun, B.A. (2022). Time isn’t kind to female T cells. Nature Aging 2 189-191
- Altmetric score 127: In the top 3% of tracked articles of a similar age.
48) Mkhikian, H. and Demetriou, M (2022). T cell senescence by N-glycan branching. Aging 14(15): 5964-5965 (epub Aug 13, 2022).
49) Annapragada, A.; Sikora, A.; Marathe, H.; Liu, S.; Demetriou, M; Fong, L.; Gao, J., Kufe, D.; Morris, Z.; Vilar-Sanchez, E.; Sei, S.; Sharon, E.; Hutson, A.; Odunsi, K. (2023). The Cancer Moonshot Immuno-Oncology Translational Network (IOTN) at age 5: accelerating cancer immunotherapies. Journal of the National Cancer Institute 115(11) 1262-1270 (epub Aug 12, 2023).
50) Sy, M; Newton, B; Pawling, J; Hayama, K.L.; Cordon, A.; Yu, Z.; Kuhle, J.; Dennis, J.W.; Brandt, A.U. and Demetriou, M. (2023). N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic study. Journal of Neuroinflammation 20, 209 1-14.
- Altmetric score 118: In the top 2% of tracked articles of a similar age.
51) Mkhikian, H.; Hayam, K.; Zhou, R; Saryan, H.; Dang, J.; Li, C-F.; and Demetriou, M (2024). Journal of Immunology (in press).
Grants
U01CA233078 NIH/NCI 9/21/18 – 8/31/24
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 – 12/31/24
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 – 8/31/21
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.
DISC2-13507 CIRM 9/1/22 – 8/31/24
Title: ‘CAR T cells targeting abnormal N-glycans for the treatment of refractory/metastatic solid
cancers’ Principal Investigator: Michael Demetriou. Aim: This grant aims to develop a novel genetically engineered Chimeric Antigen Receptor (CAR) T cell capable of killing highly diverse solid cancers by targeting abnormal N-glycans.
R41CA261408 NIH/NCI 07/1/21-6/30/24
Title: Cancer Immunotherapy Targeting Tn Antigen
Principal Investigator: Michael Demetriou
Aim: This grant aims to develop immunotherapeutic proteins targeting Tn antigen in cancer.
R42CA285234 NCI/NIH 9/21/23 – 8/31/26
Title: “Extended half-life GlyTR1 combined with checkpoint blockade for Cancer” Immunotherapy.
Principal Investigator: Michael Demetriou
Aim: To develop a longer half-life version of the GlyTR1 protein targeting an abnormal N-linked glycan on cancer and assess potential additive/synergistic activity with checkpoint inhibitors.
NCI Experimental Therapeutics program 11/1/22 – present
Title: “Immunotherapy Targeting Abnormal N-glycans for Solid Cancer”
Principal Investigator: Michael Demetriou
Aim: Using NCI facilities, the NCI Experimental therapeutics program will carryout clinical-grade GMP manufacturing, IND enabling studies and assist with IND submission of the GlyTR1 immunotherapeutic protein that has pan-cancer killing activity via targeting an abnormal N-linked carbohydrate antigen.
Graduate Programs
Cellular and Molecular Biosciences
Neurology
Research Centers
Institute for Immunology
Cancer Research Institute
Multiple Sclerosis Research Center
Link to this profile
https://faculty.uci.edu/profile/?facultyId=5788
https://faculty.uci.edu/profile/?facultyId=5788
Last updated
10/01/2024
10/01/2024