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Mouse pharmacogenomics

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  • 1. Towards systematic chemical genomics in mice and humans Chris Cotsapas PhD Daly Lab CHGR, MGH MPG, Broad [email_address]
  • 2. The shoulders of giants
    • MGH
      • Mai Saito
      • Mari Mino-Kenudson
    • Broad/MPG
      • Mark Daly
      • David Altshuler
      • Supriya Gupta
      • Jennifer Moran
    • Broad/ChemBio
      • Stuart Schreiber
    • Broad/BMI
      • Vamsi Mootha
      • Joel Hirschhorn
    • Broad/NT
      • Robert Gould
    • MIT
      • Sangeeta Bhatia
      • Salman Khetani
      • Steve Katz
    • Broad/Cancer
      • David Thomas
      • Todd Golub
    • Broad/SPARC
      • Patrick Kleyn
  • 3. The problem of drug toxicity
    • >2x 10 6 ADR hospitalizations in 30 years
    • Cost of millions
    • Drug development impediment
      • Vioxx, troglitazone etc etc etc
    • Genetic variation known
      • VKORC1, CYP2D6, CYP3A4, CYP3A5
    • Would be nice to know before unleashing on population!
  • 4.  
  • 5. Function of variation
    • Catalog of variation
      • HapMap
    • Lots of perturbations
      • screening libraries
    • Unified assay
      • HT, molecular... expression?
    • Lots of individuals
      • Tissue access
  • 6.  
  • 7.  
  • 8. Questions
    • Can we use mice as a pharmacogenetic discovery tool?
      • Can we identify molecular signatures of response using inbred mice?
      • Are they heritable; can we map determinants?
    • Can we recapitulate live animal responses in vitro ?
    • Can we use surrogate tissues (blood)?
  • 9. Liver and serum Drug Mouse inbred strain
  • 10. Reagents
    • APAP
    • 5-FU
    • Rapamycin
    • Lovastatin
    • Cyclopamine
    • 129S1/SvImJ
    • A/J
    • AKR/J
    • BALB/cByJ
    • C3H/HcJ
    • C57Bl/6J
    • DBA/2J
    • NOD/LtJ
  • 11. Specific Goals of Pilot
    • Phase I
      • Establish dosage levels for 5 drugs in one strain
      • Determine response variations
        • Serum biomarkers
        • Histology
        • Expression profiling
    • Phase II
      • Assay responses in 8 strains
        • Biomarkers, expression profiling, metabolite profiling
  • 12.  
  • 13.  
  • 14.  
  • 15. Specific Goals of Pilot
    • Phase I
      • Establish dosage levels for 5 drugs in one strain
      • Determine response variations
        • Serum biomarkers
        • Histology
        • Expression profiling
    • Phase II
      • Assay responses in 8 strains
        • Biomarkers, expression profiling, metabolite profiling
  • 16.  
  • 17. AST in congenic B6/A strains (Jax)‏
  • 18.  
  • 19.  
  • 20.  
  • 21.  
  • 22.  
  • 23.  
  • 24. In progress...
    • Three further strain comparisons
    • Transcriptional and metabolic profiling
    • Peripheral blood profiling
    • in vitro hepatocyte assays
  • 25.  
  • 26.  

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