Pharmacometabolomics Research Network

说明(申请人提供)：本方案是对PAR-07-412《大型合作项目奖预申报》项目公告的回应。申请者建议创建一个跨学科研究联盟，目标是将快速发展的代谢组学科学与分子药理学和药物基因组学结合起来，朝着创建一门新学科--药物代谢学--迈进，这一学科将改变我们的个体化治疗能力。具体地说，我们建议成立一个多机构研究联盟，包括代谢组学和代谢组生物信息学方面的卓越中心，以及分子药理学和药物基因组科学方面的卓越中心。其目的是创造一种环境，在这种环境中，将应用假设生成、检验和验证的合作迭代过程，以实现代谢学和药理学的结合，创建“药物代谢学”。这一目标的实现将有可能极大地加快我们对疾病机制、药物作用和治疗反应变异的理解。它将为治疗医生提供知识和生物标志物，可以减少为每个患者选择正确药物的不充分的反复试验过程。通过与药物遗传学研究网络的成员合作，并利用NIH已经进行的大量投资，我们计划利用代谢分析来研究药物反应表型，将用于治疗心血管和神经精神疾病的原型药物作为药物代谢组学开发和应用的“试验床”。这一过程将产生基础广泛、生物化学精确的“代谢组特征”，以补充和扩展目前用于选择药物和监测药物治疗的临床反应表型，并补充和扩展与药物反应有关的基因组、转录和蛋白质组信息。这一过程将导致产生新的假说，这些假说将在实验动物和培养细胞系统中进行测试--进而导致新的翻译假说，代谢组学分析也可以应用于这些假说。拟议的研究联盟的最终目标将是创造一种环境，使药物代谢学有可能发展成为一门真正的“跨学科”生物医学学科，有助于采用“系统药理学”方法研究药物效应，从而实现更个性化的治疗方法。 公共卫生相关性：药物代谢组学是代谢组学在了解药物效应和药物反应表型变异方面的应用。一场“治疗革命”改变了现代药物疗法。因此，我们了解哪些患者对药物治疗最有效，而不会出现药物不良反应，这一点变得越来越重要。在本申请中提出的药物代谢研究网络的创建将有助于更好地理解药物治疗并使其个性化，从而对公众健康产生重大影响。

DESCRIPTION (provided by applicant): This proposal represents a response to Program Announcement PAR-07-412 "Preapplication for Large- Scale Collaborative Project Award ". The applicants propose to create an interdisciplinary research consortium with the goal of integrating the rapidly evolving science of metabolomics with molecular pharmacology and pharmacogenomics to move toward the creation of a new discipline - "Pharmacometabolomics" a discipline that will transform our ability to individualize therapy. Specifically, we propose the formation of a multi-institution research consortium involving centers of excellence in metabolomics and metabolomic bioinformatics, joined with centers of excellence in molecular pharmacology and pharmacogenomic science. The purpose is to create an environment in which a cooperative iterative process of hypothesis generation, testing, and validation will be applied to achieve the union of metabolomic and pharmacologic science to create "Pharmacometabolomics". Achievement of that goal would have the potential to dramatically accelerate advances in our understanding of mechanisms of disease, drug action, and variation in response to therapy. It would provide a treating physician with knowledge and biomarkers that can reduce an inadequate trial-and-error process in selecting the right drug for each patient. Through a partnership with members of the Pharmacogenetics Research Network and leveraging large investments already made by NIH we plan to employ metabolomic analyses to study drug response phenotypes by using prototypic drugs used to treat cardiovascular and neuropsychiatric disease as "testbeds" for the development and application of Pharmacometabolomics. That process will generate broadly based, biochemically precise "metabolomic signatures" to complement and extend the clinical response phenotypes currently being used to select drugs and monitor drug therapy and also to complement and extend genomic, transcriptomic and proteomic information with regard to drug response. This process would result in the generation of new hypotheses that will be tested in experimental animal and cultured cell systems - leading, in turn, to new translational hypotheses to which metabolomic analyses could also be applied. The ultimate goal of the proposed research consortium would be the creation of an environment in which it will be possible to develop Pharmacometabolomics as a truly "interdisciplinary" biomedical discipline that can contribute to a "Systems Pharmacology" approach to the study of drug effects leading to a more personalized approach to therapy. PUBLIC HEALTH RELEVANCE: Pharmacometabolomics is the application of metabolomic science to understand drug effect and variation in drug response phenotypes. A "Therapeutic Revolution" has transformed modern drug therapy. Therefore, it is increasingly important that we understand which patients might best respond to drug therapy without suffering adverse drug reactions. Creation of the Pharmacometabolomics Research Network proposed in this application would have a significant public health impact by helping make it possible to better understand and individualize drug therapy.