PMT Profile
Pharmacogenetics of Membrane Transporters
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Abstract (Updated, May 2013)
Goals
The major goal of the Pharmacogenomics of Membrane Transporters (PMT) group is to develop a comprehensive functional map of genetic variants in ATP Binding Cassette (ABC) and SoLute Carrier (SLC) membrane transporters superfamilies and to identify variants in membrane transporters that contribute to variation in drug response.
Progress
In this funding cycle, we have focused on mechanistic studies in cells and in tissues to functionally characterize genetic variations in membrane transporters. Our chief findings are that MATE1 and MATE2 promoter variants contribute to variation in disposition and response to the anti-diabetic drug, metformin, which is now among the world’s most widely prescribed drugs. Differences in response to metformin between Asian, African Americans and Caucasians have been observed, suggesting that genetic variants may underlie ethnic specific differences in response to metformin. In addition, we have also identified functional variants in the ABCC2 promoter region. Using evolutionary conservation method, we identified regulatory regions of ABCG2 and performed mechanistic studies in cells and tissues. Wide range of prescriptions drugs are known to interact with the ABC transporters and thus understanding the functional variants in these transporters will contribute our understanding of these variants in drug dispositions and response.
Other key studies include the development of structural models of membrane transporters such as the Large Neutral Amino Acid transporter, LAT1, nucleoside transporters, CNTs, and transporters for γ-Aminobutyric acid, GABA, and virtual docking of prescription drug libraries to ascertain potential substrates and inhibitors of the transporters. We are also continuing our hypothesis generating genotype-to-phenotype studies in healthy volunteers from multiple ethnic groups to support the above mechanistic studies. These studies have provided a foundation for studies of genetic variation in clinical drug response. Our clinical studies of genetics of response to metformin in African Americans are well underway. Through the funding of PGRN-RIKEN CGM Network Resource, PMT has actively participated in contributing different clinical samples for pharmacogenomics studies on drug response and drug toxicity related to anti-cancer, anti-viral and anti-diabetes drugs. We continue data analyses of the genomewide association studies
Experimental Plans
We will expand our multidisciplinary research project to integrate computational and mechanistic studies in cells, animal models and in ethnically diverse human populations. We will continue to focus on determining the role of genetic variants in membrane transporters in the liver and kidney that play a role in drug disposition and response. Our clinical studies will include genotype to phenotype proof of concept studies and large collaborative clinical studies. In addition, we will accrue samples from about 2000 individuals with type 2 diabetes on metformin and identify, using genomewide approaches, variants that contribute to response and adverse response. These studies will take a mechanistic approach with the goal of identifying causal variants that can provide information to enhance drug therapy. Ultimately, our studies will contribute to the development of personalized therapies.
Research Team
Functional Genomics
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Nadav Ahituv, PhD Co-Investigator Email: nadav.ahituv@ucsf.edu Phone: (415) 476-1936 |
Leslie Z Benet, PhD Co-Investigator Email: benet@itsa.ucsf.edu Phone: (415) 476-3853 |
Deanna L. Kroetz, PhD Co-Director, Cellular Phenotyping Email: deanna.kroetz@ucsf.edu Phone: (415) 476-1159 |
Kathleen M. Giacomini, PhD Principal Investigator Email: kathy.giacomini@ucsf.edu Phone: (415) 476-1936 |
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Hobart Harris M.D., MPH Co-Investigator Email: Hobart.Harris@ucsfmedctr.org |
Xin Chen, PhD Co-Investigator Email: chenx@pharmacy.ucsf.edu Phone: (415) 502-6526 |
Computational Genomics
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Andrej Sali, PhD Co-Investigator Email: sali@salilab.org Phone: (415) 476-4227 |
Steve Brenner, PhD Co-Investigator Email: brenner@compbio.berkeley.edu Phone: (510) 643-9131 |
Hao Li, PhD Co-Investigator Email: haoli@genome.ucsf.edu Phone: (415) 502-8187 |
Clinical Studies
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Esteban Gonzalez Burchard, MD SOPHIE Core Director Email: eburch@itsa.ucsf.edu Phone: (415) 206-3491 |
Claire Brett, MD Collaborative Core Director Email: brettc@anesthesia.ucsf.edu Phone: (415) 476-9694 |
Richard Castro, MD PMT/Clinical Director Email: castror@pharmacy.ucsf.edu Phone: (415) 476-1840 |
Kathleen M. Giacomini, PhD Principal Investigator Email: kathy.giacomini@ucsf.edu Phone: (415) 476-1936 |
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Deanna L. Kroetz, PhD Co-Director, Cellular Phenotyping Email: deanna.kroetz@ucsf.edu Phone: (415) 476-1159 |
Howard Lee MD, PhD Consultant Email: Howard.Lee@ucsf.edu |
Clinical Studies-Metformin
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Kathleen M. Giacomini, PhD Principal Investigator Email: kathy.giacomini@ucsf.edu Phone: (415) 476-1936 |
Robert L. Davis, M.D., MPH Co-Investigator Email: Robert.L.Davis@kp.org Phone: (404) 364-7197 |
Monique Hedderson, PhD, MPH Co-Investigator Email: Monique.M.Hedderson@nsmtp.kp.org Phone: (510) 891-3580 |
Kristi D. Silver, MD Co-Investigator Email: Ksilver@medicine.umaryland.edu Phone: (410) 706-1628 |
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Joe Selby, MD, MPH Co-Investigator Email: joe.selby@nsmtp.kp.org |
Alan R. Shuldiner, MD
Co-Investigator Email: ashuldin@medicine.umaryland.edu Phone: (410) 706-1623 |
Genomics Core
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Pui Kwok, MD, PhD Genomics Core Director Email: kwok@itsa.ucsf.edu Phone: (415) 514-3802 |
Biostatistics Core
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John Witte, PhD Statistical Core Director Email: jwitte@itsa.ucsf.edu Phone: (415) 502-6882 |
Neil Risch, PhD Co-Investigator Email: rischn@humgen.ucsf.edu Phone: (415) 476-1127 |
Bioinformatics Core
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Thomas E. Ferrin, PhD Director, Bioinformatics Core Email: tef@cgl.ucsf.edu Phone: (415) 476-2299 |