Pharmacogenetics of Phase II Drug Metabolizing Enzymes

描述（由申请人提供）：本提案代表了继续资助马约临床药物基因组学研究网络（PGRN）资助“II期药物代谢酶的药物遗传学”的请求。马约PGRN是一个综合的、多学科的药物基因组学研究成果，基于马约数十年来对II期（结合）药物代谢酶的药物遗传学的关注。马约PGRN开始应用“基因型到表型”的研究策略，依次包括基因重测序、功能基因组学、机制和翻译研究。在当前的资助周期内，马约PGRN还纳入了全基因组技术和药物基因组学模型系统的使用，特别强调负责遗传对药物反应的影响的功能机制。我们已经使用这种方法来研究乳腺癌的内分泌治疗和抑郁症的选择性5-羟色胺再摄取抑制剂（SSRI）治疗的药物基因组学-研究源于第二阶段酶对雌激素生物转化的贡献，雌激素在乳腺癌和神经递质的生物转化中发挥重要作用，神经递质对抑郁症的病理生理学和治疗至关重要。最近，我们进行了乳腺癌的药物基因组学全基因组关联（GWA）研究，我们将很快进行类似的抑郁症SSRI治疗研究。我们建议在下一个资助周期继续这种全基因组的关注，包括乳腺癌和抑郁症药物治疗的临床和模型系统GWA研究，始终包括复制以及功能和机制研究。我们还提出了两个“网络资源”，一个旨在为所有PGRN中心提供“下一代”DNA测序，另一个专注于药物基因组学本体论。总之，本申请中的研究基于马约PGRN在DNA测序和功能基因组学方面的优势-同时结合全基因组技术-以深入了解遗传在用于治疗乳腺癌和抑郁症的药物的疗效和副作用变化中的作用。 相关性：乳腺癌是女性最常见的癌症，抑郁症是最常见的主要精神疾病。药物可用于治疗这两种严重疾病，但许多患者没有反应，有些患者出现严重的药物不良反应。马约诊所PGRN将应用现代药物基因组学技术，帮助使乳腺癌和抑郁症的药物治疗“个性化”成为可能。

DESCRIPTION (provided by applicant): 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. RELEVANCE: 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.