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Pharmacogenomics of Membrane Transporters (PMT)
Deanna L. Kroetz, Sook Wah Yee and Kathleen M. Giacomini
University of California San Francisco, San Francisco, CA
Computational and Functional Genomics Projects
Overview
• The
Pharmacogenomics
of
Membrane
Transporters (PMT) group will extend the
multidisciplinary research project focused on
membrane
transporters
that
are
major
determinants of the absorption, distribution and
elimination of many clinically used drugs.
• The two major superfamilies under study are the
SoLute Carrier Superfamily (SLC) and the ATP
Binding Cassette Superfamily (ABC).
• The primary goal of our studies is to develop a
comprehensive functional map of genetic variants
in the two superfamilies.
Populations We Are Studying
• AIM 1: (i) Identify and functionally characterize regulatory regions of membrane transporter genes; and (ii)
Characterize variants identified in regulatory regions.
• AIM 2: Associate sequence variants with membrane transporter expression levels in liver and kidney samples.
• AIM 3: Define the substrate specificity of ABC and SLC membrane transporters and develop predictive models for
substrate-dependent effects of nonsynonymous variants.
Identify and characterize
regulatory non-coding
regions, e.g. evolutionary
conserved region (ECR), 3’UTR.
1.Search transporter
template.
Using liver and/or kidney
tissues to validate the effect
of the functional SNPs with
transporter expression level.
2.Construct and assess
model
3. Define substrate
specificity.
4. Develop predictive
models for substratedependent effects of
nonsynonymous
variants.
• Study of PHarmacogenetics In Ethnically Diverse
Populations (SOPHIE). Healthy subjects (18-40 yrs).
• Four Ethnic Groups: African American, Chinese
American, European American and Mexican American
• Human Liver and Kidney Tissue Banks.
• Samples from Metformin and Large Collaborative Studies.
• Metformin disposition and response studies in Type 2
diabetes patients.
• Paclitaxel-induced
peripheral
neuropathy
and
Adriamycin-induced neutropenia in breast cancer
patients.
• Response and toxicity to antiretroviral therapy in
Ugandan HIV patients.
• Busulfan-based
autologous
bone
marrow
transplantation treatment related
Resources/Tools
PMT Project Description
• We have structured our project around three
multidisciplinary research teams and three cores.
• Teams: Computational Genomics, Functional
Genomics and Clinical Studies
• Cores: Genomics, Biostatistics and
Bioinformatics Cores
Clinical Studies Projects
• AIM 1: Maintain the SOPHIE cohort of healthy volunteers for pharmacogenomics studies.
• AIM 2: Conduct mechanistic genotype drive clinical studies and participate in collaborative studies with PGRN
investigators.
Reference
Variant
• PMT will generate the following resources that can be shared
with other investigators:
• DNA constructs of transporters and their genetic variants
(noncoding and coding regions).
• Cell lines stably expressing transporters and their genetic
variants.
• Liver and kidney tissue samples.
• DNA samples from SOPHIE and other clinical studies.
Investigators: UCSF, UCB, UMB
Kaiser Permanente
PI
Co-PI
Project Director
Clinical Director
Sook Wah
Yee
Rich
Castro
PMT Leadership
Kathy
Giacomini
Deanna
Kroetz
Kathy
Giacomini
PMT Functional and
Computational
Genomics Team
• AIM 3: Identify genetic determinants of response to Metformin, an anti-diabetic drug, using Genomewide
approaches.
• Validation.
Change in HbA1c response
marker
• Functional and
mechanistic
studies.
Genomewide Markers
• Resequencing
Deanna
Kroetz
*Nadav
Ahituv
*Co-Investigator
*Andrej
Sali
*Hao
Li
*Steven
Brenner
*Xin
Chen
*Les
Benet
*Hobart
Harris
PMT Clinical Studies
Team
*Claire
Brett
PMT Biostatistics Core
*John
Witte
*Neil
Risch
*Esteban
Burchard
*Bob
Davis
PMT Genomics Core
*Pui-Yan
Kwok
*Monique
Hedderson
*Kristi
Silver
*Joe
Selby
*Alan
Shuldiner
PMT Bioinformatics Core
*Thomas
Ferrin