Characterizing the Impact of Genetic Polymorphism on Fentanyl Efficacy and Tolerance in Pediatrics

表征遗传多态性对儿科芬太尼疗效和耐受性的影响

基本信息

批准号：
10015364
负责人：
Kristin Nicole Grimsrud
金额：
$ 14.63万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-10 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015364
关键词：
Acute Pain Adolescent Adult Adverse effects Affect Analgesics Anesthetics Animal Model Animals Area Award Biology Blood Blood specimen Brain Burn injury CRISPR/Cas technology CYP2D6 gene Child Childhood Chronic Clinical Clinical Data Clinical Research Code Complex Computer Models Controlled Study Cytochrome P450 Databases Development Discipline Doctor of Philosophy Dose Drug Interactions Drug Kinetics Enzymes Failure Fentanyl Frequencies Funding Gene Cluster Genes Genetic Genetic Polymorphism Genotype Goals Grant Human Human body Impairment In Situ Inflammation Kinetics Knock-in Knock-out Knowledge Laboratory Animal Medicine Lead Life Mentors Mentorship Metabolism Modeling Monitor Mus Mutation Neuraxis Opioid Organ Outcome Pain Pain management Patient-Focused Outcomes Patients Pediatric Hospitals Pediatrics Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacology Pharmacology Study Phenotype Physiological Population Population Heterogeneity Rattus Renal function Research Research Personnel Residencies Risk Role Sampling Sedation procedure Surgeon Testing Therapeutic Tissues Toxic effect Training Treatment Efficacy Variant absorption addiction base career career development clinically relevant cohort demographics drug distribution drug efficacy drug metabolism drug sensitivity enzyme activity evidence base genotyped patients human model improved improved outcome individual patient inhibitor/antagonist interest mu opioid receptors multidisciplinary mutant named group novel operation opiate tolerance opioid exposure opioid therapy opioid use pain score patient population pediatric patients pediatric pharmacology pharmacodynamic biomarker pharmacodynamic model pharmacokinetic model pharmacokinetics and pharmacodynamics physiologically based pharmacokinetics precision medicine professor programs prospective simulation tool translational genetics translational medicine

项目摘要

Project Summary - Kristin Grimsrud, DVM, PhD is a translational veterinary researcher and clinician whose overreaching career goal is to become an expert in pharmacogenetics and development of translational precision animal models. The research she proposes utilizes a unique pediatric burn patient human model to identify genetical polymorphisms impact on opioid metabolism and efficacy Additionally, she proposes to develop a novel rat model possessing the human variant CYP2D6*9, which is known to alter opioid metabolism. Dr. Grimsrud is an Assistant Clinical Professor and the Associate Director the Mouse Biology Program. She completed a combined DVM/PhD specializing in pharmacology and completed a residency in Laboratory Animal Medicine. The proposed career plan will build on her previous training by focusing on multidisciplinary prospective human clinical studies, advanced translational genetics, and mentorship in career development. Dr. Grimsrud has constructed a strong mentoring committee that are world experts in their disciplines. Dr. Tina Palmieri, a burn surgeon and clinical researcher, will be the primary mentor for the proposed mentoring plan. Dr. Palmieri has a Shriner’s Hospital for Children grant to evaluate genetic polymorphisms in pediatric burn patients and their associations to fentanyl efficacy. Dr. Grimsrud will lead the operations of this study for her proposed training. Together with additional secondary mentors and consultants, these experts will provide Dr. Grimsrud with the necessary guidance she needs to become an expert in human clinical research with a focus on opioids, genetics, translational animal models, as well as career development and grantsmanship. Currently little knowledge is known regarding the impact of genetic polymorphisms on fentanyl efficacy in special populations and their influence on opioid tolerance. The proposed research utilizes human and animal models to optimize fentanyl dosing in critical patients. Pediatric burn patients represent the human model due to their need for chronic opioid therapy. Repeated samples will be collected for fentanyl analysis and genotyping, along with evaluating vital parameters and pain scores for assessing efficacy. A novel translational humanized CYP2D6*9 rat model will be developed to use as a tool for pediatric pharmacology studies. Cohorts of CYP2D6*9 humanized pediatric rats will be used for chronic fentanyl administration studies to evaluate alterations in kinetics, efficacy and tolerance. Physiological based pharmacokinetic models will be developed and used for in silco analysis and extrapolation to humans to validate this model and develop an in silco simulation tool for optimizing fentanyl dosing in humans. These efforts will provide clinicians with evidence-based conclusions to guide precision dosing of opioids and provide researchers with a new animal model that can be utilized in a variety of different pharmacology studies. This award will provide Dr. Grimsrud with the necessary mentoring and research needed to start her path towards becoming a nationally-recognized independent investigator and leader in pharmacogenetics, translational and precision medicine and opioid research.

项目摘要 - Kristin Grimsrud，DVM，博士是一位转化兽医研究员和临床医生，超越的职业目标是成为药物遗传学和转化精度开发方面的专家她提出的研究利用独特的儿科烧伤患者人体模型来识别。此外，遗传多态性对阿片类药物代谢和功效的影响，她建议开发一种新的 Grimsrud 博士研究了具有人类变异 CYP2D6*9 的大鼠模型，该变异已知会改变阿片类药物的代谢。她是一名助理临床教授和小鼠生物学项目的副主任。结合了 DVM/药理学博士学位，并完成了实验动物医学住院医师实习。拟议的职业计划将以她之前的培训为基础，重点关注多学科的未来人类 Grimsrud 博士拥有临床研究、先进的转化遗传学和职业发展指导。建立了一个强大的指导委员会，由各学科领域的世界专家组成。 Palmieri 博士是一名外科医生和临床研究员，将成为拟议指导计划的主要导师。施赖纳儿童医院拨款评估小儿烧伤患者及其患者的基因多态性 Grimsrud 博士将领导这项研究的运作，以进行她提议的培训。这些专家将与其他二级导师和顾问一起为 Grimsrud 博士提供她需要必要的指导才能成为人类临床研究的专家，重点是阿片类药物、遗传学、转化动物模型，以及职业发展和资助。目前，关于基因多态性对芬太尼疗效的影响知之甚少。特殊人群及其对阿片类药物耐受性的影响拟议的研究利用了人类和动物。优化危重患者芬太尼剂量的模型代表了人体模型。他们需要长期阿片类药物治疗，将收集重复样本进行芬太尼分析和基因分型，以及评估生命参数和疼痛评分以评估疗效。将开发 CYP2D6*9 大鼠模型作为 CYP2D6*9 队列的儿科药理学研究工具。人性化的儿科大鼠将用于长期芬太尼给药研究，以评估动力学的变化，将开发并使用基于生理学的药代动力学模型。对人类进行分析和推断，以验证该模型并开发用于优化的计算机模拟工具这些努力将为上级提供基于证据的结论来指导。阿片类药物的精确剂量，并为研究人员提供了一种可用于多种用途的新动物模型该奖项将为 Grimsrud 博士提供必要的指导和研究。需要开始她成为全国认可的独立调查员和领导者的道路药物遗传学、转化医学和精准医学以及阿片类药物研究。