MAY 22, 2018 08:00 AM PDT
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Drug development with nuclear receptor knockout and humanized rat models
SPONSORED BY: Horizon Discovery
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  • Manager, In Vivo Research and Development , Horizon Discovery
      Kevin joined Horizon Discovery in 2014 during the acquisition of SAGE Labs (Sigma-Aldrich Genetic Engineering Labs). During his time in the in vivo group in St. Louis, MO USA, he has worked on developing and implementing gene editing technologies (CRISPR/Cas9 and ZFNs) for animal model generation. His primary focus has been rat ADME/TOX models for drug development. Specifically, nuclear receptor and P450 gene knock-outs and humanized rat models. Prior to SAGE Labs, Kevin was the R&D lead for micro-RNA product development at Sigma-Aldrich.

      Kevin was a USDA post-doctoral fellow at the University of South Carolina and holds a PhD from the University of Kentucky in Plant Physiology.


    DATE: May 22, 2018

    TIME: 08:00AM PDT


    The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of Phase I (Cytochrome P450s), Phase II drug metabolizing enzymes and drug transporter genes in response to stimulation from xenobiotics including prescription drugs . PXR and CAR knockout and humanized mouse models have proven useful. However, the rat being bigger in size, is a preferred model system for studying drug metabolism and pharmacokinetics. Here, we report the creation and preliminary characterization of PXR and CAR knockout rats and PXR/CAR double knockout rats. Whereas the expression of phase I and II enzymes and transporter genes were not upregulated by nuclear receptor-specific agonists in the knockout rats, confirming the disruption of respective nuclear receptor(s). Our data demonstrate that PXR appears to suppress the basal expression levels of specific drug metabolism genes, while CAR maintains and suppresses other drug metabolism genes. Overall, our findings are in good agreement with data obtained from human primary hepatocytes, nuclear receptor knock-out cell lines and mouse knock-out models. We believe these models are a useful complement to their mouse counterparts for drug development and as importantly, for functional studies on metabolic pathways involving nuclear receptors. 


    Learning Objectives:

    • Understand the benefit of rat models versus mouse models in functional studies on metabolic pathways
    • Demonstrate the utility of the PXR and CAR KO rat models
    • How rat hepatocytes can add value to drug development studies

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