Pharmacogenetics of Phase II Drug Metabolizing Enzymes

描述(由申请人提供)：本提案是对梅奥诊所药物基因组学研究网络(PGRN)“第二阶段药物代谢酶的药物遗传学”继续提供资金的请求。Mayo PGRN是一项综合的、多学科的药物基因组研究工作，基于Mayo数十年来对第二阶段(结合)药物代谢酶的药物遗传学的关注。Mayo PGRN通过应用“从基因到表型”的研究策略开始，该策略依次包括基因重新测序、功能基因组、机制和翻译研究。在目前的供资周期中，Mayo PGRN还纳入了全基因组技术和药物基因组模型系统的使用，特别强调了负责遗传效应对药物反应的作用机制。我们用这种方法研究了乳腺癌内分泌治疗和选择性5-羟色胺再摄取抑制剂(SSRI)治疗抑郁症的药物基因组学-这项研究源于II相酶对雌激素的生物转化的贡献，雌激素在乳腺癌中发挥着如此重要的作用，神经递质在抑郁症的病理生理和治疗中起着关键的作用。最近，我们对乳腺癌进行了药物基因组全关联(GWA)研究，不久我们也将对抑郁症的SSRI疗法进行类似的研究。我们建议在下一个资金周期继续这一全基因组的重点，乳腺癌和抑郁症的药物治疗的临床和模型系统GWA研究，总是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中心提供对“下一代”DNA测序的访问，另一个侧重于药物基因组本体论。总之，本申请中的研究建立在Mayo PGRN在DNA测序和功能基因组学方面的优势基础上--同时结合全基因组技术--以深入了解遗传在治疗乳腺癌和抑郁症药物疗效和副作用变异中的作用。 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。治疗这两种严重疾病的药物都有，但许多患者没有反应，一些人遭受严重的药物不良反应。梅奥诊所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“个体化”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.