Towards systematic chemical genomics in mice and humans Chris Cotsapas PhD Daly Lab CHGR, MGH MPG, Broad [email_address]
The shoulders of giants <ul><li>MGH </li></ul><ul><ul><li>Mai Saito </li></ul></ul><ul><ul><li>Mari Mino-Kenudson </li></u...
The problem of drug toxicity <ul><li>>2x 10 6  ADR  hospitalizations in 30 years </li></ul><ul><li>Cost of millions </li><...
 
Function of variation <ul><li>Catalog of variation </li></ul><ul><ul><li>HapMap  </li></ul></ul><ul><li>Lots of perturbati...
 
 
Questions <ul><li>Can we use mice as a pharmacogenetic discovery tool? </li></ul><ul><ul><li>Can we identify molecular sig...
Liver and serum Drug Mouse inbred strain
Reagents <ul><li>APAP </li></ul><ul><li>5-FU </li></ul><ul><li>Rapamycin </li></ul><ul><li>Lovastatin </li></ul><ul><li>Cy...
Specific Goals of Pilot <ul><li>Phase I </li></ul><ul><ul><li>Establish dosage levels for 5 drugs in one strain </li></ul>...
 
 
 
Specific Goals of Pilot <ul><li>Phase I </li></ul><ul><ul><li>Establish dosage levels for 5 drugs in one strain </li></ul>...
 
AST in congenic B6/A strains (Jax)‏
 
 
 
 
 
 
In progress... <ul><li>Three further strain comparisons </li></ul><ul><li>Transcriptional and metabolic profiling </li></u...
 
 
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Mouse pharmacogenomics

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Mouse pharmacogenomics

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

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