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Project no: GRS-011/04
Amount of funding: CHF 334'000
Duration: 09.2004 - 10.2007
Area of activity: Pilotprojekte, 1998 - 2018
Prof. Igor Stagljar
University of Toronto
Donnelly Centre for Cellular and Biomolecular Research (CCBR)
1 Kings College Circle
CA Toronto ON (Kanada, M5S 1A8)
- igor.stagljar@utoronto. ca
The parasite pasmodium falciparum causes the most severe form of human malaria with over 2 Mio. deaths per year. The project aims at developing an in vivo gentetic approach in yeast to characterize plasmodium falciparum proteins with their particular human transmembrane receptor in order to develop a yeast-based drug discovery assay.
The project will extend the application of the modified Membrane Yeast Two-Hybrid (MYTH) technology to identify a receptor/ligand interaction from any model organism and will establish the MYTH as a tool for drug discovery. The novel approach is effective since it’s unconventional, cheap (uses yeast as model organism) and fast (yeast is amenable to high-throughput applications).
What is special about the project?
The financial support of Gebert Rüf Stiftung will be used as an initial finance for this applied and interdisciplinary project with a possible commercial application. It is unique since the MYTH technology (patented in the research group) is the only technology that can be used to detect interactions between membrane proteins using a screening format in vivo.
We constructed a new plasmid vectors for expression of Plasmodium falciparum EBA-175 peptide ligand and human glycophorin A receptor in yeast. In addition, we successfully expressed the human glycophorin A receptor in the yeast plasma membrane and reconstituted the EBA-175/glcophorin A interaction using the modified MYTH system. We are currently setting up of the “reverse MYTH“ system to screen and identify compounds of therapeutical value that inhibit the EBA-175 ligand/glycophorin A receptor interaction.
Furthermore, we used a novel version of MYTH technology (called iMYTH) to identify six novel interactors of the yeast ABC transporter Ycf1p, a yeast homolog of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which, when disabled by mutation, causes cystic fibrosis, a hereditary disease that results in progressive disability and early death. These newly discovered protein interactors represent novel potential pharmaceutical targets. Through a series of biochemical and genetic tests, we discovered that one of these interactors, Tus1p, regulates Ycf1p transporter function in a completely novel way to stimulate its ability to remove toxins from the cell.
Last update to this project presentation 21.12.2018