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

儿童基因组和个体发育相关剂量个体化和临床优化

基本信息

批准号：
9976562
负责人：
JAMES STEVEN LEEDER
金额：
$ 68.79万
依托单位：
CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-23 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976562
关键词：
Address Advanced Practice Nurse Age Attention deficit hyperactivity disorder Bioinformatics Biological Markers Birth Brain Breast Feeding CYP2D6 gene CYP3A5 gene Child Childhood Cities Clinical Clinical Pharmacology Clinics and Hospitals Codeine Collaborations Data Data Set Development Diagnosis Diet Doctor of Philosophy Dose Drug Interactions Drug Targeting Drug usage Elements Environment Excretory function Exogenous Factors Exposure to Genes Genetic Genetic Variation Genome Genomics Goals Growth Growth and Development function Guidelines Healthcare Hospitals In Vitro Intervention Ion Channel Kansas Knowledge Learning Link Literature Liver Measurement Medical center Metabolic Biotransformation Metabolism Norepinephrine Nurses Obesity Participant Pathway interactions Patient Rights Patients Pharmaceutical Preparations Pharmacists Pharmacogenetics Pharmacogenomics Pharmacology Pharmacology and Toxicology Physicians Physiological Pilot Projects Population Precision therapeutics Process Product Labeling Pump Pupil Research Research Personnel Resources Sampling Source Specialized Center System TPMT gene Tacrolimus Techniques Technology Therapeutic Time Training Training and Education Universities absorption analytical tool atomoxetine base comorbidity dose individualization drug action drug disposition drug response prediction feeding genetic information genotyped patients improved in vivo individual patient innovation interest mathematical model medical specialties metabolic phenotype metabolomics multidisciplinary next generation next generation sequencing pediatric department pediatric pharmacology pediatrician precision medicine predicting response receptor response reuptake thiopurine tool transcriptome translational scientist whole genome

项目摘要

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.

基因组和个体相关剂量个性化和对儿童的临床优化中心的总体目标是增加与儿童药物反应变异性有关的知识体体。儿童毒理学，毒理学和治疗创新部的儿科临床药理学专业知识，儿童慈善医院儿科医院的儿科学系，与曼彻斯特大学，杜克大学，堪萨斯大学大学医学专业中心的合作伙伴与曼彻斯特大学，统计学，代理基因学和统计学基因学和统计学专业知识的合作进行了合作。使用阿托西汀，一种用于治疗注意力缺陷/多动障碍（ADHD）作为整体概念的原则证明的药物，项目1（临床）将利用响应 - >暴露 - >暴露 - >>暴露 - >剂量 - >剂量升级和“剂量升级”剂量策略来调查在毒品中的变化和遗传性变化，以替代药物的变化。（NET/5LC6A2）。在所有项目中 - 项目（临床），项目2（翻译）和试点项目 - “ - 组”技术，例如下一代测序和代谢组学，以及定量系统药理学方法，可以更好地表征药物反应中遗传和发育量的变异性。试点项目代表了对现有转录组和代谢组合数据集的探索性分析，该数据集是从96个儿科肝样本中产生的，年龄从出生到18岁。我们建议将此资源用于其他专业中心的生物信息学团队，以提出相互兴趣的研究问题。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丰富的环境，并致力于寻找适合患者的药物和剂量。