This proposal represents a request for continued funding of the Mayo Clinic Pharmacogenomics Research Network (PGRN) grant """"""""Pharmacogenetics of Phase II Drug Metabolizing Enzymes"""""""". The Mayo PGRN is an integrated, multidisciplinary, pharmacogenomic research effort based on a decades-long focus at Mayo on the pharmacogenetics of phase II (conjugating) drug metabolizing enzymes. The Mayo PGRN began by applying a """"""""genotype-to-phenotype"""""""" research strategy that included, sequentially, gene resequencing, functional genomic, mechanistic and translational studies. During the present funding cycle, the Mayo PGRN has also incorporated the use of genome-wide techniques and pharmacogenomic model systems, with a special emphasis on functional mechanisms responsible for genetic effects on drug response. We have used that approach to study the pharmacogenomics ofthe endocrine therapy of breast cancer and selective serotonin reuptake inhibitor (SSRI) therapy of depression - research that grew out of the contribution of phase II enzymes to the biotransformation of the estrogens that play such an important role in breast cancer and biotransformation ofthe neurotransmitters that are central to the pathophysiology and treatment of depression. Recently, we have performed pharmacogenomic genome-wide association (GWA) studies of breast cancer, and we will soon perform similar studies of the SSRI therapy of depression. We propose to continue this genome- wide focus during the next funding cycle, with both clinical and model system GWA studies of the drug therapy of breast cancer and depression, always including replication as well as functional and mechanistic studies. We also propose two """"""""Network Resources"""""""", one designed to provide access to """"""""Next Generation"""""""" DNA sequencing for all PGRN Centers and the other focused on pharmacogenomic ontology. In summary, the studies in this application build on Mayo PGRN strengths in DNA sequencing and functional genomics - while incorporating genome-wide techniques - to provide insight into the role of inheritance in variation in the efficacy and side effects of drugs used to treat breast cancer and depression.
Breast cancer is the most frequent cancer of women and depression is the most common major psychiatric illness. Drugs are available to treat both of these serious illnesses, but many patients fail to respond and some suffer serious adverse drug reactions. The Mayo Clinic PGRN will apply modern pharmacogenomic techniques to help make it possible to """"""""individualize"""""""" the drug therapy of breast cancer and depression.
|Ho, Ming-Fen; Weinshilboum, Richard M (2017) Immune Mediator Pharmacogenomics: TCL1A SNPs and Estrogen-Dependent Regulation of Inflammation. J Nat Sci 3:|
|St Sauver, Jennifer L; Olson, Janet E; Roger, Veronique L et al. (2017) CYP2D6 phenotypes are associated with adverse outcomes related to opioid medications. Pharmgenomics Pers Med 10:217-227|
|Sá, Ana Caroline C; Webb, Amy; Gong, Yan et al. (2017) Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics. Sci Rep 7:16068|
|Gonzalez, Velda J; Saligan, Leorey N; Fridley, Brooke L et al. (2017) Gene Expression, and Fatigue in Puerto Rican Men during Radiotherapy for Prostate Cancer: an Exploratory Study. P R Health Sci J 36:223-231|
|Giacomini, Kathleen M; Yee, Sook Wah; Mushiroda, Taisei et al. (2017) Genome-wide association studies of drug response and toxicity: an opportunity for genome medicine. Nat Rev Drug Discov 16:1|
|Dudenkov, Tanda M; Ingle, James N; Buzdar, Aman U et al. (2017) SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway. Breast Cancer Res Treat 164:189-199|
|Qin, Sisi; Liu, Duan; Kohli, Manish et al. (2017) TSPYL Family Regulates CYP17A1 and CYP3A4 Expression: Potential Mechanism Contributing to Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer. Clin Pharmacol Ther :|
|Lanz, Henriette L; Saleh, Anthony; Kramer, Bart et al. (2017) Therapy response testing of breast cancer in a 3D high-throughput perfused microfluidic platform. BMC Cancer 17:709|
|Yu, Jia; Qin, Bo; Wu, Fengying et al. (2017) Regulation of Serine-Threonine Kinase Akt Activation by NAD+-Dependent Deacetylase SIRT7. Cell Rep 18:1229-1240|
|Caraballo, Pedro J; Hodge, Lucy S; Bielinski, Suzette J et al. (2017) Multidisciplinary model to implement pharmacogenomics at the point of care. Genet Med 19:421-429|
Showing the most recent 10 out of 146 publications