Towards systematic chemical genomics in mice and humans Chris Cotsapas PhD Daly Lab CHGR, MGH MPG, Broad [email_address]

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

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

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!

>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!

Function of variation Catalog of variation HapMap Lots of perturbations screening libraries Unified assay HT, molecular... expression? Lots of individuals Tissue access

Catalog of variation

HapMap

Lots of perturbations

screening libraries

Unified assay

HT, molecular... expression?

Lots of individuals

Tissue access

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)?

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)?

Liver and serum Drug Mouse inbred strain

Reagents APAP 5-FU Rapamycin Lovastatin Cyclopamine 129S1/SvImJ A/J AKR/J BALB/cByJ C3H/HcJ C57Bl/6J DBA/2J NOD/LtJ

APAP

5-FU

Rapamycin

Lovastatin

Cyclopamine

129S1/SvImJ

A/J

AKR/J

BALB/cByJ

C3H/HcJ

C57Bl/6J

DBA/2J

NOD/LtJ

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

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

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

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

AST in congenic B6/A strains (Jax)‏

In progress... Three further strain comparisons Transcriptional and metabolic profiling Peripheral blood profiling in vitro hepatocyte assays

Three further strain comparisons

Transcriptional and metabolic profiling

Peripheral blood profiling

in vitro hepatocyte assays