Clifford Lingwood
PhD
1971: B.Sc. Hull University, Joint Honours - Biochemistry and Zoology
1974: Doctor of Philosophy; Cell Biology, University of London, England "Studies of the Division of Cycle of a Murine Tumour in vitro". Supervisor: D.B. Thomas, Supervisor
1977: Visiting Scientist, Department of Biochemical Oncology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Supervisor: Dr. S. Hakomori
1977-1980: Research Fellow, Department of Biochemistry, University of Toronto. Supervisor: Dr. H. Schachter
1981: Appointed to Hospital for Sick Chlldren
Research Synopsis
Our laboratory studies the functional role of glycosphingolipids in cell physiology and disease pathology.
Abnormal GSL metabolism is associated with many human diseases and major aspects of their metabolism remain undefined.
The glycolipid, globotriaosyl ceramide (Gb3), is the receptor for the Verotoxin (Shiga toxin) family of E. coli toxins responsible for periodic diarrhea outbreaks and the more serious hemolytic uremic syndrome (HUS), a potentially fatal renal disease, to which children are particularly susceptible.
Our studies on the metabolism of Gb3, it’s isoform distribution and defining binding partners and trafficking within cells are targeted towards development of a therapeutic for HUS.
We have also defined Gb3 as a natural resistance factor against HIV infection.
We have designed soluble Gb3 drug like analogues and study the mechanism of these novel therapeutics against HIV infection.
The GSL binding site on the HIV adhesin, Gp120 partially overlaps with that of the chemokine co-receptor. Defining the mechanism of inhibition is key to the design of more effective inhibitors.
The physical association of GSLs with membrane cholesterol results in their reduced availability for ligand binding.
The role of cholesterol in receptor function of GSLs and in GSL metabolism is currently under investigation.
GSLs may be utilized to advantage to control endoplasmic reticulum associted degradation of misfolded proteins.
Recent Publications
Anton Novak, Bo Ngan, Clifford A. LINGWOOD Cholesterol masking membrane glycosphingolipid tumor-associated antigens may allow tumors to evade immunosurveillance. Glycobiology 23: 1230-9 (2013).
Mitsumasa Saito, Murugespillai Mylvaganum, Patty Tam, Anton Novak, Beth Binnington and Clifford LINGWOOD. Structure-dependent pseudoreceptor intracellular traffic of adamantyl globotriaosyl ceramide mimics. J Biol Chem 287: 16073-87 (2012).
Mustafa Kamani, Murugespillai Mylvaganum, Robert Tian, Beth Binnington and Clifford LINGWOOD Adamantyl glycosphingolipids provide a new approach to the selective regulation of cellular glycosphingolipid metabolism. J Biol Chem 286 (24) :21413-26 (2011)
Lingwood,D, Binnington,B, Róg,T., Vattulainen,I., Grzybek,M., Coskun,U., LINGWOOD,C., Simons,K. Cholesterol modulates glycolipid conformation and receptor activity. Nature Chem Biol. 7:260-2, (2011)
Radhia Mahfoud, Adam Manis, Cameron Ackerley and Clifford A LINGWOOD A major fraction of glycosphingolipids in model and cellular cholesterol-containing membranes is undetectable by their binding proteins. J. Biol Chem 285 (46):36049-59 (2010).
Nicole Lund, Martin L. Olsson, Stephanie Ramkumar, Darinka Sakac, Vered Yahalom, Cyril Levene, Asa Hellberg, Xue-Zhong Ma, Beth Binnington, Daniel Jung, Clifford A. LINGWOOD and Donald R. Branch.. The Human Pk Blood Group Antigen Provides Protection Against HIV-1 Infection. Blood 113:4980-91 (2009).
Mahfoud, R., Manis, A., Clifford A. LINGWOOD. Fatty acid-dependent globotriaosyl ceramide receptor function in detergent resistant model membranes J Lip Res 50:1744-1755, (2009).
Yonekawa,S., LINGWOOD,C.A. andMylvaganum, M. Oxidation of the primary hydroxyl group of galactose of galactaosyl ceramide analogue by chemical method-Precursors for the synthesis of labeled conjugates. Carbohydrate Res 344:501-6 (2009).