Pharmacogenetics of Phase II Drug Metabolizing Enzymes

描述（由申请人提供）：本提案代表了梅奥诊所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”的持续资助请求。Mayo PGRN是一项综合的、多学科的药物基因组学研究成果，基于Mayo数十年来对II期（偶联）药物代谢酶的药物遗传学的关注。梅奥PGRN开始采用“基因型到表型”的研究策略，包括基因顺序重测序、功能基因组、机制和转化研究。在目前的资助周期中，梅奥PGRN还结合了全基因组技术和药物基因组模型系统的使用，特别强调负责遗传效应对药物反应的功能机制。我们使用这种方法来研究乳腺癌内分泌治疗的药物基因组学和抑郁症的选择性血清素再摄取抑制剂（SSRI）治疗——这些研究源于II期酶对雌激素生物转化的贡献，雌激素在乳腺癌和神经递质生物转化中起着重要作用，神经递质是抑郁症病理生理学和治疗的核心。最近，我们对乳腺癌进行了药物基因组全基因组关联（GWA）研究，我们将很快对抑郁症的SSRI治疗进行类似的研究。我们建议在下一个资助周期中继续这种全基因组的关注，对乳腺癌和抑郁症的药物治疗进行临床和模型系统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测序的访问，另一个专注于药物基因组学本体。总之，本应用程序中的研究建立在Mayo PGRN在DNA测序和功能基因组学方面的优势之上，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。

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.