Genomic- and Ontogeny-Linked Dose Individualization and cLinical Optimization for Kids

儿童基因组和个体遗传学关联剂量个体化和临床优化中心的总体目标是增加与儿童药物反应变异性相关的知识体系。儿童慈善医院儿科临床药理学、毒理学和治疗创新科的儿科临床药理学专业知识通过与曼彻斯特大学、杜克大学和堪萨斯大学医学中心的合作伙伴在定量系统药理学、代谢组学和统计基因组学方面的专门知识而得到加强。使用用于治疗注意力缺陷/多动障碍(ADHD)的药物托莫西汀作为总体概念的原则证明，项目1(临床)将利用反应-暴露-剂量范例和“暴露升级”剂量策略，在药物作用目标-去甲肾上腺素再摄取泵(NET/5LC6A2)的水平上，调查个体发育和遗传变异作为药物反应的变异性来源。在所有项目中--项目(临床)、项目2(翻译)和试点项目-- 将应用“组学”技术，如下一代测序和代谢组学，以及定量系统药理学方法，以更好地确定药物反应中变异的遗传和发育来源。该试点项目代表了对现有转录组和代谢组数据集的探索性分析，这些数据集来自96个儿童肝脏样本，年龄从出生到18岁不等。我们建议将这一资源提供给其他专门中心的生物信息学团队，以寻求共同感兴趣的研究问题。最后，儿童慈悲医院的专业中心致力于为下一代临床和翻译科学家的教育和培训创造一个丰富的环境，这些科学家致力于寻找适合他们患者的药物和剂量。

The overall goal of the Center for Genomic-and Ontogeny-Linked Dose Individualization and cLinical Optimization for Kids is to increase the body of knowledge related to variability in drug response in children. The pediatric clinical pharmacology expertise of the Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics at Children's Mercy Hospital is augmented by collaborations with partners at the University of Manchester, Duke University and the University of Kansas Medical Center with specialized expertise in quantitative systems pharmacology, metabolomics and statistical genomics. Using atomoxetine, a drug used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) as proof-of­ principle of the overall concept, Project 1(Clinical) will utilize a response->exposure->dose paradigm and an "exposure escalation" dosing strategy to investigate ontogeny and genetic variation as sources of variability in drug response at the level of the target of drug action, the norepinephrine reuptake pump (NET/5LC6A2). In all projects - Project (Clinical), Project 2 (Translational) and the Pilot Project – "-omic" technologies, such as next-generation sequencing and metabolomics, as well as quantitative systems pharmacology approaches will be applied to better characterize genetic and developmental sources of variability in drug response. The Pilot Project represents an exploratory analysis of an existing transcriptome and metabolomic dataset generated from 96 pediatric liver samples ranging in age from birth to 18 years. We propose to make this resource available to bioinformatic teams at other Specialized Centers to pursue research questions of mutual interest. Finally, the Specialized Center at Children's Mercy Hospital is committed to creating a rich environment for the education and training of the next generation of clinical and translational scientists dedicated to finding the drug and dose that is "just right" for their patients.