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

项目摘要-Kristin Grimsrud，DVM，PhD是一名翻译兽医研究员和临床医生，他 超越职业目标是成为药物遗传学和翻译精确度开发方面的专家 动物模型。她提出的这项研究利用一种独特的儿科烧伤患者人体模型来识别 基因多态对阿片类药物代谢和疗效的影响此外，她还建议开发一种新的 具有人类变异的CYP2D6*9的大鼠模型，已知该变异可改变阿片类药物的代谢。格里姆斯鲁德博士 老鼠生物学项目的临床助理教授和副主任。她完成了一项 结合DVM/PHD专攻药理学，并完成了实验动物医学的住院医师学位。 拟议的职业计划将以她之前的培训为基础，专注于多学科的未来人类 临床研究、高级翻译遗传学和职业发展方面的指导。格里姆斯鲁德博士已经 建立了一个强大的指导委员会，这些委员会都是各自学科的世界专家。蒂娜·帕尔米耶里医生，烧伤 外科医生和临床研究人员将是拟议的指导计划的主要导师。帕尔米耶里医生有一个 施林纳儿童医院资助评估儿童烧伤患者及其患者的基因多态 与芬太尼疗效的关联。格里姆斯鲁德博士将领导这项研究的运作，以进行她提议的培训。 连同额外的二级导师和顾问，这些专家将为格里姆斯鲁德博士提供 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， 翻译动物模型，以及职业发展和英才精神。 目前，关于基因多态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的影响。这项拟议的研究利用了人和动物 优化危重患者芬太尼剂量的模型。儿童烧伤患者代表了人体模型，因为 他们对慢性阿片类药物治疗的需求。将收集重复样本进行芬太尼分析和基因分型， 同时评估生命参数和疼痛评分以评估疗效。一种新颖的翻译人性化 将建立CYP2D6*9大鼠模型作为儿科药理学研究的工具。CYP2D6*9的队列 人源化的儿科大鼠将用于慢性芬太尼给药研究，以评估动力学的变化， 功效和耐受性。基于生理学的药代动力学模型将被开发和应用于森林动物 对人进行分析和外推，以验证该模型，并开发一个用于优化的SILCO仿真工具 芬太尼在人体内的剂量。这些努力将为临床医生提供循证的结论来指导 阿片类药物的精确剂量，并为研究人员提供了一种新的动物模型，可用于各种 不同的药理学研究。该奖项将为格里姆斯鲁德博士提供必要的指导和研究。 需要开始她的道路，成为全国公认的独立调查员和领导者 药物遗传学、转化和精确医学以及阿片类药物研究。

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.