We describe a comprehensive Program in the Pharmacogenetics of Membrane Transporters in which investigators from diverse disciplines will conduct integrated studies to elucidate the pharmacogenetics of membrane transporters. This class of proteins is of great pharmacological importance as it provides the target for about 30 percent of the most commonly used prescription drugs and is a major determinant of pharmacokinetics. We seek to identify sequence variants in a large number of transporter genes with known or suspected relevance to pharmacogenetics. These transporters represent two major groups: those that govern pharmacokinetics and neurotransmitter transporters. The function of the variants will be systematically characterized at a cellular level using assays in animal cells, oocytes and yeast. We shall evaluate the clinical significance of selected transporter variants by testing the hypothesis that variations in these genes are responsible for interindividual differences in drug response. Our lead clinical study uses the diverse patient population of Northern California Kaiser Permanente to test the hypothesis that variants in neurotransmitter transporters are associated with altered response to anti-depressants. This Research Proposal is being co-submitted with a Database Proposal from Stanford University (R. Altman, P.I.). Our program is structured around four interacting cores. The genomics core will identify sequence variants in the targeted transporters from a collection of samples. The cellular phenotyping core will facilitate studies to test the possible functional significance of the sequence variants. The clinical studies group will coordinate studies to determine whether response to particular drugs is associated with transporter sequence variants. The bioinformatics core will collect and store the information obtained by the other cores and will link to the Pharmacogenetics Network Database.
Specific Aims are as follows: (a) Identify sequence variants in genes encoding selected membrane transport proteins; (b) Determine cellular phenotypes for transporter variants through studies in heterologous systems; (c) Determine whether clinical pharmacogenetic phenotypes are associated with specific transporter variants; (d) Deposit the data in the pharmacogenetics network database. These studies will ultimately lead to improvements in rational therapeutics and human health.
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