*HENRY KRAUSE

Zebrafish High Throughput Screening Platforms for Nuclear Receptor-Related Drug Discovery and Pathway Elucidation

Challenge: With the unique property of nuclear receptors (NRs) to directly interact with genomic DNA and control the expression of genes, nuclear receptors play key roles in both embryonic development and adult homeostasis as well as in many diseases. With a total of 48 different human receptors and 6 epigenetic-regulating cofactors identified, the is still no available screening platform that covers the whole spectrum of this diverse family of receptors. Hence, although they represent a key biological target class, they are still not fully harnessed to treat diseases.

Solution: Building on the success of the first project, the team pursued the characterization of its zebrafish platform to study the human nuclear receptors and epigenetic-regulating cofactors, providing highly cost-effective, accurate high throughput screening for NR-targeted drug discovery. Embryos from these fish are collected by the thousands and rapidly screened against an equal number of drug candidates. Active compounds cause the fish to glow green in responding tissues, and directly acting molecules or metabolites can then be co-purified and identified.

Achievement/impact: The team developed 46 transgenic zebrafish lines, including 40 lines that showed clear ligand-dependant responses. Among those, 32 nuclear receptor activator lines showed clear GFP responses, while 4 repressor lines were validated. The researchers were able to identify several endogenous receptor ligands. The team also screened 8 zebrafish lines with small-molecule libraries and identified around 100 hits. Fish and mouse models of obesity, diabetes and fatty liver were also established and tested, as well as a fish model for inflammation. The project led to the creation of OrpheX Inc, a new start-up devoted to exploit zebrafish transgenic lines implicated in some behavioral disorders. OrpheX has already filled a patent based on the results obtained with one of these lines.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Principal Investigators:


Henry Krause
University of Toronto/
InDanio Bioscience

Co-investigators

Jens Tiefenbach
InDanio Bioscience

Vincent Giguère
McGill University

Completed Projet
$1,000,000/ 2.5 years
Supported by CQDM through:
• Merck
• Pfizer
• MEI
 
And by co-funding partners :
• CIHR
• InDanio Bioscience