Pharmacometabolomics Research Network

描述（由申请人提供）：本提案是对项目公告PAR-07-412“大型协作项目奖预申请”的回应。申请人提议建立一个跨学科研究联盟，目标是将快速发展的代谢组学与分子药理学和药物基因组学结合起来，建立一个新的学科——“药物代谢组学”，这一学科将改变我们个性化治疗的能力。具体来说，我们建议组建一个多机构研究联盟，包括代谢组学和代谢组学生物信息学的卓越中心，以及分子药理学和药物基因组学的卓越中心。目的是创造一个环境，在这个环境中，假设生成、测试和验证的合作迭代过程将被应用，以实现代谢组学和药理学的结合，创造“药物代谢组学”。这一目标的实现将有可能极大地加速我们对疾病机制、药物作用和治疗反应变化的理解。它将为治疗医生提供知识和生物标志物，从而减少在为每位患者选择正确药物时不充分的试错过程。通过与药物遗传学研究网络成员的合作，并利用NIH已经做出的大量投资，我们计划利用代谢组学分析来研究药物反应表型，使用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“试验台”。这一过程将产生广泛的、生物化学精确的“代谢组学特征”，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，并补充和扩展有关药物反应的基因组、转录组和蛋白质组学信息。这一过程将产生新的假设，这些假设将在实验动物和培养细胞系统中进行测试，进而导致新的转化假设，代谢组学分析也可以应用于这些假设。拟议的研究联盟的最终目标将是创造一个环境，使药物代谢组学有可能发展成为一个真正的“跨学科”生物医学学科，可以为“系统药理学”方法研究药物效应做出贡献，从而实现更个性化的治疗方法。

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.