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Bertus Eksteen, PhD

PSC Seed Grant Award
University of Calgary, Alberta, Canada
“Role of Glypican-6 in Primary Sclerosing Cholangitis”

Primary sclerosing cholangitis (PSC) is strongly associated with inflammatory bowel disease (IBD). Dr Eksteen proposed that this association occurs as a result of inappropriate recruitment of mucosal lymphocytes from the gut into the liver. I have shown that mucosal T cells are recruited to the liver in PSC due to aberrant expression of gut adhesion molecules but it remains unknown why some individuals with IBD develop PSC whilst others don’t. Glyplican-6 has been identified a major genetic risk factor for PSC. Glypicans act as extra-cellular scaffolds to which adhesion molecules and cytokines bind.

Hypothesis:
Genetic alterations in Glypican-6 increase its affinity to bind gut adhesion molecules and recruit mucosal T cells to the liver to perpetuate biliary inflammation.

Aims and Design:

• To define the expression of Glypican-6 in the human PSC liver. Dr Eksteen will define patterns of expression of Glypican-6 in the human PSC liver and in murine models of PSC by microscopy and qPCR of whole tissue as well as isolations of primary hepatic cells such as hepatic sinusoidal endothelium and biliary epithelium. He will treat isolated cells ex-vivo with combinations of cytokines, TLR agonists and microenvironmental factors to determine how expression of glypican-6 is regulated in the liver.
• To understand the function of wild-type and mutated Glypican-6. Dr Eksteen will breed conditional mutatedglypican-6 mice and assess homing of gut T cells to the liver in adoptive transfer studies and in the setting of experimental IBD. He will use multi-photon intra-vital microscopy to study T cell homing in vivo. He will measure the impact of mutated glypican-6 on disease severity and whether disruption of this molecule is able to ameliorate disease.
• How does mutated Glypican-6 alter the adhesion molecule milieu in the liver? He will measure if mutations in Glypican-6 alter binding affinity for adhesion molecules to explain its effects on lymphocyte recruitment and possibly persistence of mucosal T cells in the liver. This work will be done using Biacore technology and binding of I125 isotope labelled chemokines.

Expected findings:
He expects to find that genetic mutations in glypican-6 leads to an altered extracellular milieu in the liver that is permissive for gut T cells to enter the liver and cause biliary inflammation. This work would clarify if glypican-6 is a valid target for future therapeutic development.

Page updated: October 4th, 2011

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