GOLDILOKs: Project 2: Translational

GOLDILOKs：项目 2：转化

• 批准号: 9229381
• 负责人: JAMES STEVEN LEEDER
• 金额: $ 5.46万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9229381
• 关键词: Acidity; Address; Affect; Algorithms; Binding Proteins; Blood flow; CYP2D6 gene; Child; Childhood; Clinical; Clinical Data; Code; Complex; Data; Data Set; Development; Distal; Dose; Drug Kinetics; Drug Targeting; Enhancers; Environmental Risk Factor; Enzymes; Event; Future; Gene Duplication; Gene Expression; Genes; Genetic Variation; Genome; Genomic approach; Genomics; Genotype; Goals; Growth; Growth and Development function; Haplotypes; Human; In Vitro; Individual; Intestines; Knowledge; Link; Liver; Metabolic; Metabolic Biotransformation; Modeling; Mutation; Organ; Pathway interactions; Pediatrics; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacology; Phenotype; Pimozide; Population; Preparation; Proteins; Proteomics; Reading; Research; Role; Single Nucleotide Polymorphism; Stomach; Structure; System; Technology; Time; Tissues; Uncertainty; Variant; base; genetic makeup; genomic data; hybrid gene; improved; in vivo; individual patient; interest; mRNA Expression; next generation sequencing; novel; pharmacokinetic model; prospective; response; urinary; validation studies; virtual

The responseexposuredose paradigm and “exposure escalation” dosing strategy to be utilized in GOLDILOKs Project 1 (Clinical) is highly dependent on the ability to individualize dosing and achieve the desired exposure at the level of the individual child. Controlling the doseexposure relationship requires appropriate pharmacokinetic (PK) models that take into consideration factors contributing to the observed variability in exposure. Physiologically based pharmacokinetic (PBPK) models are of considerable interest in pediatrics due to their potential to take multiple factors into consideration at a systems level. These include developmental changes in tissue volumes and composition, organ blood flow, gastric acidity, intestinal transit time, protein binding, among others that occur during growth and development. In building and applying PBPK models, both “uncertainty” – potential vulnerabilities related to parameter estimates and implicit assumptions that may be based on limited data – and “variability” -- ontogeny, genetic variation and environmental factors – need to be considered. In this translational project, we will address several challenges relevant to building individualized Genome- Ontogeny PK (iGO-PK) models to inform optimal ATX dosing for an individual patient within the GOLDILOKs initiative. Aim 1 applies short read and long read next generation sequencing technology to refine phenotype predictions within the CYP2D6 gene locus and to resolve long range haplotypes with a distal (112kb) regulatory single nucleotide polymorphism (SNP) and the CYP2D6 coding region. By determining the content and characterizing the ontogeny of microsomal protein per gram liver (MPPGL) in pediatric liver tissue, Aim 2 will reduce uncertainty in a critical scaling factor for in vitro-in vivo extrapolations that form the basis of PBPK models. In Aim 2 we also propose to use the Simcyp PBPK framework and our pediatric liver bank to create a group of iGO-PK “virtual individuals”, each with their own unique genotype data, quantitative (proteomic) abundance values for >50 drug metabolizing enzymes and transporters and corresponding MPPGL scaling factor. We anticipate that optimized CYP2D6 phenotype prediction from genotype data and improved PBPK models will result in improved dosing algorithms for dose individualization in children.

回应曝光剂量范式和“暴露升级”给药策略可用于 Goldiloks项目1（临床）高度依赖于个性化剂量和成就的能力 所需的个人在个别孩子的水平。控制剂量→曝光关系 需要适当的药代动力学（PK）模型，以考虑有助于的因素 观察到的暴露差异。基于生理的药代动力学（PBPK）模型是 由于可能考虑多个因素，因此对儿科的兴趣很大 系统级别。这些包括组织体积和成分的发展变化，器官血液 流动，胃酸性，肠道转移时间，蛋白质结合等在生长过程中发生的 发展。在构建和应用PBPK模型时，“不确定性” - 潜在的漏洞 与可能基于有限数据的参数估计和隐式假设相关 - 需要考虑“变异性” - 个体发育，遗传变异和环境因素。在这个 翻译项​​目，我们将解决与建立个性化基因组有关的几个挑战 - 个体发育PK（IGO-PK）模型，以告知最佳ATX剂量 Goldiloks倡议。 AIM 1应用简短阅读和长期阅读下一代测序技术 优化CYP2D6基因基因座中的表型预测并解决远距离单倍型 远端（112KB）调节性单核苷酸多态性（SNP）和CYP2D6编码区。 通过确定含量并表征每克肝脏微粒体蛋白的个体发育 （MPPGL）在小儿肝组织中，AIM 2将在临界缩放系数中降低体外缩放系数的不确定性 构成PBPK模型的基础的体内外推。在AIM 2中，我们还建议使用SIMCYP PBPK框架和我们的儿科肝库创建一组Igo-PK“虚拟个人” 凭借自己独特的基因型数据，> 50药物的定量（蛋白质组学）抽象值 代谢酶和转运蛋白以及相应的MPPGL缩放系数。我们预料到这一点 从基因型数据和改进的PBPK模型中优化的CYP2D6表型预测将导致 改善儿童剂量个性化的剂量算法。