This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The UCSF PMT Project is a multi-disciplinary research program focused on the pharmacogenetics of membrane transport proteins that play a role in drug response pathways. The project seeks to understand the genetic basis for variation in drug response for drugs which interact with membrane transport proteins. This class of proteins is of great pharmacological importance as it provides the target for many commonly used prescription drugs and is a major determinant of the absorption, distribution and elimination of many clinically used drugs. This project seeks to test the hypothesis that variations in the DNA sequence of genes encoding membrane transporters underlie inter-individual differences in response to such drugs. To accomplish this, the program is structured around six interacting cores: genomics, cellular phenotyping, clinical phenotyping, biostatistics, shared resources/collaborations, and bioinformatics. The project also facilitate studies by contributing data to the publicly available knowledge base, PharmGKB (www.pharmgkb.org/).The overall aims of the PMT project are to:a) Identify sequence variants in membrane transporter genes in the SLC and ABC superfamilies.b) Determine cellular phenotypes for transporter variants through experimental and computational methods.c) Determine the biological relevance of variants in membrane transporters to clinical drug response.d) Deposit the data in PharmGKB and develop shared resources for the pharmacogenetics research community.In this collaborative project, we are developing new methods for data collection and analysis of these experiments. This includes developing automated methods to store, analyze, summarize, and disseminate to researchers the genomic, cellular, and clinical data. We work closely with the Genomics Core (GC) developing data communication and transfer protocols that enable them to efficiently package and transmit to us genotype data for individual samples and sample pools. We also develop web-based tools that the GC uses to perform the transfer and that provide real-time data validation. The data transfer tools communicate with an automated data processing pipeline, which performs further validation. We develop, test, and implement software tools to analyze the data and summarize the analysis results from multiple perspectives and at various granularities. The results are communicated rapidly to PMT investigators via programmatically constructed web pages in tabular and graphical forms. We work with the PMT investigators to identify additional analyses, both for ad hoc implementation and for incorporation into the high-throughput analyses. At the appropriate time, we transmit the data to the PharmGKB database at Stanford University. We also maintain a project intranet that contains information on the program activities, including data and analysis on transporters currently under study. The PMT public website, password-protected intranet, database, and data processing pipelines are hosted by the RBVI.Nearly 100 million nucleotides of sequence data have been collected for 663 exons from dozens of transporters, resulting in more than 1500 variants deposited in PharmGKB.For additional details see www.cgl.ucsf.edu/Research/pmt/

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-31
Application #
7723488
Study Section
Special Emphasis Panel (ZRG1-BST-D (40))
Project Start
2008-07-01
Project End
2009-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
31
Fiscal Year
2008
Total Cost
$16,532
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2018) Relaxation of structural constraints during Amicyanin unfolding. J Inorg Biochem 179:135-145
Alamo, Lorenzo; Pinto, Antonio; Sulbarán, Guidenn et al. (2018) Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease. Biophys Rev 10:1465-1477
Viswanath, Shruthi; Chemmama, Ilan E; Cimermancic, Peter et al. (2017) Assessing Exhaustiveness of Stochastic Sampling for Integrative Modeling of Macromolecular Structures. Biophys J 113:2344-2353
Chu, Shidong; Zhou, Guangyan; Gochin, Miriam (2017) Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. Org Biomol Chem 15:5210-5219
Portioli, Corinne; Bovi, Michele; Benati, Donatella et al. (2017) Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications. J Biomed Mater Res A 105:847-858
Alamo, Lorenzo; Koubassova, Natalia; Pinto, Antonio et al. (2017) Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function. Biophys Rev 9:461-480
Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4
Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A et al. (2017) Enhanced potency of bivalent small molecule gp41 inhibitors. Bioorg Med Chem 25:408-420
Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2016) Cytochrome unfolding pathways from computational analysis of crystal structures. J Inorg Biochem 155:44-55
Amlong, Corey A; Perkins, Mark G; Houle, Timothy T et al. (2016) Contrasting Effects of the ?-Aminobutyric Acid Type A Receptor ?3 Subunit N265M Mutation on Loss of Righting Reflexes Induced by Etomidate and the Novel Anesthetic Barbiturate R-mTFD-MPAB. Anesth Analg 123:1241-1246

Showing the most recent 10 out of 508 publications