Pharmacogenetics of Membrane Transporters
Abstract (Updated, May 2013)
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.
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 ¿-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
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.
Phone: (415) 476-1936
Phone: (415) 476-3853
Co-Director, Cellular Phenotyping
Phone: (415) 476-1159
SOPHIE Core Director
Phone: (415) 206-3491
Collaborative Core Director
Phone: (415) 476-9694
Phone: (415) 476-1840
Phone: (415) 476-1936
Phone: (404) 364-7197
Phone: (510) 891-3580
Email: Ksilver@medicine.umaryland.edu Phone: (410) 706-1628