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Lingwood Lab

Research interests

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Our main research focus concerns the role of the glycosphingolipid (GSL), globotriaosyl ceramide (Gb3) in verotoxin (VT) induced pathology. This E.coli toxin is the major cause of (potentially fatal) acute paediatric renal failure. The lipid moiety of Gb3 and its membrane environment affect its receptor function. VT1 and VT2 preferentially bind different Gb3 lipid isoforms, differentially organized within lipid 'rafts' on the cell surface to mediate initial differential intracellular trafficking, which coalesces within the Golgi and the endoplasmic reticulum (ER) for cytosolic VT A subunit translocation to inhibit protein synthesis. We have designed soluble analogues of Gb3 and other GSLs, which provide powerful tools to alter both these pathways and cellular GSL metabolism to protect against these toxins. The drug resistance efflux pump, MDR1, plays an important role in GSL biosynthesis to translocate precursor GSLs in to the Golgi. MDR1 inhibition provides new approaches to the substrate reduction therapy of GSL Lysosomal Storage Diseases.

The study of VT/Gb3 binding provides new insight into the biophysics of membrane lipid domain organization which define intracellular signaling pathways and vesicular trafficking routes. Gb3 is upregulated in many human tumours and their neovasculature (see picture-VT1 [red] and blood vessel marker, factor 8 [green] co-labeling), particularly drug resistant variants. VT1 represents a novel antineoplastic approach in such cases. Our studies are directed to make this a clinical reality.

Our studies show the HIV adhesin, gp120, binds Gb3 and indicate Gb3 provides resistance against HIV infection. Gb3 is the Pk antigen in the P blood group series which may define a new host risk factor for this infection and a new therapeutic target.

The binding of hsp70 family members to GSLs and our design of soluble GSL mimics allow modulation of chaperone function for potential therapeutic benefit in protein folding diseases, such as cystic fibrosis.

Publications

De Rosa M, Binnington B, Ackerley C, Wang B, Ito S, Clarke DM, Lingwood CA. Inhibition of Multidrug Resistance Protein 1 (MDR1) by AdamantylGb3, a globotriaosylceramide analog. J Biol Chem 283 (7): 4501-4511(2008).

Lund N, Branch DR, Mylvaganam M, Chark D, Ma X-Z, Sakac D, Binnington B, Fantini J, Puri A, Blumenthal R, Lingwood CA. A novel soluble mimic of the glycolipid, globotriaosyl ceramide inhibits HIV infection AIDS 20:1-11, [2006]

Keywords

  • Hemolytic uremic syndrome
  • retrograde transport
  • glycolipid trafficking
  • glycolipid synthesis

Primary University of Toronto appointment

  • Department of Laboratory Medicine and Pathobiology
  • Cross appointment Department of Biochemistry