mouse pharmacogenomics

Towards systematic chemical genomics in mice and humans

Chris Cotsapas PhDDaly Lab

CHGR, MGHMPG, Broad

chrisc@chgr.mgh.harvard.edu

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

The problem of drug toxicity

>2x106 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

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)?

Drug

Mouse inbred strain

Liver and serum

Reagents

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

Specific Goals of PilotPhase 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