Claims
- 1. A transgenic mouse expressing a human CAR receptor.
- 2. The transgenic mouse of claim 1, wherein said transgenic mouse does not express a substantially active murine CAR receptor.
- 3. A mouse comprising a mutation that reduces CAR receptor activity.
- 4. The mouse of claim 3, wherein said mouse is a transgenic mouse.
- 5. The mouse of claim 3, wherein said mutation substantially eliminates CAR receptor activity.
- 6. 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.
- 7. The method of claim 6, wherein step (a) further comprises administering a CAR receptor inverse agonist to said mouse expressing said human CAR receptor.
- 8. The method of claim 7, wherein said CAR receptor inverse agonist is clotrimazole.
- 9. 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.
- 10. The method of claim 9, wherein step (a) further comprises administering a CAR receptor agonist to said mouse expressing said human CAR receptor.
- 11. The screening method of claim 10, wherein said CAR receptor agonist is administered after said compound.
- 12. 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.
- 13. The method of claim 12, wherein said measuring said physiological effect comprises measuring the toxicity or activity mediated by the administration of said compound or measuring the half-life of said compound.
- 14. The method of claim 13, wherein said toxicity or activity is mediated by a metabolite of said compound.
- 15. 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.
- 16. The method of claim 15, wherein said measuring said rate of metabolism comprises measuring the toxicity or activity mediated by the administration of said compound, measuring the half-life of said compound, or measuring the serum level of a liver enzyme.
- 17. 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.
- 18. The method of claim 17, wherein said measuring said physiological effect comprises measuring the toxicity or activity mediated by the administration of said first compound or measuring the half-life of said first compound.
- 19. The method of claim 18, wherein said toxicity or activity is mediated by a metabolite of said first compound.
- 20. The method of claim 18, wherein step (b) comprises measuring the half-life of said first compound in the presence and absence of said second compound, whereby said second compound is determined to activate the metabolism of said first compound if said second compound decreases said half-life, or said second compound is determined to inhibit the metabolism of said first compound if the said second compound increases said half-life.
- 21. The method of claim 6, 9, 12, 15, or 17, wherein said mouse expressing said human CAR receptor does not express a substantially active murine CAR receptor.
- 22. 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.
- 23. The method of claim 22, wherein step (a) further comprises administering a CAR receptor inverse agonist to said mouse comprising said mutation.
- 24. The method of claim 23, wherein said CAR receptor inverse agonist is androstanol.
- 25. 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.
- 26. The method of claim 25, wherein step (a) further comprises administering a CAR receptor agonist to said mouse comprising said mutation.
- 27. The method of claim 26, wherein said CAR receptor agonist is TCPOBOP, and said TCPOBOP is administered after said compound.
- 28. 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.
- 29. The method of claim 28, wherein said measuring said physiological effect comprises measuring the toxicity or activity mediated by the administration of said compound or measuring the half-life of said compound.
- 30. The-method-of claim 29, wherein said toxicity or activity-is mediated by a metabolite of said compound.
- 31. 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.
- 32. The method of claim 31, wherein said measuring said rate of metabolism comprises measuring the toxicity or activity mediated by the administration of said compound, measuring the half-life of said compound, or measuring the serum level of a liver enzyme.
- 33. 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.
- 34. The method of claim 33, wherein said measuring said physiological effect comprises measuring the toxicity or activity mediated by the administration of said first compound or measuring the half-life of said first compound.
- 35. The method of claim 34, wherein said toxicity or activity is mediated by a metabolite of said first compound.
- 36. The method of claim 34, wherein step (b) comprises measuring the half-life of said first compound in the presence and absence of said second compound, whereby said second compound is determined to activate the metabolism of said first compound if the decrease in said half-life effected by said second compound is smaller in said mouse comprising said mutation than in a mouse having wild-type CAR receptor activity, or said second compound is determined to inhibit the metabolism of said first compound if the increase in said half-life effected by said second compound is smaller in said mouse comprising said mutation than in a mouse having wild-type CAR receptor activity.
- 37. The method of claim 22, 25, 28, 31, or 33, wherein said mouse is a transgenic mouse.
- 38. The method of claim 22, 25, 28, 31, or 33, wherein said mutation substantially eliminates CAR receptor activity.
- 39. The method of claim 6, 15, 22, or 31, wherein said compound is eliminated from drug development.
- 40. The method of claim 17 or 33, wherein said first compound activates the metabolism of said second compound, and said first compound or said second compound is eliminated from drug development.
- 41. The method of claim 6, 9, 22, or 25 wherein said CAR target gene is CYP2B10 or CYP2B6.
- 42. The method of claim 6, 9, 12,15,17, 22, 25, 28, 31, or 33, wherein at least one of said compound, said first compound, or said second compound is a member of a library of at least 5 compounds, all of which are simultaneously administered to said mouse comprising said mutation or said mouse expressing said human CAR receptor.
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
[0001] This invention was made with government support under NIH grant NIDDK RO1 DK46546. The government therefore has certain rights in the invention.
Continuations (1)
|
Number |
Date |
Country |
Parent |
09666250 |
Sep 2000 |
US |
Child |
10219590 |
Aug 2002 |
US |