Screening systems and methods for identifying modulators of xenobiotic metabolism
AssigneeBaylor College of Medicine
InventorsDavid D. Moore, Ping Wei, Steven S. Chua
Life of this patent
Estimating the term…
Abstract
The present invention provides mice having reduced CAR receptor activity and mice expressing a human CAR receptor. These mice are useful in screening methods to identify CAR ligands, including compounds that modulate CAR receptor activity, compounds likely to have CAR-mediated toxicity, and analogs of these compounds with less potential toxicity.
Claims65
A transgenic mouse expressing a human CAR receptor.
A transgenic mouse expressing a human CAR receptor, wherein said transgenic mouse exhibits an induction of a xenobiotic response in the presence of a xenobiotic inducer.
A transgenic mouse comprising a mutation in a CAR gene, wherein said comprises a reduction or absence of CAR receptor activity.
A screening method for determining whether a compound activates a CAR receptor, said method comprising the steps of:
- (a) administering a compound to a transgenic mouse expressing a human CAR receptor;
- and
- (b) measuring induction of a CAR target gene, whereby said compound is determined to activate said CAR receptor if said compound mediates induction of said CAR target gene.
A screening method for determining whether a compound inhibits a CAR receptor, said method comprising the steps of:
- (a) administering said compound to a transgenic mouse expressing a human CAR receptor;
- and
- (b) measuring expression of a CAR target gene in the presence and absence of said compound, whereby said compound is determined to inhibit said CAR receptor if said compound decreases said expression of said CAR target gene.
A screening method for determining whether a compound modulates the activity of a CAR receptor, said method comprising the steps of:
- (a) administering said compound to a transgenic mouse expressing a human CAR receptor;
- and
- (b) measuring a physiological effect mediated by the administration of said compound, whereby said compound is determined to modulate the activity of said CAR receptor if the magnitude of said physiological effect in said mouse expressing said human receptor differs from that in a mouse comprising a mutation that reduces CAR receptor activity.
A screening method for determining whether the metabolism of a compound is regulated by modulation of the activity of a CAR receptor, said method comprising the steps of:
- (a) administering said compound to a transgenic mouse expressing a human CAR receptor;
- and
- (b) measuring the rate of metabolism of said compound, whereby said metabolism of said compound is determined to be regulated by modulation of the activity of said CAR receptor if said rate of metabolism is faster in said mouse expressing said human receptor than in a mouse comprising a mutation that reduces CAR receptor activity.
A screening method for determining whether the metabolism of a first compound is modulated by a second compound, said method comprising the steps of:
- (a) administering said first compound in the presence and absence of said second compound to a transgenic mouse expressing a human CAR receptor;
- and
- (b) in the presence and absence of said second compound, measuring a physiological effect that is mediated by the administration of said first compound, whereby said second compound is determined to modulate the metabolism of said first compound if said second compound effects a change in said physiological effect mediated by said administration of said first compound.
A screening method for determining whether a compound activates a CAR receptor, said method comprising the steps of:
- (a) administering a compound to a mouse, said mouse comprising a mutation that reduces CAR receptor activity;
- and
- (b) measuring induction of a CAR target gene, whereby said compound is determined to activate said CAR receptor if said induction is smaller in said mouse comprising said mutation than in a mouse having wild-type CAR receptor activity.
A screening method for determining whether a compound inhibits a CAR receptor, said method comprising the steps of:
- (a) administering said compound to a mouse, said mouse comprising a mutation that reduces CAR receptor activity;
- and
- (b) measuring expression of a CAR target gene in the presence and absence of said compound, whereby said compound is determined to inhibit said CAR receptor if the decrease in said expression effected by said compound is smaller in said mouse comprising said mutation than in a mouse having wild-type CAR receptor activity.
A screening method for determining whether a compound modulates the activity of a CAR receptor, said method comprising the steps of:
- (a) administering said compound to a mouse, said mouse comprising a mutation that reduces CAR receptor activity;
- and
- (b) measuring a physiological effect mediated by the administration of said compound, whereby said compound is determined to modulate the activity of said CAR receptor if the magnitude of said physiological effect in said mouse comprising said mutation differs from that in a mouse having wild-type CAR receptor activity.
A screening method for determining whether the metabolism of a compound is regulated by modulation of the activity of a CAR receptor, said method comprising the steps of:
- (a) administering said compound to a mouse, said mouse comprising a mutation that reduces CAR receptor activity;
- and
- (b) measuring the rate of metabolism of said compound, whereby said metabolism of said compound is determined to be regulated by modulation of the activity of said CAR receptor if said rate of metabolism is slower in said mouse comprising said mutation than in a mouse having wild-type CAR receptor activity.
A screening method for determining whether the metabolism of a first compound is modulated by a second compound, said method comprising the steps of:
- (a) administering said first compound in the presence and absence of said second compound to a mouse, said mouse comprising a mutation that reduces CAR receptor activity;
- and
- (b) in the presence and absence of said second compound, measuring a physiological effect that is mediated by the administration of said first compound, whereby said second compound is determined to modulate the metabolism of said first compound if the change effected by said second compound in said physiological effect mediated by said administration of said first compound is smaller in said mouse comprising said mutation than in a mouse having wild-type CAR receptor activity.
Dependencies are inferred from the claim text.